Title of Invention

METHOD FOR PRODUCTION OF RECOMBINANT PROTEINS IN MICROORGANISMS

Abstract

1. A method for production of dressing materials, plasters or for use in vulnery drugs comprising incorporating a functional plasminogen produced in microorganisms wherein said functional plasminogen is produced by steps of: a) Fusing a nucleic acid of sequence coding for at least the functional part of the plasminogen with a nucleic acid sequence coding for at least one signal peptide, where in functional part of the plasminogen comprises the proteolytic domain of plasminogen or a mutant or a fragment thereof, which codes for at least 20 mg/1 of functional Glu- or Lys-plasminogen, wherein said nucleic acid sequence coding for the functional plasminogen and the nucleic acid sequence coding for at least the signal peptide being coupled with codons for cleavage sites of proteases providing for the cleavage of the signal peptide; b) incorporating the fusion product of step a) into an expression vector being suitable for microorganism like fungi comprises inducible or constitutive promoter like GPA-promoter from P. Pastoris; and c) transforming a host accounted to the microorganisms with thus obtained nucleic acid, which is a plasmid preferably selected from the group pPLG11.2, pPLG12.1, pPLG13.1, pPLG14.2, pPLG15.1, PPLGl6.3, pPLG17.2, pPLG18.1, pPLG19.2, pPLG20.1, pAC37.1, pJW9.1, pMHS476.1, pSM54.2, pSM49.8, pSM82.1, and pSM58.1.

Full Text

FORM 2 THE PATENTS ACT, 197 0 (39 of 1970) COMPLETE SPECIFICATION (See Section 10, rule 13) METHOD FOR PRODUCTION OF RECOMBINANT PROTEINS IN MICROORGANISMS N-ZYME BIOTEC GMBH of RIEDSTRASSE GERMANY, GERMAN Company 642 95 DARMSTADT, The following specification particularly describes the nature of the invention and the manner in which it is to be performed :- r DESCRIPTION The human fibrinolytic system includes as central element the protease plasmin (Pm). On the one hand plasmin is capable of degrading fibrin and on the other hand of activating matrix metalloproteinases (MMPs) and growth factors, which are in turn jointly responsible for the degradation of the extracellular matrix and for wound healing. Plasmin originates thereby from its precursor molecule, the plasminogen. Until now, two physiologic activators of plasminogen (also referred to as plasminogen activators, PA) are known. These are the tissue-type plasminogen activator (tissue-type PA; t-PA) and the urokinase-type plasminogen activator (urokinase-type PA; u-PA). In addition the system is regulated via a set of protease inhibitor, e.g. α2-antiplasmin. The two most important biological properties of plasminogen and plasmin respectively are directly connected to the two different activators. The so called t-PA mediated way is responsible for fibrin homeostasis, whilst the u-PA mediated way is to be highlighted in cell migration and tissue remodeling. It could be shown in particular, that in the case of u-PA deficient mice chronic, non healing wounds occur. The same does apply to mice, the genes of which plasminogen and t-PA and u-PA respectively were deactivated. Moreover, the life time of the animals was clearly shortened, which is inter alia due to thromboses and organ collapse. An overview about the plasminogen/plasmin system was published by Desire Collen (Thrombosis and Haemostasis, 82,1999 (1)). The therapeutic use of plasmin is situated for the treatment of heart attack or stroke patients, in the case of which a rapid fibrin clot dissolving is essential for the survival, and thus represents an alternative treatment to the one with plasminogen activators, which achieve the fibrin clot hydrolysis only indirectly. The above-mentioned mouse models show that plasmin is moreover a potential therapeutic, which can be used in the treatment of non or only slow healing wounds. Normally the activation of plasminogen by t-PA takes place only in the presence of fibrin, as after completion of the blood coagulation cascade. In absence of a substrate plasmin is almost immediately inhibited by a2-antiplasmin. This interaction is admittedly clearly slowed via bonding of plasmin to fibrin and the fibrin clot degradation is thereby enabled. Different strategies of plasminogen activation are used for therapy, since in case of a heart attack or a stroke; the dissolving of blood clots is frequently inevitable for the surviving of the patients. The infusion of streptokinase for example leads to a rapid recanalisation of the vessel lumina. Thereby the activation of plasminogen with streptokinase, a bacterial protein, is not based upon a proteolytic activation but on a complexation. Then this complex can activate other plasminogen molecules to plasmin. 2 Further on urokinase is used therapeutically, which admittedly like streptokinase cannot distinguish fibrin-bound plasminogen from free plasminogen on a molecular level. Therefore recombinant human t-PA was developed, which proved itself as superior to streptokinase in the clinical studies. But these diagnostic findings could not be confirmed by other studies. Precisely the recombinantly produced plasminogen activators such as rt-PA (plus different derivatives), recombinant single chain urokinase-PA and recombinant staphylokinase accentuate the importance of the production systems produced with molecular-genetically methods for the production of recombinant proteins for the use in the modern therapy. Plasminogen is the precursor molecule of the fibrinolytic enzyme plasmin. The cDNA (Malinowski et al.. Biochemistry, 23,1984 (12); Forsgren et al., FEBS Lett. 213.1987 (2)) as well as the gene inclusive of the non coding introns (Petersen et al., J. Biol. Chem., 265,1990 (3)) for human plasminogen were already published in the scientific literature. Human plasminogen (hPg), the proenzyme of the serine protease plasmin, is a glycoprotein consisting of a polypeptide chain of 791 amino acids with a molecular weight of 92.000 and a theoretical isoelectric point of 7.1. The carbohydrate rate is at 2 % (Cohen, 1999, (1)). Plasminogen is produced in the liver, the plasma concentration is at approximately 200 mg/1 (1.5-2 μM). The molecule is divided into 7 structure domains; accounted thereto is the N-terminal preactivation peptide (Glu-1 - Lys-77), five partially homologous Kringle domains and the catalytically active proteinase domain (Val-562 - Asn-791; Collen, 1999 (1)). The structure motive of the catalytic triad common to all serine proteases consists of the amino acids His-603, Asp-646, and Ser-741. The Kringle domain 1 serves as recognition sequence for binding the plasminogen to fibrin (Petersen et al., 1990 (3)) and different cell surface receptors. Among the post-translation a I modifications the two essential glycosylation sites Asn-289 and Thr-346, which are both localized in the Kringle domain 3, are especially to be accentuated for the function of plasminogen (activating ability via miscellaneous proteinases and streptokinase respectively, receptor binding properties). Considering this modifications two major forms of plasminogen are distinguished: plasminogen I features the above described glycosylation pattern plasminogen II is lacking of the modification at Asn-289 Another glycosylation site is the amino acid Ser-248. The amino acid Ser-578 can be existent in phosphorylated form. The activation takes place in the organism via proteolytic cleavage between the amino acids Arg-561 and Val-562. Subsequently another proteolytic activation takes place between Lys-77 and Lys-78 to the Lys-78-hPg. Alternatively this bond can be initially hydrolyzed also directly 3 in the Glu-Pg. The active plasmin Lys-78-hPm is bonded via disulphide bridges in every case. Thereby the heavy chain of the hPm (1/78-561) is responsible for the interaction with the substrates, e.g. fibrinogen and fibrin. The light chain (562-791) resulting from the C-terminus represents the catalytically active subunit. Already known from literature is a method, which was used for recombinant production of the fibrin binding domain of the plasminogen in Pichia pastoris with a yield of 17 mg/1 (Duman et al., Biotechnol AppI Biochem. 28; 39-45,1998 (4)). The glycosylation of this domain (Kringle 1-4) could be proven by the authors. Another citation describes the production of the two domains Kringle 4 and 5 of the human plasminogen (Guan et al., Sheng Wu Gong Cheng Xue Bao, 17, 2001 (5)). The objective was to identify the domain, which can inhibit the growth of endothelic cells. However the plasminogen domains recombinantly produced by the two working groups in Pichia pastohs do not possess the decisive catalytic domain for the physiological functionality. Gonzalez-Gronow et al. (Biochimica et Biophysica Acta, 1039, 1990 (6)) compared to each other the expression of recombinant human plasminogen in Escherichia coli and COS-cells, a kidney cell line of apes. The microbial production in E. coli failed, what is ascribed by the authors to the inadequate glycosylation. The production of the peptide chain was successful, but in a form not capable of activation, i.e. the treatment with activators (urokinase and t-PA) did not result in active plasmin. The absent glycosylation results in a protein, which is lacking of the important physiological functions with regard to activation ability (no detectable enzyme activity) as well as in respect of endothelic cell recognition (Gonzalez-Gronow et al., Biochimica et Biophysica Ada, 1039. 1990 (6)). Moreover the post-translational modification with the carbohydrates significantly influences the half-life in the blood of mammals. Whereas the authors could produce functional plasminogen in COS-cells. Other authors describe the functional expression in insect cells (Whitefleet-Smith et al., Arch. Biochem. Biophys., 271,1989 (7)). However in the use of mammal and insect cells the time-consuming and cost-intensive cultivation conditions as well as the attainable, low protein amounts are disadvantageous. Further on mammal cells are unsuitable to produce greater amounts of a proenzyme due to the intracellular expression and the proteases in the cytoplasm (Nilsen and Castellino, Protein Expression and Purification, 16, 1999 (8) and Busby et al., J. Biol. Chem., 266,1991 (9)). Typically in the baculovirus / lepidopteran (insect cells) system the expression yields are solely in the range of 3-10 mg/ml. In W00250290 the recombinant production of functional mini- and micro-plasminogen in yeast was disclosed. For this the authors expressed the genes for the catalytic domain of human plasminogen with (mini-plasminogen) or without a Kringle domain (micro-plasminogen) in the host organism Pichia pastoris. The so recombinantly produced mini- and 4 micro-plasminogen respectively was subsequently purified, processed to mini- and micro-plasmin respectively and its activity was demonstrated in the animal experiment. The claimed yield of the recombinant proteins is at 100 mg/1 for mini-plasminogen and at 3 mg/1 for micro-plasminogen. However the larger a protein is the more difficult is its recombinant production, what is confirmed in the disclosure of W00250290 by the clear decrease in the yield of micro- to mini-plasminogen in the order of two decimal powers. One example of an embodiment for the expression of longer plasminogen variants such as Lys- or Glu-plasminogen was not presented. The recombinant production of functional plasminogen in microorganisms was not yet disclosed, so that one skilled in the art can execute it. Therefore it is the objective of the present invention to produce in a low priced method functional human plasminogen and to process it into catalytically active plasmin. This objective is solved by a method of recombinant production for the production of plasminogen with a microorganism according to claim 1. Further solutions are mentioned in the independent claims. The dependent claims reflect preferred embodiments. Surprisingly it was found, that the recombinant microbial production of functional Glu- or Lys-plasminogen is possible in microorganisms. Further on it was found, that the recombinant production of micro-, mini-, Lys- and Glu-plasminogen is possible in unexpected high amounts. Subject matter of the invention is the cloning of the plasminogen gene in expression vectors, preferred of the micro- and mini-plasminogen gene and more preferred of the Glu- or Lys-plasminogen gene or in each case of a functional variant thereof and the recombinant production of functional plasminogen, preferably functional human plasminogen using molecular genetic methods. Furthermore, the invention describes the identification of proteases, which catalyze the activation of plasminogen to plasmin. The plasminogen and plasmin respectively, which is produced through this invention, is free of contaminations such as animal proteins or viruses, which naturally occur in the isolation from humans, cattle and other mammals and which can lead to side effects in the patients. The invention is characterized by a method of recombinant production comprising at least the following step: a.) fusion of the nucleic acid sequence coding for at least the functional part of the plasminogen peptide with a nucleic acid sequence coding for at least one signal peptide, the nucleic acid sequence coding for the functional plasminogen peptide and the nucleic acid sequence coding for at least the signal peptide being coupled with codons for cleavage sites of proteases providing for the cleavage of the signal peptide. The production of therapeutical proteins is carried out increasingly with recombinant production systems. Due to cost factors it is a strive to carry out the recombinant production in microbial, especially in bacterial organisms. These systems implicate the advantage, that besides a comparatively low price 5 production, protein yields can be achieved in the g/1-range and the recombinant proteins are not contaminated with viruses or proteins such as prions, which can be harmful to the patients. As bacterial production systems are often not capable of producing correctly folded protein, the production is frequently carried out in eukaryotic systems such as yeasts, insect cells or mammal cells in addition to the in vitro back folding of the misfolded proteins. The eukaryotic production strains and production cell lines offer the advantage, that glycosylated proteins can be produced with them. It applies especially for insect cells or mammal cells, that the recombinant protein production is very cost intensive and the yields are frequently very low. In addition they have the disadvantage, that they can be also contaminated with viruses and proteins being harmful to humans. This is not the case in using eukaryotic microorganisms. The instrumental equipment for the cultivation of eukaryotic microorganisms is comparable to the one for bacterial organisms, contaminations with mamma! viruses and proteins are not present and protein yields in the g/1-range are also possible. Especially preferred is a eukaryotic host organism which is accounted to the branch of yeasts, preferably to the Ascomycota. It is further on preferred, that it is accounted to the Saccharomycotina, especially to the class of the Saccharomycetes, here especially to the order of the Saccharomycetales. According to especially preferred embodiments, the host organism is further on accounted to the family Saccharomycetaceae, here especially to the genus Pichia. Preferred eukaryotic microorganisms used according to invention are exemplary the baker's yeast Saccharomyces cerevisiae, other examples are Candida, the methanotrophic yeasts Pichia pastohs, Pichia methanolica and Hansenula polymorpha or filamentous fungi of the genus Aspergillus, such as AspergiHus niger, Aspergillus oryzae, and Aspergillus nidulans. Especially preferred is Pichia pastoris. The method for recombinant production is further on characterized in, that a nucleic acid molecule coding for at least the functional part of plasminogen is incorporated into an expression vector for this microorganism, the nucleic acid molecule coding preferably for human plasminogen is fused with the nucleic acid molecule coding for at least one signal peptide, preferably a prepropeptide, preferably for the transport into the endoplasmatic reticulum, codons for cleavage sites of proteases providing for the cleavage of the signal sequence or the prepropeptide in the host organism are inserted between the two nucleic acid molecules. Preferably used is a nucleic acid molecule coding for human plasminogen. In addition to a nucleic acid molecule coding for human plasminogen nucleic acid molecules can be used, which code for plasminogen from other mammals. This leads to the production of plasminogen of the respective mammals. Further on the recombinant human plasminogen is formed according to the present method by overexpression and can be, if desired, secreted into the culture medium from which it can be separated from the host cells via centrifugation. filtration or sedimentation and can be subjected to the protein purification without complex cell disruption processes, which can be carried out via methods known by the skilled in the art. The activation of plasminogen into plasmin is solved by proteases, which are capable of processing plasminogen into catalytically active plasmin. In the following terms used in the context of the present invention are defined: 6 "Method for recombinant production" means, that a peptide or a protein is expressed from a nucleic acid sequence, preferably a DNA-sequence, via a suitable host organism, the nucleic acid sequence was formed from a cloning and a fusion of individual nucleic acid sections. "Cloning" shall comprise here all known cloning methods in accordance with the state of the art, however which will not be described in detail, because they belong to the self-evident tools of the one skilled in the art. "Expression in a suitable expression system" shall comprise here all known expression methods in accordance with the state of the art, especially those, which are mentioned in the claims. Under the "functional plasminogen-peptide part" the part of the plasminogen or plasminogen-peptide shall be understood, which can perform the biologically relevant functions of the plasminogen. These biologically relevant functions are at least the activation ability into plasmin by plasminogen activators such as for example tissue plasminogen activator, urokinase, vampire-bat plasminogen activator, streptokinase, staphylokinase, Pla-protein from Yersinia pestis etc., and the proteolytic activity, which is characterized by the hydrolysis of fibrin. The term "plasminogen activator(s)" used in the description and the examples shall refer to proteolytic as well as non-proteolytic plasminogen activators. Additionally in the case of Glu-plasminogen it is to be understood the processing ability into Lys-plasminogen via the plasmin-catalyzed cleavage of the preactivation peptide. The increased activation ability of plasminogen up to the factor 1000 after binding to fibrin, laminin, fibronectin, vitronectin, heparan sulfate proteoglycan, collagen type 4 and other substrates is likewise accounted to the biological functions. Among the biologically relevant functions of plasmin, which have to be warranted after processing of the plasminogen, is to be understood the degradation of laminin, the degradation of fibronectin, of vitronectin, of heparan sulfate proteoglycan, the activation of procoUagenases, the activation of promatrix metalloproteases, the activation of latent macrophage elastase, prohormones and growth factors such as the TGF(3-1 (latent transforming growth factor). VEGF (vascular endothelial growth factor) or bFGF (basic fibroblast growth factor). Another biological function is the inhibition ability by plasmin inhibitors such as 02-antiplasmin and a2-macroglobulin. Accounted to the biologically relevant functions is moreover the bonding to fibrin, laminin, fibronectin, vitronectin, heparan sulfate proteoglycan, and collagen type 4, the bonding to receptors such as the α-enolase, annexin II or amphoterin. 7 First of all plasminogen is formed as inactive Glu-plasminogen. This Glu-plasminogen can be converted into Lys-plasminogen by plasmin through cleavage of the so called preactivation peptide. Both is converted by tissue plasminogen activators (so in this case only through the above-mentioned proteolytic activators) through proteolytic cleavage into plasmin, which consists of subunits connected via sulphide bridges. The smaller subunit includes the proteolytic domain and the phosphorylation site, the larger subunit carries the three glycosylations and is responsible for the bonding to fibrin. Further on the glycosylations are important for the stability in plasma. Through the formation of a l:l-complex with streptokinase or staphylokinase, plasminogen can be converted additionally into a proteolytically active enzyme, which is capable of processing plasminogen into plasmin. According to this, functional plasminogen is plasminogen, which can be processed by plasminogen activators into proteolytically active plasmin. Further on functional plasminogen includes preferably the fibrin binding domain and can include preferably at least one of the three glycosylations. Smallest forms of functional plasminogen are micro- and mini-plasminogen, a larger form of Lys-plasminogen. Glu-plasminogen, which still includes the preactivation peptide, is also functional plasminogen. However it is imaginable, that regions can be omitted especially within the larger chain without interfering significantly the above-mentioned functionality (inter alia proteolysis, fibrin binding). It is self-evident for the one skilled in the art to produce different forms of the plasminogen (referred to as plasminogen derivatives in the following), which include a functional catalytic domain. Under functional it is to be understood as already described, that the plasminogen variant features proteolytic activity after activation with plasminogen activators such as streptokinase or urokinase. the catalytic domain can comprise deletions and amino acid exchanges or can be fused with other amino acids or peptides or proteins the large domain can comprise all of the intermediates from Glu20 to Arg580 (based on the sequence of the pre-plasminogen), which can be activated with plasminogen activators into active plasmin As precise example shall be mentioned three forms of Lys-plasminogen: Variant 1: N-terminal amino acid: Met88 Variant 2: N-terminal amino acid: Lys97 Variant 3: N-terminal amino acid: Val98 The plasminogen derivatives are preferably about a number of 1 to 50 amino acids shorter or longer than the corresponding micro-, mini-, Lys- or Glu-plasminogen or preferably feature an exchange of 1 to 10 amino acids, these derivatives further on exhibit the property to be 8 activated by plasminogen activators. Between the particular micro-, mini-, Lys- or Glu-plasminogen and the corresponding plasminogen derivative there is a sequence homology (sequence match) of over 80%, preferred of over 85%, more preferred of over 90%, furthermore preferred of over 95%, especially preferred of over 98% and further especially preferred of over 99%. Preferably the plasminogen derivatives feature the following characteristics: the catalytic domain can comprise at least one deletion and/or at least one amino acid exchange and/or be fused with at least another amino acid or at least another peptide or at least another protein. the large domain can comprise all of the intermediates from Glu20 to Arg580 (based on the sequence of the pre-plasminogen), which are activable with plasminogen activators into active plasmin a plasminogen derivative features an amino acid sequence homology (match) preferred of over 80%, more preferred of over 85%, further more preferred of over 90%, especially preferred of over 95% and further especially preferred of over 99% With "microorganism" all such life-forms are comprised, which feature only minor dimensions. Thereby shall be comprised eukaryotic as well as prokaryotic microorganisms. Especially to be mentioned would be bacteria, yeasts, fungi and viruses. "Nucleic acid" shall comprise DNA as well as RNA, both in all imaginable configurations, e.g. in form of double stranded nucleic acid, in form of single stranded nucleic acid, combinations thereof, as well as linear or circular nucleic acids. Under "signal sequence" is understood a peptide sequence, which is capable of warranting the transport of another peptide sequence in or across a membrane, e.g. into the endoplasmatic reticulum. Thereby exemplary a prepropeptide, a prepeptide or a propeptide can be concerned. With "cleavage site" such points are indicated in a peptide sequence, which provide for the cleavage of a signal sequence, a prepropeptide or propeptide from the other peptide sequence or generally the cleavage of a peptide sequence into two parts in a host organism. A "nucleic acid coding for at least one signal peptide or a prepropeptide" is a nucleic acid sequence, which codes for a peptide or a protein structure, which provides for the other polypeptide a transfection into membranes, e.g. into the endoplasmatic reticulum. With "primer" a starter oligonucleotide is indicated. Herewith are meant short chained, single strand oligoribo- or desoxyribonucleotides, which are complementary to a region on a single strand nucleic acid molecule and can hybridize with it into a double strand. The free S'-hydroxy end in this double strand serves as substrate for DNA-polymerases and as starting 9 point for the polymerization reaction of the whole single strand into the double strand. The primers are especially used in the PCR, i.e. the polymerase chain reaction known to the one skilled in the art. With "plasmid" the nucleic acid molecules are indicated, which are not integrated into the chromosome and occur in many prokaryotic and some eukaryotic microorganisms with a length of about 2 kb up to more than 200 kb. "Ligation" is the term for the connection of the ends of two nucleic acid molecules by means of one ligase or in line with a self-ligation, i.e. via an intramolecular ring closure reaction, in which the two single strained ends of a linear DNA-molecule dimerize provided that their ends can form base pairs with each other. "Restriction endonuclease" is the term for a class of bacterial enzymes, which cleave phosphodiester bonds within specific base sequences in both strains of a DNA-molecule. "Electroporation" is a method of introducing nucleic acids into cells. Thereby the cell membranes of the receiver cells, which are localized in suspension and growing exponentially, are made permeable for high molecular molecules by brief electrical pulses of high field strength while exposing them to the nucleic acid solution. Under "overexpression" is understood an augmented production of functional plasminogen by a cell in comparison to a production by the wild type of this cell. Normally an overexpression is then spoken about, when the expressed foreign gene amounts to about 1 -40 % of the total cellular protein of the host cell in case of intracellular production. Under "expression vector" are to be understood such vectors, which allow the transcription of the foreign gene cloned into the vector and the subsequent translation of the formed mRNA (messenger-RNA) after incorporating into a suitable host cell. Expression vectors normally contain the control signals, which are necessary for the expression of genes in cells of prokaryotes or eukaryotes. In the present invention promoters which are preferably inducible by methanol such as the AOXl-promoter or especially preferred constitutive promoters such as the YPTl-promoter or the GAP-promotor are used for the control of the gene expression in yeasts such as Pichia pastoris. Especially preferred is the constitutive GAP-promoter. "AOXl" is a gene of the alcohol oxidase 1 from P. pastoris; "GAP" is a gene of the glyceraldehyde-3-phosphate dehydrogenase from P. pastoris and "YPTl" is a gene of a GTP-binding protein from P. pastoris. 10 The signal peptides of the proteins coded by the genes PHO-1, SUC-2, PHA-E or alpha-MF are frequently used for the secretory production in yeasts. „PH01" is a gene of the acid phosphatase from P. pastoris; „SUC-2" is a gene of the secretory invertase from S. cerevisiae; „PHA-E" is a gene of the acid phosphatase from Phaseolus vulgaris Agglutinis; and „alpha-MF" is a gene of the alpha-mating factors from S. cerevisiaea. Especially preferred are the codons for the cleavage sites of proteases and codons for the cleavage sites for the cleavage of the propeptide for the protease Kex2 or the protease Stel3. Especially preferred the connection takes place in step a) above with codons, which code for a Kex2 cleavage site and additionally two Stel3 cleavage sites. In a preferred embodiment of the present invention the nucleic acid molecule coding for the signal peptide or prepropeptide comes from yeast, especially from the yeast Saccharomyces cerevisiae. A more preferred embodiment is directed onto a nucleic acid molecule coding for the signal peptide or the prepropeptide, which codes for the signal peptide or prepropeptide of the a-factor of the yeast Saccharomyces cerevisiae. The formed fusion product described above in step a) is preferably amplified via PCR and then further on preferably purified. In W002/50290 the recombinant production of mini- and micro-plasminogen is disclosed with the expression vector pPICZaA suitable for yeast that contains the inducible AOX1-promoter and the prepropeptide of the yeast alpha-factor. These smaller variants of plasminogen have either absolutely no (such as micro-plasminogen) or only one Kringle domain (such as mini-plasminogen). The expression vector pPICZαA contains the cleavage sites for the proteases Kex2 and Stel3. However the Stel3 cleavage sites were deleted in the cloning of the corresponding expression vectors of mini- and micro-plasminogen. A set of promoters is known for inducible expression systems in yeast. Hereto accounted are inter alia the AOX1-promoter, AOX2, CUP1 (Roller A, Valesco J, Subramani S.,Yeast 2000: 16(7), 651-6), PH01 (EP0495208), HIS4 (US 4885242), FLD1 (Shen et al, Gene 1998: 216(1). 93-10) and the XYU-promoter (Den Haan and Van Zyl, Appl. Microbiol. Biotechnol. 2001: 57(4), 521-7). By means of the methanol inducible AOXl-promoter the heterologous protein production can be directed selectively and a homogeneous biomass can be obtained. Before the expression of the alien protein is induced the host organisms can achieve a high growth density without selection disadvantages, which would occur in the expression of an alien protein. Contrary to their smaller variants, which are expressed in W002/50290 under control of the AOXl-promoter, the recombinantly produced Glu- und Lys-plasminogen in the present invention includes all five Kringle domains, what complicates their recombinant production because of the following reasons: 11 possible loss of the expression cassette due to growth disadvantages for the host organisms in the expression of the alien proteins; proteolytic degradation of the expressed proteins and low yield The production of Glu- oder Lys-plasminogen was not disclosed in W002/50290 due to the described disadvantages. These difficulties were solved in the present invention inter alia in the way, that the recombinant protein includes a signal peptide, a Kex2 and at least one Stel3, preferably two Stel3 protease cleavage sites. Further on, in a preferred embodiment a glycerol feed was carried out as another carbon source between 0.1 and 10 ml/h, preferably between 0.5 and 5 ml/h, further preferred between 0.8 and 1.5 ml/h and the culture medium was buffered at a neutral pH of 7.0. Attention was paid to sufficient oxygen feed. In a preferred embodiment attention was paid to integrate the recombinant nucleic acid not in connection to the 5-site of the AOX1 gene but in connection to the 5'-site of the glyceraldehyde phosphate dehydrogenase gene from P. pastohs. At this a non inducible but a constitutive promoter was used. Constitutive promoters, which are active in yeast and can be used are the GAP-promoter, the YPTl-promoter (Sears et al., Yeast 1998: 14(8), 783-90), the TKL-promoter (Den Haan and Van Zyl, Appl.Microbiol. Biotechnol. 2001: 57(4), 521-7), the ACT-promoter (Kang et al, Appl. Microbiol. Biotechnol. 2001: 55(6), 734-41) and the PMA1-promoter (Yeast 2000: 16(13). 1191-203). Preferred promoters are the GAP-promoter and the YPTl-promoter. An especially preferred promoter is the GAP-promoter. Contrary to an inducible promoter a constitutive promoter has the disadvantage, that the alien protein to be expressed is produced constitutively, so during the whole growth phase. Through this, disadvantages occur for the host cell, what is demonstrated inter alia in a slowed growth. Due to the prevailing selection pressure, host cells which have lost the recombinant expression cassette, have an advantage and can overgrow the recombinant host cells. Through this, a heterogeneous mixed population can arise, which shall be avoided. However it was surprisingly found, that the constitutive GAP-promoter enables a higher yield according to a preferred embodiment of the present invention. In a preferred embodiment a constitutive promoter, e.g. the GAP-promoter is operatively coupled to a nucleic acid, coding for at least the functional part of the plasminogen sequence 12 and being fused with nucleic acid sequence coding for at least one signal peptide, the nucleic acid sequence coding for the functional plasminogen and the nucleic acid sequence coding for at least the signal peptide being coupled with codons for cleavage sites of the proteases, which provide for the cleavage of the signal peptide. In an especially preferred embodiment a constitutive promoter, e.g. the GAP-promoter, is operatively coupled to the nucleic acid sequence of the micro-, mini-, Lys- or Glu-plasminogen, which is fused with the nucleic acid sequence of a signal peptide from the yeast. In this regard it was surprisingly found, that the constitutive GAP-promoter according to a preferred embodiment of the present invention enables a yield, which is about 10-times higher (see example 7c, production of Lys-plasminogen, 1375 U/l, which converted results in 125 mg/1). In another preferred embodiment a glycerol feed is carried out as another carbon source between 0.1 and 10 ml/h. preferably between 0.5 and 5 ml/h, further preferred between 0.8 and 1.5 mi/h and the culture medium was buffered at a neutral pH of 7.0. Thereby the growth rate u [1/h] reaches values between 0.002 and 0.10, preferably between 0.004 and 0.020. further preferred between 0.008 und 0.010. In using the GAP-promoter Lys-plasminogen yields were obtained after a fermentation period of time of 250 hours of at least 660 U/l (60 mg/1), preferred 1000 U/l (= 91 mg/1), preferred 1500 U/l (= 136 mg/1), further preferred 2000 U/l (= 182 mg/ml), especially preferred 2500 U/l (= 227 mg/1), and further especially preferred 2750 U/l (= 250 mg/1). In the recombinant production of mini- and micro-plasminogen accordingly higher yields were obtained. The yields in case of mini-ptasminogen are between from 100 mg to 2 g per liter, preferred from 300 mg/1 -1.5 g/1, further preferred from 400 mg/1 -1 g/1, further more preferred from 500 mg/1 - 800 mg/1 and especially preferred from 600 - 700 mg/1. The yields of micro-plasminogen are further at least of 10% above the ones of mini-plasminogen. Insignificantly inferior yields were obtained in the recombinant production of Glu-plasminogen in comparison to Lys-plasminogen. The method according to invention is suitable for the production of mini-, micro-. Lys-and Glu-plasminogens. Preferred embodiments are hence centered to the recombinant production of mini-, micro-, Lys- and Glu-plasminogen, which are each coupled to a signal or prepro sequence, in an expression vector, which contains a constitutive promoter, e.g. the GAP-promoter. In a further preferred embodiment the signal sequence consists of the signal peptide or prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae. In an especially preferred embodiment a constitutive promoter, e.g. the GAP-promoter, is operatively coupled to a nucleic acid of the sequences Seq. ID. No. 7 or 9 or one of the sequences Seq. ID. No. 13 or 15 or one of the sequences Seq. ID. No. 50 to 59 and is expressed in a suitable expression vector. 13 In a further preferred embodiment a constitutive promoter, e.g. the GAP-promoter, is operatively coupled to a nucleic acid, coding at least for the functional part of the plasminogen sequence. In an especially preferred embodiment a constitutive promoter, e.g. the GAP-promoter, is operatively coupled to a nucleic acid of the sequences Seq. ID. No. 13, 15, 7 and 9 or one of the sequences Seq. ID. No. 50 to 59 or the sequence Seq. ID. No. 11 and is expressed in a suitable expression vector. Glu-plasminogen (data calculated with the program EditSeq™ (DNASTAR)) Molecular weight: 88431.67 Dalton 791 amino acids isoelectric point: 7.121 charge at pH 7.0:1.351 Glycosylation sites: 0-268, N-308, 0-365 (the numbering refers to the pre-plasminogen consisting of 810 amino acids) ANmerkung: dieser Fehler ist in der deutschen Anmeldung ebenfalls vorhanden. Lys-plasminogen (data calculated with the program EditSeq™ (DNASTAR)) Molecular weight: 79655.71 Dalton 741 amino adds isoelectric point 7.492 charge at pH 7.0: 5.287 Glycosylation sites: 0-268, N-308. 0-365 (the numbering refers to the pre-ptasminogen consisting of 810 amino acids) Mini-plasminogen (data calculated with the program EditSeq™ (DNASTAR)) Molecular weight: 38169.63 Dalton 348 amino acids isoelectric point 7.203 charge at pH 7.0: 0.893 Glycosylation sites: not any Micro-plasminogen (data calculated with the program EditSeq™ (DNASTAR)) Molecular weight: 27230.41 Dalton 249 amino acids 7.934 isoelectric point at pH 7.0: 3.733 Glycosylation sites: not any In the following the method according to invention is described in detail. The fusion product generated in step a) of the present invention can be implemented moreover into an expression vector suitable for microorganisms. This expression vector is preferably chosen from the group comprising pPICZaA, B and C and pPICZ A. B and C and pGAPZaA, B and C and pGAPZA, B and C and pPIC6aA, B and C and pPIC6A, B and C as 14 welt as pA0815, pPIC3.5K and pPIC9K. The introduction into the expression vector is carried out again preferably by ligation. The PCR product as well as the expression vector are preferably cut with the restriction endonucleases Kspl and Xhol, before they are ligated with a T4 DNA-ligase. The ligated nucleic acid can be transformed via electroporation in an microorganism, preferably E. coli, and the DNA can be isolated from the transformed strains obtained in that way and separated via endonucleolytic cleavage preferably with Xhol or Sful and Kspl. The nucleic acid obtained in that way can be a plasmid preferably chosen from the group pMHS476.1, PSM54.2, pSM49.8, pSM82.1, und pSM58.1, pAC37.1, pJW9.1. pPLGl.l, pPLG2.1, pPLG3.2, pPLG4.2, pPLG5.3, pPLG6.1, pPLG7.1, pPLG8.3, pPLG9.1, pPLGlO.l, pPLGH.2, pPLG12.1, pPLG13.1, pPLG14.2. pPLG15.1, pPLG16.3, pPLG17.2, pPLG18.1, pPLG19.2 and pPLG20.1. As primer for the above-mentioned amplification two oligonucleotide primers are used preferably chosen from the group comprising N034 (sequence ID-No. 1), N036 (sequence-ID-No. 2), N036a (sequence-ID-No. 19). N036b (sequence-ID-No. 20), N036c (sequence-ID-No. 21), N036d (sequence-ID-No. 22), N036e (sequence-ID-No. 23). N036f (sequence-ID-No. 24). N036g (sequence-ID- No. 25), N036h (sequence-ID-No. 26), N036i (sequence-ID-No. 27), N036j (sequence- ID-No. 28), N057 (sequence ID-No. 3), N037 (sequence ID-No. 4). N035 (sequence ID-No. 5) and N056 (sequence ID-No. 6). According to the present invention the following embodiments are especially preferred: Codons coding for the cleavage site of the protease Kex2 and the plasminogen fusion gene, which features the nucleic acid sequence shown in sequence ID-No.7orl3. Codons coding for the cleavage site of the protease Kex2 and the plasminogen fusion protein, which features the amino acid sequence shown in sequence ID-No.8orl4. Codons coding for the cleavage site of the protease Kex2 and the protease Stel3 and the plasminogen fusion gene, which features the nucleic acid sequence shown in sequence ID-No. 9 or 15. Codons coding for the protease Kex2 and the protease Stel3 and the plasminogen fusion protein, which features the amino acid sequence shown in sequence ID-No. 10 or 16. Preferably the above-mentioned plasmid. which is preferably chosen from the above-mentioned group, is transformed into a microbial host. The transformation can be carried out for example by electroporation. The microorganism used is preferably a eukaryotic microorganism, which is accounted to the branch of the fungi. Preferred microorganisms are accounted to the Ascomycota, preferred Sacchariomycotina and therefrom preferred is the class of the Saccharomycetes, further preferred the order of the Saccharomycetales, more preferred the family of the Saccharomycetaceae and therefrom especially preferred the genus Pichia, Saccharomyces, Hansenuia and Aspergillus. According to an especially preferred embodiment of the present invention the nucleic acid sequence coding at least for the functional part of the plasminogen is overexpressed from a 15 microbial host organism transformed with the fusion product generated in the above described step a) and at least the functional part of plasminogen is secreted, preferably it is secreted into the culture medium. According to another preferred embodiment the functional part of the nucleic acid sequence of plasminogen is one of the sequences ID-No. 60, 61, 62, 63, 64, 65 or 66. According to another preferred embodiment the functional part of the nucleic acid sequence of plasminogen corresponds to the complete plasminogen sequence. Preferably a human functional plasminogen is produced with the method of recombinant production according to the present invention. This plasminogen, which can be obtained by the method of recombinant production according to the present invention or the plasmin resulting by the influence of proteases thereof, can be used for the production of a pharmaceutic for the treatment of wounds, especially for treatment of slow or poorly healing wounds, for the treatment of thrombotic events or for the prevention of thrombotic events. It was detected in addition, that the produced plasminogen according to invention as well as the obtained plasmin therefrom feature anti-coagulative properties. These advantageous properties enable in addition the use of ptasminogen and/or plasmin as anti-thrombotic as well as anti-coagulative active agents for the prophylaxis and/or the treatment of heart attack, thrombosis, restenosis, hypoxia, ischemia, coagulation necrosis, inflammations of the blood vessels, as well as for treatment subsequent to a heart attack, subsequent to a bypass surgery, subsequent to an angioplasty as well as subsequent to a balloon dilatation. The plasminogen can be used also for the thrombolytic therapy in the case of acute heart attack, for the recanalization of arteriovenous shunts as well as for the reperfusion of occluded coronary arteries in the case of acute heart attack. Further uses of the produced plasminogen according to invention comprise the prophylaxis and treatment of acute lung embolism, of fresh or older coagulations of venous thromboses, acute and subacute arterial thromboses, venous thromboses, acute arterial occlusions of the extremities, chronic occlusive arteriopathies, thrombosis of arteriovenous shunts, deep venous thromboses of the hip and the extremities, early thromboses in the area of desobliterated vessels, acute central vessel occlusion at the eye, conjunctivitis in case of plasminogen type-1 deficiency, burn injuries and frostbites, alkali or acid burns as well as disseminated intravasal coagulation during shock. In case of these indications plasminogen and/or plasmin are used together preferably with an anticoagulant. As anticoagulants are suitable heparin, heparin derivatives or acetylsalicylic acid. The present invention is hence also centered to pharmaceutical compositions, comprising a plasminogen, which was produced according to the method of recombinant production of the present invention, or the plasmin obtained therefrom, in combination with a pharmaceutically acceptable substrate, additive and/or solvent, where required. In addition the pharmaceutical compositions can contain preferably an anticoagulative active agent, especially heparin, heparin derivatives or acetylsalicylic acid. 16 The plasminogen produced according to invention and/or the plasmin obtainable therefrom are used in the external treatment of wounds preferably in pharmaceutical compositions, which are suitable for the topic application. Thereby plasminogen and/or plasmin are used in a concentration of 0.01 - 500 U per gramme of pharmaceutical composition, preferred 0.1 - 500 U, further preferred 0.1 - 250 U, further more preferred 0.5 - 250 U per gramme of pharmaceutical composition and especially preferred in a concentration of 1 - 150 U of plasminogen and/or plasmin per gramme of pharmaceutical composition. If plasters or other materials for dressings are used instead of semi solid formulations in form of for example ointments, pastes, gels etc., the above given concentration regions per 2 cm2 of plaster surface and surface of the materials for dressings respectively are to be considered. The pharmaceutical compositions according to invention are produced with the common solid or fluid substrates or diluents and the commonly used pharmaceutical auxiliary agents according to the desired type of application in a suitable dosage in a known way. The preferred pharmaceutical formulations or compositions are present in a pharmaceutical form, which is suitable for the local external application. Such pharmaceutical forms are for example ointments, pastes, gels, coatings, dispersions, emulsions, suspensions or special formulations, such as nanodispersed systems in form of liposomes, nanoemulsions or lipid nanoparticles, as well as tenside free formulations, polymer stabilized or particulate stabilized emulsions. Methods for the production of diverse formulations as well as the different application methods are known to the one skilled in the art and are described in detail for example in "Remington's Pharmaceutical Sciences. Mack Publishing Co., Easton PA". The compositions produced for the parenteral application are suitable in case of using the pharmaceutical compositions for the prophylaxis and/or treatment of heart attack, thrombosis, restenosis, hypoxia, ischemia, coagulation necrosis, inflammations of the blood vessels, acute heart attack as well as for treatment subsequent to a heart attack, subsequent to a bypass surgery, subsequent to an angioplasty as well as subsequent to a balloon dilatation. In addition the pharmaceutical compositions are suitable in case of diverse systemic applications comprising the use in case of acute lung embolism, thrombolytic therapy in the case of acute heart attack, fresh or older coagulations of venous thromboses, acute and subacute arterial thromboses, recanalization of arteriovenous shunts, venous thromboses, reperfusion of occluded coronary arteries in the case of acute heart attack, acute arterial occlusions of the extremities, chronic occlusive arteriopathies, thrombosis of arteriovenous shunts, deep venous thromboses of the hip and the extremities, early thromboses in the area of desobliterated vessels, acute central vessel occlusion at the eye, conjunctivitis in case of plasminogen type-1 deficiency, burn injuries, alkali or acid burns and frostbites, disseminated intravasal coagulation during shock. 17 Another possibility for application arises in case of plasminogen deficiency, such as the inherited or cogenital plasminogen deficiency (homozygote type-1 plasminogen deficiency), which can result e.g. in conjunctivitis lignosa or thrombophilia. The possibility exists herein to treat the illness via for example intravenous administration of the recombinant plasminogen, inclusive of the forms Glu-, Lys-, mini- and micro-plasminogen as well as the derived variants thereof (Heinz et al., Klin. Monatsblatt Augenheilkunde 2002. 219(3): 156-8). In another possibility for application a resolution of the pseudo membranes and the normalization of the respiratory passages as well as the improved healing of wounds can be achieved in case of administration of plasminogen. This application was described for a newborn child (The New England Journal of Medicine 1998,339, 23,1679-1686). Thus the recombinantly produced plasminogen is used potentially together with the plasmin obtained therefrom or also just plasmin in pharmaceutical compositions, which are suitable for the prophylaxis and/or treatment of acute lung embolism, thrombolytic therapy in case of acute heart attack, fresh or older coagulations of venous thromboses, acute and subacute arterial thromboses, recanalization of arteriovenous shunts, venous thromboses, reperfusion of occluded coronary arteries in the case of acute heart attack, acute arterial occlusions of the extremities, chronic occlusive arteriopathies, thrombosis of arteriovenous shunts, deep venous thromboses of the hip and the extremities, early thromboses in the area of desobliterated vessels, acute central vessel occlusion at the eye. conjunctivitis in case of plasminogen type-1 deficiency, burn injuries, alkali or acid burns and frostbites, disseminated intravasal coagulation during shock. The plasminogen produced recombinantly according to invention is used preferably in pharmaceutical compositions, which are suitable for the topic treatment of burn injuries, frostbites, alkali or acid burns, injuries and/or wounds, especially poorly healing wounds. Therein the recombinant plasminogen is used preferably together with at least one activator (plasminogen activators such as for example urokinase or streptokinase). Another preferred possibility is to convert the plasminogen produced according to invention totally or partially before its use via an activator into plasmin and to use it in the herein described indications and formulations in form of plasmin or plasmin with plasminogen. As parenteral applications are especially to be considered the intravenous, intravasale, intraperitoneal, subcutaneous as well as the intramuscular application. In case of the parenteral formulations especially in form of solutions for injection or infusion the protein is used in a concentration of 0.1 -100 million units, preferred 10 to 100 million units per 10 ml solution, further preferred 1 to 10 million units per 10 ml solution and especially preferred 3 to 5 million units per 10 ml solution. In case of suitable formulations for the oral application the protein is used in a concentration of 0.1 to 100.000 units per gramme of formulation, preferred 100 to 80.000 units per gramme of formulation and especially preferred 1.000 to 50.000 units per gramme of formulation. 18 Further advantageous formulations are represented for example by protease containing plasters, dressings or other materials for dressings. These formulations are especially suitable for the topical application in case of wound healing, or for the treatment of burn injuries, frostbites, alkali or acid burns and/or injuries. The plasminogen produced recombinantly according to invention is preferably used in the pharmaceutical compositions, especially the wound healing agents, plasters as well as materials for dressings together with at least one activator (plasminogen activators such as for example urokinase or streptokinase) or converted in advance into plasmin via the above described activators and used as plasmin potentially together with plasminogen and potentially with at least one activator in and/or on the pharmaceutical compositions and formulations. Especially preferred is the use of plasminogen, preferred plasminogen with one activator, or plasmin or plasmin together with plasminogen and one activator in and/ or on plasters and materials for dressings, which are suitable for the wound healing, especially for the treatment of poorly healing wounds, as well as for the treatment of burn injuries, frostbites, alkali or acid burns or other injuries. The materials for dressings, wound healing dressings or plasters contain the plasminogen produced according to invention and/or plasmin obtained therefrom in a concentration of 0-01 - 500 units of plasminogen and/or plasmin per cm of the pharmaceutical formulation, preferred 0.1 to 500 units of plasminogen and/or plasmin per cm2 of dressing material and plaster respectively. Preferably the plasminogen and/or plasmin is contained in a concentration of 0.1 - 250 units, further more preferred 0.5 - 250 units and especially preferred of 1 - 150 units of plasminogen and/or one plasmin resulting therefrom per cm2 of pharmaceutical formulation in the plaster or dressing material. For the activation of 1 mg plasminogen urokinase is used between 100 ug and 1 ng, preferred between 10 μg and 10 ng urokinase are used. For the activation of 1 mg plasminogen streptokinase is used between 1 mg and 1 μg, preferred between 300 μg and 3 μg streptokinase are used. For the activation of 1 mg plasminogen protease from S. griseus is used between 100 μg and 10 ng, preferred between 10 ug and 100 ng protease from S. griseus are used. For the activation of 1 mg plasminogen protease VIII is used between 100 μg and 10 ng, preferred between 10 μg and 100 ng protease VIII are used. Preferably the nucleic acid sequence coding for the functional part of the plasminogen is a DNA-sequence. The present invention concerns moreover the following plasmids: Plasmid pPLGl.l Plasmid pPLG2.1 Plasmid pPLG3.2 Plasmid pPLG4.2 Plasmid pPLG5.3 Plasmid pPLG6.1 Plasmid pPLG7.1 19 Plasmid pPLG8.3 Plasmid pPLG9.1 Plasmid pPLGlO.l Plasmid pPLGll.2 Plasmid pPLG12.1 Plasmid pPLG13.1 Plasmid pPLG14.2 Plasmid pPLG15.1 Plasmid pPLG16.3 Plasmid pPLG17.2 Plasmid pPLG18.1 Plasmid pPLG19.2 Plasmid pPLG20.1 Plasmid pMHS476.1 (deposit No.: DSM 14678) Plasmid pSM54.2 (deposit No.: DSM 14682) Plasmid pSM49.8 (deposit No.: DSM 14681) Plasmid pSM82.1 (deposit No.: DSM 14679) Plasmid pSM58.1 (deposit No.: DSM 14680) Plasmid pAC37.1 (deposit No.: DSM 15369) Plasmid pJW9.1 (deposit No.: DSM 15368). (The deposit numbers refer to the deposition at the German Collection of Microorganisms and Cell Cultures Ltd., Mascheroder Weg lb, D-38124 Braunschweig.) Further on the present invention concerns a DNA-sequence suitable for expression, which comprises the nucleic acid sequence coding at least for the functional part of plasminogen, obtainable by the method of recombinant production according to the present invention. Moreover it concerns the microbial host organism, which comprises the fusion product contained in the above described step a) and one nucleic acid sequence derived therefrom. Further the present invention concerns a vector, a DNA- molecule or an RNA-molecule, which comprises the fusion product contained in the above described step a) or one nucleic acid sequence derived therefrom. Finally the present invention concerns also a method of screening for the identification of plasminogen activators, especially plasminogen activating proteases, whereas the functional plasminogen is used, produced according to the above described method of recombinant production. For this purpose preferably after preincubation of the proteases the resulting plasmin activity is measured with the functional plasminogen as produced according to the present invention. The resulting plasmin activity can be measured with a synthetic peptide substrate. Especially preferred the resulting plasmin activity is measured with N-tosyl-Gly-Pro-Lys-pNA. The invention is explained in more detail by the drawings, which illustrate the following: 20 Fig. 1: Physical map of the plasmid pMHS476.1 (5682 bp). The gene of the prepropeptide of the alpha-factor is connected by the codons fora Kex2 cleavage site with the human Lys-plasminogen gene and is under the control of the AOX1-promoter. Fig. 2: Physical map of the plasmid pSM54.2 (5694 bp). The gene of the prepropeptide of the alpha-factor is connected by the codons for a Kex2 cleavage site and two Stel3 cleavage sites with the human Lys-plasminogen gene and is under the control of the AOX1-promoter. Fig. 3: Physical map of the plasmid pSM49.8 (5715 bp). The human preplasminogen gene is under the control of the AOXl-promoter. Tig. 4: Physical map of the plasmid pSM82.1 (3913 bp). The gene oi the prepropeptide oi the alpha-factor is connected by the codons for a Kex2 cleavage site with the human Lys-plasminogen gene and is under the control of the AOXl-promoter. Fig. 5: Physical map of the plasmid pSM58.1 (5925 bp). The gene of the prepropeptide of the alpha-factor is connected by the codons for a Kex2 cleavage site and two Stel3 cleavage sites with the human Glu-plasminogen gene and is under the control of the AOXl-promoter. Fig. 6: Physical map of the plasmid pAC37.1 (11400 bp). The gene of the prepropeptide of the alpha-factor is connected by the codons for a Kex2 cleavage site and two Ste13 cleavage sites with the human Lys-plasminogen gene and is under the control of the AOXl-promoter. Fig. 7: Physical map of the plasmid pJW9.1 (5925 bp). The gene of the prepropeptide of the alpha-factor is connected by the codons for a Kex2 cleavage site and two Stel3 cleavage sites with the human Lys-plasminogen gene and is under the control of the GAP-promoter. Fig. 8: Physical map of the plasmid pPLGl.l. The gene of the prepropeptide of the alpha-factor is connected by the codons for a Kex2 cleavage site and two Stel3 cleavage sites with the human mini-plasminogen gene and is under the control of the AOXl-promoter. Fig. 9: Physical map of the plasmid pPLG11.2. The gene of the prepropeptide of the alpha-factor is connected by the codons for a Kex2 cleavage site and two Stel3 cleavage sites with the human mini-plasminogen gene and is under the control of the GAP-promoter. Fig. 10: Detection of the fibrinolysis activity in the Klarhof (clearing zone) assay. According to the invention all microorganisms can be considered as host organisms, which are capable of carrying out the glycosylation and, if desired, the secretion of proteins. 21 Exemplary shall be mentioned here: S. cerevisiae, P. pastoris, P. methanolica and H. polymorpha or the filamentous fungus Aspergillus sp. Especially a use of the functional plasminogen and plasmin respectively produced according to the present method of production is to be considered in a pharmaceutical formulation. In such a formulation the functional plasminogen can be mixed with a pharmaceutically acceptable substrate or auxiliary agent as well as other suitable auxiliary agents or additives in a way known to the one skilled in the art. The Kex2 cleavage site provides for the cleavage of the propeptide by the protease Kex2 localized in the Golgi apparatus. This protease also referred to as protease YscF or as Kexin is a proprotein processing serine protease, which cuts C-terminally from basic amino acid pairs (e.g.: Lys-Arg). The Stel3 cleavage site provides for the cleavage of the propeptide by the protease Stel3 localized in the Golgi apparatus. Stel3 (also referred to as protease YscVI or as dipeptidyl aminopeptidase A) is localized in the late Golgi and removes step by step N-terminal Xaa-Ala dipeptides, e.g. from the unripe a-factor of the yeast S. cerevisiae. In addition to the cleavage sites for the proteases Kex2 and Stel3 other cleavage sites can be inserted, which are recognized as substrate by proteases localized in the endoplasmatic reticulum or in the Golgi apparatus. It is also possible to fuse with the plasminogen gene exclusively a signal sequence (prepeptide) responsible for the transport into the endoplasmatic reticulum, i.e. the propeptide e.g. of the mating factor of the yeast S. cerevisiae is not necessarily required. The microbiological, molecularbiological and protein chemical methods mentioned in the examples are well known to the one skilled in the art. The following reference books shall be mentioned as reference: Maniatis et al.. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor press. 1989 (10); Gassen & Schrimpf, Gentechnische Methoden, Spektrum Akademischer Verlag, Heidelberg, 1999 (11); EasySelect™ Pichia Expression Kit Instruction Manual, Invitrogen, Groningen, The Netherlands, catalog-No. K1740-01. The Pichia pastons strains and expression systems come also from Invitrogen and are described in the above-mentioned Instruction Manual. In case of pPICZA, B and C in short 3.3 kb Pichia pastoris expression vectors are concerned. The vectors have a zeocin resistance gene for the direct selection of Pichia transformants. Moreover the vectors have a C-terminal tag sequence, which provides for a fast purification and the detection of fusion proteins. In case of pPICZalpha A, B and C 3.6 kb Pichia pastoris expression vectors are concerned, which have also the zeocin resistance gene as well as the above-mentioned C- terminal tag sequence. In addition they contain the alpha-factor secretion signal of Saccharomyces cerevisiae for an efficient transport of proteins into the medium. 22 In addition the plasminogen can be activated. Thereto the plasminogen can be incubated exemplary with a protease, which was identified with the method of screening according to invention. Preferably the plasminogen is incubated thereto with protease from S. griseus, with protease VIII or protease XVIII, with ficin, metalloendopeptidase, clostripain, with endoproteinase Glu-C. protease XIII, proteinase A, trypsin, endoproteinase Asp-N or elastase. It is furtheron imaginable to activate plasminogen by incubation of plasminogen with one of the proteases t-PA, u-PA, or vb-PA (vampire bat-PA). In another preferred embodiment the plasminogen is activated by incubation with staphylokinase or with streptokinase. Streptokinase or staphylokinase form with plasminogen a l:l-complex. By this complex formation the plasminogen bound in the complex receives a conformation change, so that it becomes proteolytically active and is capable of activating plasminogen into plasmin. The functional plasminogen or the activated functional plasminogen produced according to the present method of recombinant production is capable of hydrolyzing fibrin. Further it is capable of activating promatrix metalloproteases and growth factors. The invention will be explained in more detail by examples as follows. Example la: Amplification of the Lys-plasminogen gene with insertion of the codons for a Kex2 cleavage site at the 5'-end The plasmid pPLGKG (Forsgren et al., FEBS Lett. 1987 Mar 23;213(2):254-60 (2)), which contains the gene for pre-Glu-plasminogen, was isolated from the strain E. coli HBlOl(pPLGKG) by using the QIAGEN plasmid midi kit (QIAGEN, Hilden). 150 ng pPLGKG-DNA were linearized with 10 U of the restriction endonuclease EcoRI (Roche, Mannheim) and afterwards purified with the QIAquick PCR purification kit (QIAGEN, Hilden). For the amplification of the plasminogen gene the oligonucleotide primer pair N034 (Seq. ID No. 1) and N036 (Seq. ID No. 2) were used. The oligonucleotide primer N036 has besides the bases complementary to the plasminogen gene the codons for the Kex2 cleavage site. For the PCR were used 0.5 U Pwo-DNA-polymerase (Hybaid, Heidelberg), each with 400 nM of the oligonucteotide primer, each with 200 uM dNTP, 3 ng of linearized pPLGKG-DNA and the respective reaction buffer in a final volume of 50 μl. The primer binding temperature was 58°C. The resulting PCR product was tested for the expected size by agarose gel electrophoresis and purified with the QIAquick PCR purification kit. 23 Example lb: Cloning of the plasminogen gene into the vector pPICZaA 400 ng of the PCR product were cut with each 10 U of the restriction endonucleases Kspl and Xhol (Roche, Mannheim). 300 ng DNA of the plasmid pPICZaA (Invitrogen, Groningen, The Netherlands), which contains the prepropeptide sequence of the a- factorfrom S. cerevisiae, were also cut with 10 U of the restriction endonucleases Kspl 15 and Xhol. The thus treated DNA was separated electrophoretically in a 0.9% agarose gel and the obtained fragments were extracted from the gel with the QIAquick gel extraction kit (QIAGEN, Hilden). The vector DNA was merged with the insert DNA and ligated at 4°C over night with 1 U T4-DNA-ligase (Roche, Mannheim). The DNA of the ligation batch was afterwards purified with the QIAquick PCR purification kit and used for the transformation of E. coli JM109 by electroporation. The electroporated E. coli JM109 cells were incubated for lh at 37°C in 1 ml SOC-medium, afterwards plated onto LB agar solid medium with 20 μg/μl zeocin (Invitrogen, Groningen, The Netherlands) and incubated at 37°C over night. From one of the thus obtained E. coil strains the DNA was isolated with the QIAGEN plasmid mini kit (QIAGEN, Hilden) and after endonucleolytic cleavage with the enzymes Xhol and Kspl 300 ng were separated by agarose gel electrophoresis. The isolated plasmid contained a fragment of the expected size and was referred to as pMHS476.1 (Fig. 1). The correct sequence of the fusion gene from the prepropeptide gene of the alpha-factor of the yeast Saccharomyces cerevisiae and the Lys-plasminogen gene as well as the codons for the cleavage site sequence of the protease Kex2 was confirmed by sequence analysis (Seq. ID No. 7). Example lc: Transformation of Pichia pastoris with the plasmid pMHS476.1 With the QIAGEN plasmid midi kit plasmid-DNA of the plasminogen expression vector pMHS476.1 was isolated from the strain E. coli JM109 (pMHS476.1). 10 μg pMHS476.1-DNA were linearized with 100 U Pmel (New England Biolabs, Frankfurt) and used for the electroporation of Pichia pastoris KM71H his 4;; HIS 4 arg 4 aoxl:: ARG 4 genotype of Pichia pastoris Y-11430 (Northern Regional Research Laboratories, Peoria, USA) according to the protocol shown in the EasySelect™ Pichia Expression Kit Instruction Manual. The colonies grown with 100 μg/ml zeocin after three to four days on YPDS solid medium (EasySelect™ Pichia Expression Kit Instruction Manual) were plated with 100 μg/ml zeocin onto YPDS solid medium and were used for the inoculation of liquid cultures. The colonies were referred to as Pichia pastoris KM71H/pMHS476.1-l/a, whereas "a" represents the consecutive numbering of the colonies beginning at 1. Example 1d: Growth of Pichia pastoris KM71H/pMHS476.1-l/l to -1/3 and induction of the plasminogen gene expression 24 For the production of the precultures 100 ml BMGY-medium (EasySelect™ Pichia Expression Kit Instruction Manual) were incubated in in 1 I baffle flasks at 28°C and 250 rpm up to a OD6oo = 20 - 30. Afterwards the precultures were centrifugated for 10 min at 4645 g and 4°C. The thus gathered cells were resuspended in BMMY-medium (0.5 % methanol), so as to obtain a bio-moist mass concentration of 80 g/1. 60 ml of these main cultures were incubated for 118 h in 300 ml baffle flasks at 28°C and 250 rpm. After 24 and 72 hours 2% methanol were added. The baffle flasks and the high revolutions per minute of 250 rpm were used to provide for a sufficient oxygen feed, which is necessary in using the AOX-promoter. Example le: Measurement of the plasminogen activity in the supernatant of the main cultures after activation with streptokinase The samples of the main cultures were centrifugated for 10 min at 16 000 g. 300 μl of the supernatant were incubated for 20 min at 37°C with 1 μl streptokinase (S8026) (Sigma, Deisenhofen). To 750 μl 100 mM sodium phosphate buffer pH 8, 0.36 mM CaC12, 0.9% NaCI were pippeted 100 μl N-tosyl-Gly-Pro-Lys-pNA solution (9.5 mg dissolved in 75 mg glycine/10 ml, 2% Tween® 20) and incubated for 10 min at 37°C. For starting the reaction 250 pi of the supernatant pretreated with streptokinase were added and further incubated at 37°C. The extinction increase was measured photometrically at 405 nm. For the determination of control values supernatants of a parallely grown P. pastoris KM71 H culture as well as supernatants without streptokinase activation were used. For the samples taken after 72 h of induction following activity values were determined (1 U/I = 1 μmol N-tosyl-Gly-Pro-Lys-pNA conversion per minute per liter of culture supernatant): KM71H/pMHS476.1-l/l: 2 U/l; KM71H/pMHS476.1-l/2: 2 U/l; KM71H/pMHS476.1-l/3; 1 U/l. After 118 h of induction following activity values taw be determined: KM71H/pMHS476.1-1/1: 7 U/l; KM71H/pMHS476.1-l/2: 9 U/l; KM71H/pMHS476.1-l/3: 8 U/l. Example 2a: Amplification of the Lys-plasminogen gene with insertion of the codons of a Kex2 cleavage site and of two Stel3 cleavage sites at the 5'-end The amplification of the Lys-plasminogen gene for the cloning into the vector pPICZaA with insertion of the codons for a Kex2 cleavage site and two Stel3 cleavage sites 10 was carried out with the two oligonucleotide primers N034 and N057 (Seq. ID No. 3) by using the conditions mentioned in example la. The oligonucleotide primer N057 has beside the bases complementary to the plasminogen gene the codons for the Kex2 cleavage site and the Stel3 cleavage sites. Example 2b: Cloning of the amplified Lys-plasminogen gene as described in example 2a into the vector pPICZaA The cloning of the Lys-plasminogen gene into the vector pPICZaA for the production of a fusion gene from the gene of the prepropeptide of the alpha-factor of the yeast S. cerevisiae and the human plasminogen gene with insertion of the codons for the cleavage sites of the 25 proteases Kex2 and Stel3 was carried out analogous to the cloning described in example lb. The obtained plasmid was referred to as pSM54.2 (Fig. 2). The correct sequence (Seq. ID No. 9) was confirmed by sequence analysis. Example 2c: Transformation of Pichia pastoris with the plasmid pSM54.2 As described for pMHS476.1 in example lc Pichia pastoris KM71H was transformed with the plasmid pSM54.2. The obtained colonies were referred to as Pichia pastoris KM71H/pSM54.2-1/a, whereas "a" again represents the consecutive numbering of the colonies beginning at 1. Example 2d: Cultivation of Pichia pastoris KM71H/pSM54.2-l/l to -1/3 and induction of the plasminogen gene The production of the precultures and of the main cultures as well as the induction with methanol was carried out analogous to the conditions described in example 1d. Example 2e: Measurement of the plasminogen activity in the samples of the main cultures after activation with streptokinase The plasminogen activity after activation with streptokinase was determined as described for KM71H/pMHS476.1-l/l to -1/3 in example le. For the samples taken after 72 h of induction following activity values were obtained: KM71H/pSM54.2-1/1: 2 U/l; KM71H/pSM54.2-l/2: 8 U/l; KM71H/pSM54.2-l/3: 6 U/l- After 118 h of induction following activity values could be determined; KM71H/pSM54.2-l/l; 8 U/l; KM71H/pSM54.2-l/2; 17 U/l; KM71H/pSM54.2-l/3:13 U/l. Example 3a: Amplification of the plasminogen gene with own signal sequence and cloning into the vector pPICZA; transformation of Pichia pastoris The amplification of the plasminogen gene inclusive of the sequence coding for the own signal peptide (pre-plasminogen) fof the cloning into the vector pPICZA was carried out with the two oligonucleotide primers N034 and N037 (Seq. ID No. 4) by using the conditions described in example la. The cloning of the preplasminogen gene into the vector pPICZA was carries out analogous to the cloning described in example lb, whereas the vector as well as the PCR product were cut with the restriction endonucleases Sfu\ and Kspl. The obtained plasmid was referred to as pSM49-8 (Fig. 3). The correct sequence (Seq. ID No. 11) was confirmed by sequence analysis. As described for pMHS476.1 in exarnple lc Pichia pastoris KM71H was transformed with the plasmid pSM49.8. The obtained colonies were referred to as Pichia pastoris KM71H/pSM49.8-1/a. whereas "a" again represents the consecutive numbering of the colonies beginning at 1. 26 Example 4a: Amplification of the human Glu-plasminogen gene with insertion of the codons of a Kex2 cleavage site and cloning into the expression vector pPICZa (alpha)A; transformation of Pichia pastoris The amplification of the Glu-plasminogen gene for the cloning into the vector pPICZaA with insertion of the codons for a Kex2 cleavage site was carried out with the two oligonucleotide primers N034 and N035 (Seq. ID No. 5) by using the conditions described in example la. The oligonucleotide primer N035 has beside the bases complementary to the Glu-plasminogen gene the codons for the Kex2 cleavage site. The cloning of the Glu-plasminogen gene into the vector pPICZaA for the production of a fusion gene. from, the gene of the. preptopeptide of the alpha-factor of the yeast S. cerevlsiae and the human Glu-plasminogen gene with insertion of the codons for the cleavage sites of the protease Kex2 was carried out analogous to the cloning described in example lb. The obtained plasmid was referred to as pSM82.1 (Fig. 4). The correct sequence (Seq. ID No. 13) was confirmed by sequence analysis As described for pMHS476.1 in example lc Pichia pastoris KM71H was transformed with the plasmid pSM82.1. The obtained colonies were referred to as Pichia pastoris KM71H/pSM82.1/a, whereas "a" again represents the consecutive numbering of the colonies beginning at 1. Example 5a: Amplification of the human Glu-plasminogen gene with insertion of the codons of a Kex2 cleavage site and of two Stel3 cleavage sites at the 5'-end and cloning into the expression vector pPICZaA; transformation of Pichia pastoris The amplification of the Glu-plasminogen gene for the cloning into the vector pPICZaA with insertion of the codons for a Kex2 cleavage site and of two Stel3 cleavage sites was carried out with the two oligonucleotide primers N034 and N056 (Seq. ID No. 6) by using the conditions described in example la. The oligonucleotide primer N056 has beside the bases complementary to the Glu-plasminogen gene the codons for the Kex2 cleavage site and the Ste13 cleavage sites. The cloning of the Glu-plasminogen gene into the vector pPICZaA for the production of a fusion gene from the gene of the prepropeptide of the alpha-factor of the yeast S. cerevisiae and the human Glu-plasminogen gene with insertion of the codons for the cleavage sites of the proteases Kex2 and Stel3 was carried out analogous to the cloning described in example lb. The obtained plasmid was referred to as pSM58.1 (Fig. 5). The correct sequence (Seq. ID No. 15) was confirmed by sequence analysis As described for pMHS476.1 in example lc Pichia paston's KM71H was transformed with the plasmid pSM58.1. The obtained colonies 27 were referred to as Pichia pastoris KM71H/pSM58.1/a, whereas "a" again represents the consecutive numbering of the colonies beginning at 1. Example 6a: Insertion of tne Lys-plasminogen gene from pSM54.2 into the vector pPIC9K 150 ng of the vector pPIC9K (Invitrogen, Groningen, The Netherlands) were cut with each 10 U of the restriction endonucleases Sad and Not\ (both Roche Diagnostics, Mannheim). 300 ng of the plasminogen expression plasmid pSM54.2 (see example 2b), were also cut with the enzymes Sad and Not\. The thus treated DNA was separated by gel electrophoresis with a 0.9% agarose gel. In each case the larger fragment was extracted from the gel by means of the QIAgen gel extraction kit (Qiagen, Hilden). The two fragments were combined and ligated at 4°C over night with 1 U T4-DN A-ligase. The transformation of E. coli DH5a, the isolation and the characterization of the resulting plasmid was carried out analogous to the description in example lb, whereas instead of the antibiotic zeocin the antibiotic ampicillin was used for the selection of transformants. The thus constructed plasmid was referred to as pAC37.1 (Fig. 6). Example 6b: Transformation of Pichia pastoris with the plasmid pAC37.1 As described for the transformation of Pichia pasforis KM71H with pMHS476.1 in example lc, Pichia pastoris KM71 was transformed with the plasmid pAC37.1 linearized with the restriction endonuclease Sa/1. The transformed cells were plated onto the histidine free medium MD-agar (Multi-Copy Pichia Expression Kit instruction manual) and incubated. The obtained colonies were referred to as Pichia pastoris KM71/pAC37.1-3/a, whereas "a" again represents the consecutive numbering of the colonies beginning at 1. Example 6c: Cultivation of Pichia pastoris KM71/pAC37.1-3/l and induction of the plasminogen gene The production of the precultures and of the main cultures as well as the induction with methanol was carried out analogous to the conditions described in example 1d. The induction was carried out over 216 h. It was started with a methanol concentration of 0.5%, after 24 h and then in periods of 48 h 2% methanol were re-feeded. Example 6d: Measurement of the plasminogen activity in the samples of the main cultures after activation with streptokinase The plasminogen activity after activation with streptokinase was determined as described for KM71H/pMHS476.1-l/l to -1/3 in example le. For the samples-taken after 120 h of induction an actl^ty of 120 U/l was obtained. After 216 h of induction an activity of 190 U/l could be measured. 28 Example 6e: Induction of Pichia pastoris KM71/pAC37.1-3/l in minimal-medium (BSM) and measurement of the plasminogen activity in the samples of the main cultures after activation with streptokinase After the growth of Pichia pastoris KM71/pAC37.1-3/l in BMGY-complex medium (see example 1d) 80 g of the centrifugated cells were resuspended in 100 ml of BSM-minimal medium for the induction phase. The composition of the BSM (Basal Salts Medium) -minimal medium is as follows: H3P04, 85 %: 26.0 ml/1; CaCl2H2O: 0.6 g/1; K2SO4; 18.0 g/1; MgS04-7H20:14.0 g/l; KOH: 4.0 g/1; glycerine: 20 ml/1; antifoam: 1.0 ml/I; trace solution: 8.0 mi/I; biotin solution (0.2 g/1): 8.0 mi/1. Composition of the trace solution: H2S04: 5.0 ml/I; CuS04-5H20: 6.0 g/1; Kl: 0.08 g/1; MnSGv H2O: 3.0 g/1; Na2MoO4: 0.2 g/1; H3BO3: 0.02 g/1; C0Cl2: 0.5 g/1; ZnCl2: 20.0 g/1; FeSO4-7H2O: 65.0 g/1. For the induction 2% methanol were added daily. The plasminogen activity after activation with streptokinase was determined as described for KM71H/pMHS476.1-1/1 to -1/3 in example le. After 120 h of induction a pfasminogen activity of 193 U/l was determined, after 168 h 289 U/l could me measured. Example 6f: Detection of the plasminogen activity in the samples of the main cultures after activation with streptokinase in the Klarhof (clearing zone) fibrinolysis test For the preparation of the Klarhof (clearing zone) fibrinolysis test (Stack, M. S., Pizzo, S. V., and Gonzalez-Gronow, M. (1992): Effect of desialylation on the biological properties of human plasminogen. Biochem. J. 284, 81-86) (13) 1.5 g GTG-low-melting agarose were melted by boiling up in 75 ml 50 mM sodium phosphate buffer pH 7.4. 35 ml of a fibrinogen solution (225 mg/37.5 ml 50 mM sodium phosphate buffer pH 7.4) were mixed bubble free with 350 pi thrombin solution (10 U/ml in 50 mM sodium phosphate buffer pH 7.4), stirred into the agarose solution and poured in a petri dish. After solidifying of the fibrin agar 1 mm sized holes were engraved into the agar. For detecting the fibrinolysis activity of the recombinantly produced plasminogen after streptokinase activation in each case 20 μl of the following solutions were pipetted into the holes and incubated for 20 h at 37°C: 0.5 mg/ml plasminogen (Roche, Mannheim) culture supernatant KM71/pAC37.1-3/l from example 6e 0.5 mg/ml plasminogen, activated by streptokinase culture supernatant KM71/pAC37.1-3/l from example 6e, activated by streptokinase 0.25 mg/ml plasminogen, activated by streptokinase 29 6: culture supernatant KM71/pAC37.1-3/1 from example 6e, diluted 1:2. activated by streptokinase 7: 0.125 mg/ml plasminogen, activated by streptokinase 8: culture supernatant KM71H, produced as described in example 6e for KM71/pAC37.1-3/1, activated by streptokinase For the activation with streptokinase 2 μl streptokinase (100 U/μl, Sigma, Deisenhofen) were pipetted to 40 pi of the respective solutions and incubated for 60 min at 37°C. The spots obtained by fibrinolytic activity are shown in Fig. 10. Example 6g: Purification of the plasminogen produced recombinantly in Pichia pastoris KM71/pAC37.1-3/l by affinity chromatography 50 ml of the culture supernatant of Pichia pastoris KM71/pAC37.1-3/l from example 6c/6d were dialyzed at 4°C contra 4 I 50 mM sodium phosphate buffer pH 7.5. After 24 h the dialysis buffer was exchanged and dialyzed for another 24 h. The dialysate was afterwards pressed through a 0.02 pm filter and then given onto a lysine-sepharoseTM 4B column (diameter: 16 mm, height: 95 mm) (Amersham Biosciences) equilibrated with 50 mM sodium phosphate buffer pH 7.5. Unspecifically bound proteins were washed off the column with 50 mM sodium phosphate buffer pH 7.5, 0.5 M NaCI. The bound plasminogen was eluted with 50 mM sodium phosphate buffer pH 7.5, 0.01 M E-aminocaproic acid. Individual samples were analyzed by 7.5% SDS-PAGE with subsequent silver staining (Fig. 11). The recombinant plasminogen contained in the fractions is localized in the gel on the height of the human plasminogen added as reference. Fig. 11 shows a 7.5 % SDS-PAGE of the purification fractions from example 6g. In Fig. 11 the used abbreviations have the meanings as follows: M: size standard (from top to bottom: 116 kDa, 66 kDa. 45 kDa, 35 kDa) D: dialysate, N: non binding fraction, W: washing fraction, F1-F5 plasminogen containing elution fractions, Pig: plasminogen (American Diagnostica, Pfungstadt) Example 6h: Fermentation of Pichia pastoris KM71/pAC37.1-3/l for the evaluation of the pH value and the substrate influence 50 ml of YEP-G-medium (10 g/1 yeast extract, 20 g/1 casein peptone, 20 g/1 glycerol) in a 1 I wide neck flask without baffles were inoculated with 2 ml glycerol cryo-culture Pichia pastoris KM71/pAC37.1-3/l and incubated for 9 h at 30°C and 300 rpm. 5 ml of this culture were used to inoculate 50 ml of MG-medium (5 g/1 yeast nitrogen base w/o amino acids, 20 30 g/1 glycerol, 2.5 mi/1 biotin solution (0.2g/l)) in a 11 wide neck shaking flask without baffles. This second preculture was incubated for 16 h at 30°C and 300 rpm. The main culture was fermented in the multi fermentation apparatus "stirrer-pro" (DASGIP, Julich), which allows the parallel fermentation of four cultures at different conditions. Therefore in each case 150 ml BSM-medium (see example 6e) were inoculated with 15 ml of the second preculture. The fermentations were started at pH 6, the target pH value was headed for after initiating the substrate dosage. The different conditions and results of the parallel fermentations are shown in tab. 1. Tab.l: Exp. pH substrate feed rate OD6oo plasminogen cone. I 6 methanol profile 187 1.4mg/l II 7 methanol profile 160 6.1 mg/1 III 6 methanol/ glycerol 1ml/h 270 10.1 mg/1 IV 6 methanol profile 130 3.4 mg/1 In experiment IV 30 g/1 peptone was added to the medium. Before the initiation of the methanol dosage glycerol feed medium (500 g/1 water free glycerol, 10 mi/1 trace solution, 10 ml /I biotin solution [see example 6e]) was added for 4 h with a constant rate of 24 ml/h. For the profile in the experiments I, II aficl IV the following term was given in as dosage function f(x)=Pl+(P2/l+exp(-P3(t-P4))))+(P5/(l+exp(-P6(t-P7)))) with P1=0; P20.7; P3=0.2; P4=15; P5=P6=P7=0. It can be seen from tab. 1, that the plasminogen concentrations at neutral pH value and mixed glycerol/ methanol dosage are the highest. Example 7a: Insertion of ms Lys-plasminogen gene from pAC37.1 into the vector pGAPZaA 150 ng of the vector pGAPZaA (Invitrogen, Groningen, The Netherlands) were cut with each 10 U of the restriction endonucleases Xhol and Notl (both Roche Diagnostics, Mannheim). 300 ng of the plasminogen expression plasmid pAC37.1 (see example 6a), were also cut with the enzymes Xhol and Notl. The thus treated DNA was separated by gel electrophoresis with a 0.9% agarose gel. The 2715 bp large plasminogen gene fragment from pAC37.1 as well as the 3073 bp large vector fragment from pGAPZaA were extracted from the gel by means of the QIAgen gel extraction kit (Qiagen, Hilden). The two fragments were combined and ligated at 4°C over night with 1 U T4-DNA-ligase. The transformation of E. coli DH5a, the isolation and the characterization of the resulting plasmid was carried out analogous to the description in example lb, whereas instead of the 31 antibiotic zeocin the antibiotic ampicillin was used for the selection of transformants. The thus constructed plasmid was referred to as pJW9.1 (Fig. 7). Example 7b: Transformation of Pichia pastoris with the plasmid pJW9.1 As described for the transformation of Pichia pastoris KM71H with pMHS476.1 in example lc, Pichia pastoris KM71H was transformed with the plasmid pJW9.1 linearized with the restriction endonuclease 6/nl. The transformed cells were plated onto the YPDS-agar with 100 μg/ml zeocin (EasySelect™ Pichia Expression Kit instruction manual) and incubated. The obtained colonies were referred to as Pichia pastoris KM71H/pTW9.1-a, whereas "a" again represents the consecutive numbering of the colonies beginning at 1. Example 7c: Fermentation of Pichia pastoris KM71H/pJW9.1-3 for the evaluation of the pH value at the glycerol feed rate The precultures and the fermentation in the "stirrer-pro" were carried out as described in example 6i. The results are shown in tab. 2. Tab. 2: Exp. pH substrate feed rate OD6oo plasminigen conc. I 6.5 glycerol l ml/h 220 18.6mg/l II 7.0 glycerol l ml/h 203 22.2mg/l III 6.5 glycerol 0.5ml/h 142 10.1mg/l IV 7.0 glycerol 0.5ml/h 99 3.8mg/l Also in case of glycerol feed the best yields were obtained by fermentation at neutral pH value, whereas the influence of the substrate dosage (feed rate) on the product formation can be seen clearly. Example 7d: Fermentation of Pichia pastoris KM71H/pJW9.1-3 50 ml of YEP-G-medium (10 g/1 yeast extract, 20 g/1 casein peptone. 20 g/1 glycerol) in a 1 I wide neck flask without baffles were inoculated with Pichia pastoris KM71H/pJW9.1-3 and incubated for 9 h at 30°C and 300 rpm. 10 ml of this culture were used to inoculate 40 ml of MG-medium (5 g/1 yeast nitrogen base w/o amino acids, 20 g/1 glycerol, 2.5 mi/1 biotin solution (0.2 g/1)) in a 1 I wide neck shaking flask without baffles. This culture was incubated for 16 h at 30°C and 300 rpm. 32 3 1 of BSM-medium (see example 6e) were inoculated with 30 ml of this culture in a 7.5 I laboratory fermenter (type Labfors, Infers AG, CH). The fermentation was carried out at 251:1C and a constant gas feed rate of 3.21/min. After 24 h glycerol solution (500g/l glycerol, 10 ml/I trace solution, 10 mi/I biotin solution [see example 6e]) was added. The dosage rate was increased step by step from 10 ml/h up to 45 ml/h during the fermentation. After 250 h a plasminogen activity of 1375 U/l could be measured after streptokinase activation. Example 8: Identification of plasminogen activators 24 commercially purchasable proteases were tested on their eligibility for the plasminogen activation. The experiments thereto were carried out in 100 mM sodium phosphate buffer pH 8, 0.36 mM CaC12,0.9% NaCI. The proteases supplied in a powdery form were dissolved in buffer, the proteases supplied in solution were used directly and diluted respectively with buffer if needed. 25 ul of the protease solutions were mixed with 25 μl plasminogen according to the present invention (20 mg/ml) and incubated for 10 min at 37°C. Afterwards the plasmin activity was measured with regard to the substrate N-tosyl-Gly-Pro-Lys-pNA. For this 200 pi substrate solution (9.5 mg N-tosyl-Gly-Pro-Lys-pNA, dissolved in 75 mg glycine/10 ml, 2% Tween® 20) were pipetted to 850 μl buffer, merged with the 50 pi of the preincubated plasminogen protease mixture and further incubated at 37°C. The increase of the extinction was measured photometrically at 405 nm. For the measurement of the extinction increase due to the proteases tests were carried out, in which instead of the preincubated plasminogen protease mixture a likewise preincubated buffer protease mixture was used. The protease from S. gris6u&', protease VIII, protease XX111, protease XIX, protease XVIII, ficin, metalloendopeptidase, clostripain, Glu-C, protease Xlll, chymopapain, chymotrypsin, protease X, bromelain, kallikrein and proteinase A were purchased from Sigma, Deisenhofen; trypsin, papain, Asp-N, dispase I, Lys-C, thrombin and elastase came from Roche, Mannheim; the proteinase K was supplied by QIAGEN, Hilden. The produced protease stock solutions had the protein concentrations given in the Table. 3. The dilution factor F indicates in which ratio the stock solutions are diluted for the measurements Following plasmin activities could be determined after activation (1 U/mg = 1 umol N- tosyl-Gly-Pro-Lys-pNA conversion per minute per mg protein): Table 3: Protease plasmin activity after activation conc. protein [mg/ml F Protease from S. griseus 613.3 U/mg 0.77 1000 Protease VI11 9 U/mg 3.58 1000 Protease XXI11 * 17.8 50000 Protease XIX * 2.78 100 33 Protease XVI11 0.7 U/mg 1.79 100 Ficin 0.01 U/mg 0.81 1 Metalloendopeptidase 8.9 U/mg 0.01 1 Clostripain 1.7 U/mg 0.25 1 Endopoteinase Protease XI11 0.01 U/mg 0.43 1 Chymopapain * 2.02 1 Chymotrypsin * 0.14 1 Protease X * 2.01 1 Bromelain * 0.81 1 Kallikrein * 0.56 1 Proteinase A 0.02 U/mg 0.36 1 Trypsin 11 kU/mg 3.40 100000 Papain * 0.64 10 Endoproteinase Asp-N 4.3 U/mg 0.004 1 Dispase 1 * 0.2 1 Endoproteinase Lys-C * 0.01 1 Thrombin 83.0 U/mg 0.59 500 Elastase 0.63 U/mg 0.36 5 Proteinase K * 3.60 100 * For the proteases protease XXIII, protease XIX, chymopapain, endoproteinase Lys-C, chymotrypsin, papain, dispase I, protease X, bromelain, kallikrein and proteinase K no plasminogen activation could be detected. Example 9: Pharmaceutical formulations The recombinant functional plasminogen used in the following examples was obtained by means of the inventive method of production. In this connexion the term "plasminogen" refers to recombinant micro-, mini-, Lys- or Glu-plasminogen and the term "plasmin" to plasmin, which was obtained by proteolytic cleavage of recombinant micro-, mini-, Lys- or Glu-plasminogen. The activation of micro-, mini-, Lys- or Glu-plasminogen can be obtained by use of the same plasminogen activators, especially plasminogen activating proteases as described above, but is not limited to these examples, whereas the ratio of units activator to units plasminogen (micro-, mini-, Lys-or Glu-plasminogen) is about 1 :1000. The plasminogen can be activated proteolytically, i.e. by the proteases tissue plasminogen activator, urokinase or the proteases protease VIII or protease from S. griseus described in the patent as well as by complexation with streptokinase or staphylokinase. Example 9a: Pharmaceutical formulations Hydrogels 34 Base formulation for hydrogels (l00g) Plasminogen 100U Plasminogen activator(s) 0.1 U Hydroxyethyl cellulose 10 000 3.5 g optional conservation (sorbinic acid/potassium sorbate 0.1-0.4%. PHB-ester 0.1%) purified water ad 100.0 The hydroxyethyl cellulose resp. instead of it hypromellose resp. methyl cellulose can be used alternatively in an amount of 0.5 -15-0 g. Gel Plasminogen 1000U Plasminogen activator(s) 1 U Glycerol (85%) 150.0g Hydroxyethyl cellulose 10 000 32.5 g optional conservation (sorbinic acid/potassium sorbate 0.1-0.4%, PHB-ester0.1%) Ringer's solution without lactate ad 1000.0 g alternatively: 100 g contain: Plasminogen 100 U Plasminogen activator(s) 0.1 U Hydroxyethyl cellulose 30 000 2.5 g Glycerol85% l0.0g optional conservation (sorbinic acid/potassium sorbate 0.1-0.2%, PHB-ester0.1%) purified water ad 100.0 alternatively: lOOggel contain: Plasminogen 100 U Plasminogen activator(s) 0.1 U Polyacrylic acids 1 g Propylene glycol 8 g Mid-chained triglyceride 8 g Diethylamine (for adjusting pH) q.s. Optional conservation (sorbinic acid/ potassium sorbate 0.1-0.2%, PHB-ester0.1%) 2-Propanol 0 -1 g 35 Water ad l00g Hydrophilic ointment (Macrogol ointment) 50g contain Plasminogen 50 U Plasminogen activator(s) 0.05 U Macrogol 400 30.0 g Macrogol 4000 l0.0g optional conservation (sorbinic acid/potassium sorbate 0.1-0.2%, PHB-ester 0.1%) Purified water ad 50.0 g alternatively: Water-free Macrogol ointment lOOg contain; Plasminogen 100U Plasminogen activator(s) 0.1U Macrogol 300 50g Macrogol 1500 adl00g alternatively: Water resorbing ointment Plasminogen 100U Plasminogen activator(s) 0.1U Cetylstearyl alcohol 29g Paraffin, viscous 34g Vaseline, white 100g Hydrophobic ointment Plasminogen 100U Plasminogen activator(s) 0.1U Vaseline 80.0g Paraffin thin fluid ad 1 OOg Hydrophobic paste Plasminogen 100U Plasminogen activator(s) 0.1U Hypromellose 400 20g Vaseline, white ad l00g alternatively: 36 Plasminogen 100U Plasminogen activator(s) 0.1U Carbomer (e.g. carbopol 974p) 15g Paraffin, viscous 40g Vaseline, white ad 100g Creme Plasminogen 100U Plasminogen activator(s) 0.1U Mid-chained triglycerides 20g Emulgating cetylstearyl alcohol l0g Lanolin l0g Sorbitol l0g optional conservation (sorbinic acid/potassium sorbate 0.1-0.2%, PHB-ester 0.1%) purified water ad 100 g Nonionic hydrophiiic creme Plasminogen , 100U Plasminogen activator(s) 0.1 U Cetyl alcohol 20 g 2-Ethyllauromyristat l0g Glycerol 85% 6 g Potassium sorbate 0.14 g Citric acid 0.07 g Water ad 100 g Nonionic creme Plasminogen 100U Plasminogen activator(s) 0.1 U Polysorbat 60 5 g Cetylstearyl alcohol 10 g Glycerol 85% lOg Vaselin, white 25 g optional conservation (sorbinic acid/potassium sorbate 0.1-0.2%, PHB-ester 0.1%) Water ad 100 g Liposomal formulation 37 Plasminogen 100 U Plasminogen activator(s) 0.1 U Soja lecithin. Chicken lecithin 15 g optional conservation (sorbinic acid/potassium sorbate 0.1-0.2%, PHB-ester 0.1%, resp. diazodinyl urea l-2g) Water ad 100-Og Capsule One capsule with 0.25g powder/granulate contains: Plasminogen 5 U Plasminogen activator(s) 0.005 U Starch 0.1 g Siliciumdioxide 0.02 g Magnesium stearate 0.002 g Polymethacrylate copolyrnerisates/polymethacrylic acid 0.015 g Triethylcitrate 0.0005 g Talkum 0.001 g Cellulose, microcrystalline ad 0.25 g alternatively: One capsule with 0.25 g powder/granulate contains: Plasminogen 5 U Plasminogen activator(s) 0.005 U Siliciumdioxide 0.01 g Magnesiumstearat 0.002 g Polymethacrylat copolymerisates/polymethacrytic acid 0.015 g Triethylcitrate 0.0001 g Talkum 0.001 mg Mannitol ad 0.25 g Pill 100 mg pill granulate contain: Plasminogen 5U Plasminogen activator(s) 0.005 U Starch 30 mg Siliciumdioxide 2mg Magnesiumstearate 4mg Polymethacrylate copolymerisates/polymethacrylic acid 5 mg Triethylcitrate 0-1 mg 38 Talkum 0.0001 mg Cellulose, microcrystalline ad 100 mg Pellets 100 g pellets contain: Plasminogen 2000 U Plasminogen activator(s) 2 U Starch 20 g Sucrosestearate 20 g Siliciumdioxide 2 g Magnesiumstearate 3 g Polyvinylpyrrolidone 0 -1 g Polymethacrylate copolymensates/polymethacrylic acid 5 g Talkum 0.2 g Triethylcitrate 0.1 g Cellulose, microcrystalline ad 100 g Injection solution Plasminogen 500 U Plasminogen activator(s) 0.5 U Ethanol 0 -1 g 10 Propylene glycol 10 g Polyethylene glycol 0 -1 g Sodium chloride q.s. optional buffer (sodium hydrogen phosphate/sodium dihydrogen phosphate) purified Water ad 100 ml Instead of micro-, mini-, Lys- or Glu-plasminogen in case of the numerated formulations also the same amount based on the activity of plasmin can be used. If plasmin is used directly, no plasminogen activator(s) has/have to be contained in the pharmaceutical formulation. Example 9b: Pharmaceutical formulations a) Hydrogels Basic formulation for hydrogels (100 g) Plasmin 100U Hydroxyethyl cellulose 400 2.5 - 5.0 g purified water ad 100.0 g The time for swelling takes 1 to 3 h. 39 The use of 1 -1000 U plasmin per gramme hydrogel is possible. b) Hydrophilic ointment Basic formulation of a hydrophilic ointment (1000 g); Plasmin 1000U Glycerol, water-free 85.0 g Hydroxyethyl cellulosel 0.000 32.5 g optionally polyhexanide 0.2 weight-% Ringer's solution without lactate ad 1000.0 g Polyhexanide can be added optionally as antimicrobial active agent in a concentration up to 0.2 weight-%. Instead of hydroxyethyl cellulose 10.000 (Natrosol 250® HX PHARM) also hydroxyethyl cellulose 400 (e.g. Tyiose® H 300 or Natrosol 250® HX PHARM) can be added. Ointment Basic formulation for ointment (50 g) Plasmin 50 U Macrogol 400 30.0 - 32.5 g Macrogol 4000 12.5 - 7.5 g purified water ad 50.0 g The use of 1 -10000 U plasmin per gramme ointment is possible, c) Preparation: 12.5 g macrogol 4000 and 30.0 g macrogol 400 (in case of supple ointments 7.5 g macrogol 4000 and 32.5 g macrogol 400) are heated in the water bath in an ointment dish until the smelting of the macrogol. After cooling down the appropriate amount of plasmin, which was produced by means of the inventive method, dissolved in 7.5 g of purified water is added and afterwards homogenized. d) Capsule Basic formulation for 0.5 g Plasmin 5U Lactose 0.42 g Starch 0.06 g Magnesium stearate 0.02 g The use of 0.1 -100 U plasmin per capsule is possible. e) Injection solution / infusion solution Basic formulation for 100 ml Piasmin 500 U Ethanol 0.01 g 40 Propylene glycol purified water 30 ml ad 100 ml The use of 1 - 500 U plasmin per ml of solution is possible. Instead of plasmin also micro-, mini-, Lys- or Glu-plasminogen can be used in the mentioned amounts for the plasmin based on the activity in units, if at the same time at least one plasminogen activator is added in an amount of 1 :10000 to 1 :100, preferred in an amount of 1:1000 based on the plasminogen activity. Example 10a: Amplification and cloning of different forms of the mini- and the micro-plasminogen gene and cloning into the vector pPICZaA; transformation of Pichia pastoris Mini- and micro-plasminogen represent shortened plasminogen derivatives, which are lacking of the N-terminal domains, but which are still activable into active plasmin. The amplification of the mini- and micro-plasminogen genes for cloning into the vector pPICZaA was carried out with the oligonucleotide primer N034 for the 3'-end and in each case with one of the primers N036a-j (Seq. ID No. 19 to 28) for the particular 5'-end in using the conditions described in example la. The oligonucleotide primers N036a,c,e,g,i have beside the bases complementary to the plasminogen gene the codons for the Kex2 cleavage site, the primers N036b,d,f,h,j have in addition subsequent to the codons for the Kex2 cleavage site the codons for two Stel3 cleavage sites. The primer N034 has further on a Kspl cleavage site, the primers N036 a-j have a Xhol cleavage site. protease- plasmid N-terminal cleavage site name amino acid* Kex2 pPLGl.l A463 Kex2, 2xSre13 PPLG2.1 A463 Kex2 pPLG3.2 K550 Kex2, 2xStel3 pPLG4.2 K550 Kex2 pPLG5.3 L551 Kex2, 2xStel3 pPLG6.1 L551 Kex2 pPLG7.1 A562 Kex2, 2xStel3 pPLG8.3 A562 Kex2 pPLG9.1 S564 Kex2,2xStel3 pPLGlO.l S564 The cloning of the mini- and micro-plasminogen genes into the vector pPICZaA was carried out analogous to the cloning described in example lb, whereas the vector as well as the particular PCR product were cut with the restriction endonucleases Xhol and Kspl. The used primers, the names of the plasminogen derivative, the coded protease cleavage sites, the labeling of the obtained plasmids and the N-terminal amino acid of the secreted plasminogen derivative are summarized in the following table. 5'-primer 3'-primer name N036a N034 mini-plasminogen N036b N034 mini-plasminogen N036c N034 micro-plasminogen N036d N034 micro-plasminogen N036e N034 micro-plasminogen N036f N034 micro-plasminogen N036g N034 micro-plasminogen N036h N034 micro-plasminogen N036i N034 micro-plaSminogen N036J N034 micro-plasminogen 41 * The numeration refers to the 810 amino acid long preplasminogen (Seq. ID No. 12) Fig. 8 shows exemplary the plasmid pPLGl.l. As described for pMHS476.1 in example lc Pichia pastohs KM71H was transformed with the plasmid pPLGl.l. The obtained colonies were referred to as Pichia pastoris KM71H/pPLGl.l-l/a, whereas "a" again represents the consecutive numbering of the colonies beginning at 1. The generation of strains on basis of the plasmids pPLG2.1, pPLG3.2, pPLG4.2, pPLG5.3, pPLG6.1, pPLG7.1, pPLG8.3, pPLG9.1 and pPLGlO.l was carried out according to the production of the strain KM71H/pPLGl.l-l/a. Oligonucleotide Primer N036a-j N036a AAAAACTCGAGAAAAGAGCACCTCCGCCTGTTG N036b AAAAACTCGAGAAAAGAGAGGCTGAAGCTGCACCTCCGCCTGTTG N036c AAAAACTCGAGAAAAGAAAACTTTACGACTACTG N036d AAAAACTCGAGAAAAGAGAGGCTGAAGCTAAACTTTACGACTACTG N036e AAAAACTCGAGAAAAGACTTTACGACTACTGTG N036f AAAAACTCGAGAAAAGAGAGGCTGAAGCTCTTTACGACTACTGTG N036g AAAAACTCGAGAAAAGAGCCCCTTCATTTGATTGTG N036h AAAAACTCGAGAAAAGAGAGGCTGAAGCTGCCCCTTCATTTGATTGTG N036i AAAAACTCGAGAAAAGATCATTTGATTGTGGGAAGCC N036J AAAAACTCGAGAAAAGAGAGGCTGAAGCTTCATTTGATTGTGGGAAGCC Example 10b: Amplification and cloning of different forms of the mini- and the micro-plasminogen gene and cloning into the vector pGAPZaA; transformation of Pichia pastoris The amplification of the mini- and micro-plasminogen genes for cloning into the vector pGAPZaA was carried out with the Oligonucleotide primer N034 for the 3'-end and in each case with one of the primers N036a-j (Seq. ID No. 19 to 28) for the particular 5'-end in using the conditions described in example la. The Oligonucleotide primers N036a,c,e,g,i have beside the bases complementary to the plasminogen gene the codons for the Kex2 cleavage site, the primers N036b,d,f,h,j have in addition subsequent to the codons for the Kex2 cleavage site the codons for two Stel3 cleavage sites. The primerfJW has further on a Kspl cleavage site, the primers N036 a-j have a Xhol cleavage site. The cloning of the mini- and micro-plasminogen genes into the vector pGAPZaA was carried out analogous to the cloning described in example lb, whereas the vector as well as the particular PCR product were cut with the restriction endonucleases Xhol and Kspl. Summarized the used primers, the names of the plasminogen derivative, the coded protease 42 cleavage sites, the labeling of the obtained plasmids and the N-terminal amino acid of the secreted plasminogen derivative can be taken from the following table. * The numeration refers to the 810 amino acid long preplasminogen (Seq. ID No. 12) Fig. 9 shows exemplary the plasmid pPLG11.2. As described for pJW9.1 in example 7a Pichia pasfons KM71H was transformed with the plasmid pPLG11.2 linearized by the restriction endonuclease Bln\. The obtained colonies were referred to as Pichia pastoris KM71H/pPLG11.2-l/a, whereas "a" again represents the consecutive numbering of the colonies beginning at 1. The generation of strains on basis of the plasmids pPLG12.1, pPLG13.1, pPLG14.2, pPLG15.1, pPLG16.3. pPLGl7.2, pPLG18.1, pPLG19.2 and pPLG20.1 was carried out according to the production of the strain KM71H/pPLGl.l-l/a. Sequence protocol Sequence 1: Oligonucleotide primer N034 AAAAACCGCGGTCAATTATTTCTCATCACTCCC Sequence 2: Oligonucleotide primer N036 AAAAACTCGAGAAAAGAAAAGTGTATCTCTCAGAGTG Sequence 3: Oligonucleotide primer N057 AAAAACTCGAGAAAAGAGAGGCTGAAGCTAAAGTGTATCTCTCAGAGTG Sequence 4: Oligonucleotide primer N037 AAAAATTCGAAAAATGGAACATAAGGAAGTGG Sequence 5: Oligonucleotide primer N035 AAAAACTCGAGAAAAGAGAGCCTCTGGATGACTAT Sequence 6: Oligonucleotide primer N056 AAAAACTCGAGAAAAGAGAGGCTGAAGCTGAGCCTCTGGATGACTAT Sequence 7: human Lys-plasminogen fusion gene with the codons for the Kex2 cleavage site and the gene of the signal sequence of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCT CCAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGT TACTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAAT AACGGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTA TCTCTCGAGAAAAGAAAAGTGTATCTCTCAGAGTGCAAGACTGGGAATGGAAAGAACTAC AGAGGGACGATGTCCAAAACAAAAAATGGCATCACCTGTCAAAAATGGAGTTCCACTTCT CCCCACAGACCTAGATTCTCACCTGCTACACACCCCTCAGAGGGACTGGAGGAGAACTAC TGCAGGAATCCAGACAACGATCCGCAGGGGCCCTGGTGCTATACTACTGATCCAGAAAAG AGATATGACTACTGCGACATTCTTGAGTGTGAAGAGGAATGTATGCATTGCAGTGGAGAA AACTATGACGGCAAAATTTCCAAGACCATGTCTGGACTGGAATGCCAGGCCTGGGACTCT CAGAGCCCACACGCTCATGGATACATTCCTTCCAAATTTCCAAACAAGAACCTGAAGAAG AATTACTGTCGTAACCCCGATAGGGAGCTGCGGCCTTGGTGTTTCACCACCGACCCCAAC AAGCGCTGGGAACTTTGCGACATCCCCCGCTGCACAACACCTCCACCATCTTCTGGTCCC ACCTACCAGTGTCTGAAGGGAACAGGTGAAAACTATCGCGGGAATGTGGCTGTTACCGTT TCCGGGCACACCTGTCAGCACTGGAGTGCACAGACCCCTCACACACATAACAGGACACCA 44 GAAAACTTCCCCTGCAAAAATTTGGATGAAAACTACTGCCGCAATCCTGACGGAAAAAGG GCCCCATGGTGCCATASy^CAACAGCCAAGTGCGGTGGGAGTACTGTAAGATACCGTCC TGTGACTCCTCCCCAGTATCCACGGAACAATTGGCTCCCACAGCACCACCTGAGCTAACC CCTGTGGTCCAGGACTGCTACCATGGTGATGGACAGAGCTACCGAGGCACATCCTCCACC ACCACCACAGGAAAGAAGTGTCAGTCTTGGTCATCTATGACACCACACCGGCACCAGAAG ACCCCAGAAAACTACCCAAATGCTGGCCTGACAATGAACTACTGCAGGAATCCAGATGCC GATAAAGGCCCCTGGTGTTTTACCACAGACCCCAGCGTCAGGTGGGAGTACTGCAACCTG AAAAAATGCTCAGGAACAGAAGCGAGTGTTGTAGCACCTCCGCCTGTTGTCCTGCTTCCA GATGTAGAGACTCCTTCCGAAGAAGACTGTATGTTTGGGAATGGGAAAGGATACCGAGGC AAGAGGGCGACCACTGTTACTGGGACGCCATGCCAGGACTGGGCTGCCCAGGAGCCCCAT AGACACAGCATTTTCACTCCAGAGACAAATCCACGGGCGGGTCTGGAAAAAAATTACTGC CGTAACCCTGATGGTGATGTAGGTGGTCCCTGGTGCTACACGACAAATCCAAGAAAACTT TACGACTACTGTGATGTCCCTCAGTGTGCGGCCCCTTCATTTGATTGTGGGAAGCCTCAA GTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACATTCC TGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACCTTG ATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCTTCA TCCTACAAGGTCATCCTGGGTGCACACCAAGAAGTGAATCTCGAACCGCATGTTCAGGAA ATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTA AGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCAGCTTGTCTGCCATCCCCAAATTAT GTGGTCGCTGACCGGACCGAATGTTTCATCACTGGCTGGGGAGAAACCCAAGGTACTTTT GGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCTGTGATTGAGAATAAAGTGTGCAATCGC TATGAGTTTCTGAATGGAAGAGTCCAATCCACCGAACTCTGTGCTGGGCATTTGGCCGGA GGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAA TACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCACGCCCCAATAAGCCTGGT GTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGTGATGAGAAATAATTGA Sequence 8: human Lys-plasminogen with Kex2 cleavage site and the signal peptide of alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDV AVLPFSNSTNNGLLPIMTTIASIAAKEEGVSLEKRKVYLSECKTGNGKNY RGTMSKTKNGITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQG PWCYTTDPEKRYDYCDILECEEECMHCSGENYDGKISKTMSGLECQAWDS QSPHAHGYIPSKFPNKNLKKNYCRNPDRELRPWCFTTDPNKRWELCDIPR CTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTCQHWSAQTPHTHNRTP ENFPCKNLDENYCRNPDGKRAPWCHTTNSQVRWEYCKIPSCDSSPVSTEQ LAPTAPPELTPWQDCYHGDGQSYRGTSSTTTTGKKCQSWSSMTPHRHQK TPENYPNAGLTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGTEASV VAPPPWLLPDVETPSEEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPH RHSIFTPETNPRAGLEKNYCRNPDGDVGGPWCYTTNPRKLYDYCDVPQCA APSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQVSLRTRFGMHFCGGTL ISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEP TRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQGTF GAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSG GPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN* 45 Sequence 9: human Lys-plasminogen fusion gene with the codons for the Kex2 cleavage site and two Stel3 cleavage sites and the gene for the signal sequence of the alpha factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCT CCAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGT TACTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAAT AACGGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTA TCTCTCGAGAAAAGAGAGGCTGAAGCTAAAGTGTATCTCTCAGAGTGCAAGACTGGGAAT GGAAAGAACTACAGAGGGACGATGTCCAAAACAAAAAATGGCATCACCTGTCAAAAATGG AGTTCCACTTCTCCCCACAGACCTAGATTCTCACCTGCTACACACCCCTCAGAGGGACTG GAGGAGAACTACTGCAGGAATCCAGACAACGATCCGCAGGGGCCCTGGTGCTATACTACT GATCCAGAAAAGAGATATGACTACTGCGACATTCTTGAGTGTGAAGAGGAATGTATGCAT TGCAGTGGAGAAAACTATGACGGCAAAATTTCCAAGACCATGTCTGGACTGGAATGCCAG GCCTGGGACTCTCAGAGCCCACACGCTCATGGATACATTCCTTCCAAATTTCCAAACAAG AACCTGAAGAAGAATTACTGTCGTAACCCCGATAGGGAGCTGCGGCCTTGGTGTTTCACC ACCGACCCCAACAAGCGCTGGGAACTTTGCGACATCCCCCGCTGCACAACACCTCCACCA TCTTCTGGTCCCACCTACCAGTGTCTGAAGGGAACAGGTGAAAACTATCGCGGGAATGTG GCTGTTACCGTTTCCGGGCACACCTGTCAGCACTGGAGTGCACAGACCCCTCACACACAT AACAGGACACCAGAAAACTTCCCCTGCAAAAATTTGGATGAAAACTACTGCCGCAATCCT GACGGAAAAAGGGCC CCATGGTGCCATACAACCAACAGC CAAGTGCGGTGGGAGTACTGT AAGATACCGTCCTGTGACTCCTCCCCAGTATCCACGGAACAATTGGCTCCCACAGCACCA CCTGAGCTAACCCCTGTGGTCCAGGACTGCTACCATGGTGATGGACAGAGCTACCGAGGC ACATCCTCCACCACCACCACAGGAAAGAAGTGTCAGTCTTGGTCATCTATGACACCACAC CGGCACCAGAAGACC CCAGAAAACTACCCAAATGCTGGC CTGACAATGAACTACTGCAGG AATCCAGATGCCGATAAAGGCCCCTGGTGTTTTACCACAGACCCCAGCGTCAGGTGGGAG TACTGCAACCTGAAAAAATGCTCAGGAACAGAAGCGAGTGTTGTAGCACCTCCGCCTGTT GTCCTGCTTCCAGATGTAGAGACTCCTTCCGAAGAAGACTGTATGTTTGGGAATGGGAAA GGATACCGAGGCAAGAGGGCGACCACTGTTACTGGGACGCCATGCCAGGACTGGGCTGCC CAGGAGCCCCATAGACACAGCATTTTCACTCCAGAGACAAATCCACGGGCGGGTCTGGAA AAAAATTACTGCCGTAACC CTGATGGTGATGTAGGTGGTC CCTGGTGCTACACGACAAAT CCAAGAAAACTTTACGACTACTGTGATGTCCCTCAGTGTGCGGCCCCTTCATTTGATTGT GGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCC CACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTGGAATGCACTTCTGT GGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTGCTTGGAGAAGTCC CCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCAAGAAGTGAATCTCGAACCG CATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAAAAGATATTGCC TTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCAGCTTGTCTGCCA TCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCACTGGCTGGGGAGAAACC CAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCC CAG CTCC CTGTGATTGAGAATAAA GTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACCGAACTCTGTGCTGGG CATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTTTGCTTC GAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCACGCCCC AATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGTGATG AGAAATAATTGA 46 Sequence 10: human Lys-plasminogen with Stel3 and Kex2 cleavage sites and the signal peptide of the alpha factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDV AVLPFSNSTNNGLLFINTTIASIAAKEEGVSLEKREAEAKVYLSECKTGN GKNYRGTMSKTKNGITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDN DPQGPWCYTTDPEKRYDYCDILECEEEC^1HCSGENYDGKISKTMSGLECQ AWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRELRPWCFTTDPNKRWELC DIPRCTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTCQHWSAQTPHTH NRTPENFPCKNLDENYCRNPDGKRAPWCHTTNSQVRWEYCKIPSCDSSPV STEQLAPTAPPELTPWQDCYHGDGQSYRGTSSTTTTGKKCQSWSSMTPH RHQKTPENYPNAGLTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGT EASWAPPPWLLPDVETPSEEDCMFGNGKGYRGKRATTVTGTPCQDWAA QEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGGPWCYTTNPRKLYDYCDV PQCAAPSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQVSLRTRFGMHFC GGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRL FLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTECFITGWGET QGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQ GDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVM RNN* Sequence 11: human preplasminogen gene ATGGAACATAAGGAAGTGGTTCTTCTACTTCTTTTATTTCTGAAATCAGGTCAAGGAGAG CCTCTGGATGACTATGTGAATACCCAGGGGGCTTCACTGTTCAGTGTCACTAAGAAGCAG CTGGGAGCAGGAAGTATAGAAGAATGTGCAGCAAAATGTGAGGAGGACGAAGAATTCACC TGCAGGGCATTCCAATATCACAGTAAAGAGCAACAATGTGTGATAATGGCTGAAAACAGG AAGTCCTCCATAATCATTAGGATGAGAGATGTAGTTTTATTTGAAAAGAAAGTGTATCTC TCAGAGTGCAAGACTGGGAATGGAAAGAACTACAGAGGGACGATGTCCAAAACAAAAAAT GGCATCACCTGTCAAAAATGGAGTTCCACTTCTCCCCACAGACCTAGATTCTCACCTGCT ACACACCCCTCAGAGGGACTGGAGGAGAACTACTGCAGGAATCCAGACAACGATCCGCAG GGGCCCTGGTGCTATACTACTGATCCAGAAAAGAGATATGACTACTGCGACATTCTTGAG TGTGAAGAGGAATGTATGCATTGCAGTGGAGAAAACTATGACGGCAAAATTTCCAAGACC ATGTCTGGACTGGAATGCCAGGCCTGGGACTCTCAGAGCCCACACGCTCATGGATACATT CCTTCCAAATTTCCAAACAAGAACCTGAAGAAGAATTACTGTCGTAACCCCGATAGGGAG CTGCGGCCTTGGTGTTTCACCACCGACCCCAACAAGCGCTGGGAACTTTGCGACATCCCC CGCTGCACAACACCTCCACCATCTTCTGGTCCCACCTACCAGTGTCTGAAGGGAACAGGT GAAAACTATCGCGGGAATGTGGCTGTTACCGTTTCCGGGCACACCTGTCAGCACTGGAGT GCACAGACCCCTCACACACATAACAGGACACCAGAAAACTTCCCCTGCAAAAATTTGGAT GAAAACTACTGCCGCAATCCTGACGGAAAAAGGGCCCCATGGTGCCATACAACCAACAGC CAAGTGCGGTGGGAGTACTGTAAGATACCGTCCTGTGACTCCTCCCCAGTATCCACGGAA CAATTGGCTCCCACAGCACCACCTGAGCTAACCCCTGTGGTCCAGGACTGCTACCATGGT GATGGACAGAGCTACCGAGGCACATCCTCCACCACCACCACAGGAAAGAAGTGTCAGTCT TGGTCATCTATGACACCACACCGGCACCAGAAGACCCCAGAAAACTACCCAAATGCTGGC CTGACAATGAACTACTGCAGGAATCCAGATGCCGATAAAGGCCCCTGGTGTTTTACCACA GACCCCAGCGTCAGGTGGGAGTACTGCAACCTGAAAAAATGCTCAGGAACAGAAGCGAGT 47 GTTGTAGCACCTCCGCCTGTTGTCCTGCTTCCAGATGTAGAGACTCCTTCCGAAGAAGAC TGTATGTTTGGGAATGGGAAAGGATACCGAGGCAAGAGGGCGACCACTGTTACTGGGACG CCATGCCAGGACTGGGCTGCCCAGGAGCCCCATAGACACAGCATTTTCACTCCAGAGACA AATCCACGGGCGGGTCTGGAAAAAAATTACTGCCGTAACCCTGATGGTGATGTAGGTGGT CCCTGGTGCTACACGACAAATCCAAGAAAACTTTACGACTACTGTGATGTCCCTCAGTGT GCGGCCCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGG GTTGTGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACA AGGTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCT GCCCACTGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACAC CAAGAAGTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAG CCCACACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAA GTAATCCCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTC ATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAG CTCCCTGTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAA TCCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGT GGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGG GGTCTTGGCTGTGCACGCCCCAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTT ACTTGGATTGAGGGAGTGATGAGAAATAATTGA Sequence 12: human preplasminogen MEHKEWLLLLLFLKSGQGEPLDDYVNTQGASLFSVTKKQLGAGSIEECA AKCEEDEEFTCRAFQYHSKEQQCVIMAENRKSS11 IRMRDWLFEKKVYL SECKTGNGKNYRGTMSKTKNGITCQKWSSTSPHRPRFSPATHPSEGLEEN YCRNPDNDPQGPWCYTTDPEKRYDYCDILECEEECMHCSGENYDGKISKT MSGLECQAWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRELRPWCFTTDP NKRWELCDIPRCTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTCQHWS AQTPHTHNRTPENFPCKHLDENYCRNPDGKRAPWCHTTNSQVRWEYCKIP SCDSSPVSTEQLAPTAPPELTPWQDCYHGDGQSYRGTSSTTTTGKKCQS WSSMTPHRHQKTPENYPNAGLTMNYCRNPDADKGPWCFTTDPSVRWEYCN LKKCSGTEASWAPPPWLLPDVETPSEEDCMFGNGKGYRGKRATTVTGT PCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGGPWCYTTNPRK LYDYCDVPQCAAPSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQVSLRT RFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQ EIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTECF ITGWGETQGTFGAGLLKSAQLPVIENKVCNRYEFLNGRVQSTELCAGHLA GGTD S CQGD S GGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFV TWIEGVMRNN* Sequence 13: human Glu-plasminogen fusion gene with the codons for the Kex2 cleavage site and the gene for the signal sequence of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCT CCAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGT TACTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGC CATTTTC CAACAGCACAAAT 48 AACGGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTA TCTCTCGAGAAAAGAGAGCCTCTGGATGACTATGTGAATACCCAGGGGGCTTCACTGTTC AGTGTCACTAAGAAGCAGCTGGGAGCAGGAAGTATAGAAGAATGTGCAGCAAAATGTGAG GAGGACGAAGAATTCACCTGCAGGGCATTCCAATATCACAGTAAAGAGCAACAATGTGTG ATAATGGCTGAAAACAGGAAGTCCTCCATAATCATTAGGATGAGAGATGTAGTTTTATTT GAAAAGAAAGTGTATCTCTCAGAGTGCAAGACTGGGAATGGAAAGAACTACAGAGGGACG ATGTCCAAAACAAAAAATGGCATCACCTGTCAAAAATGGAGTTCCACTTCTCCCCACAGA CCTAGATTCTCACCTGCTACACACCCCTCAGAGGGACTGGAGGAGAACTACTGCAGGAAT CCAGACAACGATCCGCAGGGGCCCTGGTGCTATACTACTGATCCAGAAAAGAGATATGAC TACTGCGACATTCTTGAGTGTGAAGAGGAATGTATGCATTGCAGTGGAGAAAACTATGAC GGCAAAATTTCCAAGACCATGTCTGGACTGGAATGCCAGGCCTGGGACTCTCAGAGCCCA CACGCTCATGGATACATTCCTTCCAAATTTCCAAACAAGAACCTGAAGAAGAATTACTGT CGTAACCCCGATAGGGAGCTGCGGCCTTGGTGTTTCACCACCGACCCCAACAAGCGCTGG GAACTTTGCGACATCCCCCGCTGCACAACACCTCCACCATCTTCTGGTCCCACCTACCAG TGTCTGAAGGGAACAGGTGAAAACTATCGCGGGAATGTGGCTGTTACCGTTTCCGGGCAC ACCTGTCAGCACTGGAGTGCACAGACCCCTCACACACATAACAGGACACCAGAAAACTTC CCCTGCAAAAATTTGGATGAAAACTACTGCCGCAATCCTGACGGAAAAAGGGCCCCATGG TGCCATACAACCAACAGCCAAGTGCGGTGGGAGTACTGTAAGATACCGTCCTGTGACTCC TCCCCAGTATCCACGGAACAATTGGCTCCCACAGCACCACCTGAGCTAACCCCTGTGGTC CAGGACTGCTACCATGGTGATGGACAGAGCTACCGAGGCACATCCTCCACCACCACCACA GGAAAGAAGTGTCAGTCTTGGTCATCTATGACACCACACCGGCACCAGAAGACCCCAGAA AACTACCCAAATGCTGGCCTGACAATGAACTACTGCAGGAATCCAGATGCCGATAAAGGC CCCTGGTGTTTTACCACAGACCCCAGCGTCAGGTGGGAGTACTGCAACCTGAAAAAATGC TCAGGAACAGAAGCGAGTGTTGTAGCACCTCCGCCTGTTGTCCTGCTTCCAGATGTAGAG ACTCCTTCCGAAGAAGACTGTATGTTTGGGAATGGGAAAGGATACCGAGGCAAGAGGGCG ACCACTGTTACTGGGACGCCATGCCAGGACTGGGCTGCCCAGGAGCCCCATAGACACAGC ATTTTCACTCCAGAGACAAATCCACGGGCGGGTCTGGAAAAAAATTACTGCCGTAACCCT GATGGTGATGTAGGTGGTCCCTGGTGCTACACGACAAATCCAAGAAAACTTTACGACTAC TGTGATGTCCCTCAGTGTGCGGCCCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCG AAGAAATGTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGG CAAGTCAGTCTTAGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCA GAGTGGGTGTTGACTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAG GTCATCCTGGGTGCACACCAAGAAGTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTG TCTAGGCTGTTCTTGGAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCT GCCGTCATCACTGACAAAGTAATCCCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCT GACCGGACCGAATGTTTCATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGC CTTCTCAAGGAAGCCCAGCTCCCTGTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTT CTGAATGGAAGAGTCCAATCCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCACTGAC AGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACATTTTA CAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCACGCCCCAATAAGCCTGGTGTCTATGTT CGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGTGATGAGAAATAATTGA Sequence 14: human Glu-plasminogen with Kex2 cleavage site and the signal peptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRPPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDV AVLPFSNSTNNGLLFINTTIASIAAKEEGVSLEKREPLDDYVNTQGASLF 49 SVTKKQLGAGSIEECAAKCEEDEEFTCRAFQYHSKEQQCVIMAENRKSSI IIRMRDWLFEKKVYLSECKTGNGKNYRGTMSKTKNGITCQKWSSTSPHR PRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILECEEE CMHCSGENYDGKISKTMSGLECQAWDSQSPHAHGYIPSKFPNKNLKKNYC RNPDRELRPWCFTTDPNKRWELCDIPRCTTPPPSSGPTYQCLKGTGENYR GNVAVTVSGHTCQHWSAQTPHTHNRTPENFPCKNLDENYCRNPDGKRAPW CHTTNSQVRWEYCKIPSCDSSPVSTEQLAPTAPPELTPWQDCYHGDGQS YRGTSSTTTTGKKCQSWSSMTPHRHQKTPENYPNAGLTMNYCRNPDADKG PWCFTTDPSVRWEYCNLKKCSGTEASWAPPPWLLPDVETPSEEDCMFG NGKGYRGKRATTVTGTPCQDWAAQEPHRHS I FTPETNPRAGLEKNYCRNP DGDVGGPWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRWGG CVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYK VILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPA CLPSPNYWADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEF LNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGC ARPNKPGVYVRVSRFVAWABGVMRNN* Sequence 15: human Glu-plasminogen fusion gene with the codons for the Kex2 cleavage site and two Stel3 cleavage sites and the gene for the signal sequence of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCT CCAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGT TACTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAAT AACGGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTA TCTCTCGAGAAAAGAGAGGCTGAAGCTGAGCCTCTGGATGACTATGTGAATACCCAGGGG GCTTCACTGTTCAGTGTCACTAAQAAGCAGCTGGGAGCAGGAAGTATAGAAGAATGTGCA GCAAAATGTGAGGAGGACGAAGAATTCACCTGCAGGGCATTCCAATATCACAGTAAAGAG CAACAATGTGTGATAATGGCTGAAAACAGGAAGTCCTCCATAATCATTAGGATGAGAGAT GTAGTTTTATTTGAAAAGAAAGTGTATCTCTCAGAGTGCAAGACTGGGAATGGAAAGAAC TACAGAGGGACGATGTCCAAAACAAAAAATGGCATCACCTGTCAAAAATGGAGTTCCACT TCTCCCCACAGACCTAGATTCTCACCTGCTACACACCCCTCAGAGGGACTGGAGGAGAAC TACTGCAGGAATCCAGACAACGATCCGCAGGGGCCCTGGTGCTATACTACTGATCCAGAA AAGAGATATGACTACTGCGACATTCTTGAGTGTGAAGAGGAATGTATGCATTGCAGTGGA GAAAACTATGACGGCAAAATTTCCAAGACCATGTCTGGACTGGAATGCCAGGCCTGGGAC TCTCAGAGCCCACACGCTCATGGATACATTCCTTCCAAATTTCCAAACAAGAACCTGAAG AAGAATTACTGTCGTAACCCCGATAGGGAGCTGCGGCCTTGGTGTTTCACCACCGACCCC AACAAGCGCTGGGAACTTTGCGACATCCCCCGCTGCACAACACCTCCACCATCTTCTGGT CCCACCTACCAGTGTCTGAAGGGAACAGGTGAAAACTATCGCGGGAATGTGGCTGTTACC GTTTCCGGGCACACCTGTCAGCACTGGAGTGCACAGACCCCTCACACACATAACAGGACA CCAGAAAACTTCCCCTGCAAAAATTTGGATGAAAACTACTGCCGCAATCCTGACGGAAAA AGGGCCCCATGGTGCCATACAACCAACAGCCAAGTGCGGTGGGAGTACTGTAAGATACCG TCCTGTGACTCCTCCCCAGTATCCACGGAACAATTGGCTCCCACAGCACCACCTGAGCTA ACCCCTGTGGTCCAGGACTGCTACCATGGTGATGGACAGAGCTACCGAGGCACATCCTCC ACCACCACCACAGGAAAGAAGTGTCAGTCTTGGTCATCTATGACACCACACCGGCACCAG AAGACCCCAGAAAACTACCCAAATGCTGGCCTGACAATGAACTACTGCAGGAATCCAGAT 50 GCCGATAAAGGCCCCTGGTGTTTTACCACAGACCCCAGCGTCAGGTGGGAGTACTGCAAC CTGAAAAAATGCTCAGGAACAGAAGCGAGTGTTGTAGCACCTCCGCCTGTTGTCCTGCTT CCAGATGTAGAGACTCCTTCCGAAGAAGACTGTATGTTTGGGAATGGGAAAGGATACCGA GGCAAGAGGGCGACCACTGTTACTGGGACGCCATGCCAGGACTGGGCTGCCCAGGAGCCC CATAGACACAGCATTTTCACTCCAGAGACAAATCCACGGGCGGGTCTGGAAAAAAATTAC TGCCGTAACCCTGATGGTGATGTAGGTGGTCCCTGGTGCTACACGACAAATCCAAGAAAA CTTTACGACTACTGTGATGTCCCTCAGTGTGCGGCCCCTTCATTTGATTGTGGGAAGCCT CAAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACAT TCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACC TTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCT TCATCCTACAAGGTCATCCTGGGTGCACACCAAGAAGTGAATCTCGAACCGCATGTTCAG GAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAAAAGATATTGCCTTGCTAAAG CTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCAGCTTGTCTGCCATCCCCAAAT TATGTGGTCGCTGACCGGACCGAATGTTTCATCACTGGCTGGGGAGAAACCCAAGGTACT TTTGGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCTGTGATTGAGAATAAAGTGTGCAAT CGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACCGAACTCTGTGCTGGGCATTTGGCC GGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGAC AAATACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCACGCCCCAATAAGCCT GGTGTCTATGTTCGTGT^TOiK^GGTTTGTTACTTGGATTGAGGGAGTGATGAGAAATAAT TGA Sequence 16: human Glu-plasminogen with Stel3 and Kex2 cleavage sites and the signal peptide of the alpha factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDV AVLPFSNSTNNGLLFINTTIASIAAKEEGVSLEKREAEAEPLDDYVNTQG ASLFSVTKKQLGAGSIEECAAKCEEDEEFTCRAFQYHSKEQQCVIMAENR KSSIIIRMRDWLFEKKVYLSECKTGNGKNYRGTMSKTKNGITCQKWSST SPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILE CEEECMHCSGENYDGKISKTMSGLECQAWDSQSPHAHGYIPSKFPNKNLK KNYCRNPDRELRPWCFTTDPNKRWELCDIPRCTTPPPSSGPTYQCLKGTG ENYRGhWAVTVSGHTCQHWSAQTPHTHNRTPENFPCKNLDENYCRNPDGK RAPWCHTTNSQVRWEYCKIPSCDSSPVSTEQLAPTAPPELTPWQDCYHG DGQSYRGTSSTTTTGKKCQSWSSMTPHRHQKTPENYPNAGLTMNYCRNPD ADKGPWCFTTDPSVRWEYCNLKKCSGTEASWAPPPWLLPDVETPSEED CMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNY CRNPDGDVGGPWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGR WGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRP SSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDK VIPACLPSPNYWADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCN RYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSW GLGCARPNKPGVYVRVS R FVTWIEGVMRNN* Sequence 17: Sequence of the Glu-plasminogen (pSM49.8, pSM58.1 and pSM82.1) secreted into the medium 51 EPLDDYVNTQGASLFSVTKKQLGAGSIEECAAKCEEDEEFTCRAFQYHSK EQQCVIMAENRKSSIIIRMRDWLFEKKVYLSECKTGNGKNYRGTMSKTK NGITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDP EKRYDYCDILECEEECMHCSGENYDGKISKTMSGLECQAWDSQSPHAHGY IPSKFPNKNLKKNYCRNPDRELRPWCFTTDPNKRWELCDIPRCTTPPPSS GPTYQCLKGTGENYRGNVAVTVSGHTCQHWSAQTPHTHNRTPENFPCKNL DENYCRNPDGKRAPWCHTTNSQVRWEYCKIPSCDSSPVSTEQLAPTAPPE LTPWQDCYHGDGQSYRGTSSTTTTGKKCQSWSSMTPHRHQKTPENYPNA GLTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGTEASWAPPPWL LPDVETPSEEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPE TNPRAGLEKNYCRNPDGDVGGPWCYTTNPRKLYDYCDVPQCAAPSFDCGK PQVEPKKCPGRWGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLT AAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALL KLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQGTFGAGLLKEA QLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEK DKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN* Sequence 18: Sequence of the Lys-plasminogen (pMHS476.1, pSM54.2, pAC37.1 and pJW9.1) secreted into the medium KVYLSECKTGNGKNYRGTMSKTKNGITCQKWSSTSPHRPRFSPATHPSEG LEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILECEEECMHCSGENYDGK ISKTMSGLECQAWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRELRPWCF TTDPNKRWELCDIPRCTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTC QHWSAQTPHTHNRTPENFPCKNLDENYCRNPDGKRAPWCHTTNSQVRWEY CKIPSCDSSPVSTEQLAPTAPPELTPWQDCYHGDGQSYRGTSSTTTTGK KCQSWSSMTPHRHQKTPENYPNAGLTMNYCRNPDADKGPWCFTTDPSVRW EYCNLKKCSGTEASWAPPPWLLPDVETPSEEDCMFGNGKGYRGKRATT VTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGGPWCYTT MPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQV SLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLE PHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYWADR TECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCA GHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRV SRFVTWIEGVMRNN* Sequence 19: Oligonucleotide primer N036a AAAAACTCGAGAAAAGAGCACCTCCGCCTGTTG Sequence 20: Oligonucleotide primer N036b AAAAACTCGAGAAAAGAGAGGCTGAAGCTGCACCTCCGCCTGTTG Sequence 21: Oligonucleotide primer N036c 52 AAAAACTCGAGAAAAGAAAACTTTACGACTACTG Sequence 22: Oligonucleotide primer N036d AAAAACTCGAGAAAAGAGAGGCTGAAGCTAAACTTTACGACTACTG Sequence 23: Oligonucleotide primer N036e AAAAACTCGAGAAAAGACTTTACGACTACTGTG Sequence 24: Oligonucleotide primer N036f AAAAACTCGAGAAAAGAGAGGCTGAAGCTCTTTACGACTACTGTG Sequence 25: Oligonucleotide primer N036g AAAAACTCGAGAAAAGAGCCCCTTCATTTGATTGTG Sequence 26: Oligonucleotide primer N036h AAAAACTCGAGAAAAGAGAGGCTGAAGCTGCCCCTTCATTTGATTGTG Sequence 27: OligonuclecrfiAe primer N036J AAAAACTCGAGAAAAGATCATTTGATTGTGGGAAGCC Sequence 28: Oligonucleotide primer N036J AAAAACTCGAGAAAAGAGAGGCTGAAGCTTCATTTGATTGTGGGAAGCC Sequence 29: Mini-plasminogen (pPLGl.l and pPLG2.1) APPPWLLPDVETPSEEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPHR HSIFTPETNPRAGLEKNYCRNPDGDVGGPWCYTTNPRKLYDYCDVPQCAA PSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQVSLRTRFGMHFCGGTLI SPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPT RKDIALLICLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQGTFG AGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGG PLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN* Sequence 30: Micro-plasminogen (pPLG3.2 and pPLG4.2) KLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQVSLR 53 TRFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHV QEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTEC FITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHL AGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRF VTWIEGVMRNN* Sequence 31: Micro-plasminogen (pPLG5.3 and pPLG6.1) LYDYCDVPQCAAPSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQVSLRT RFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQ EIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTECF ITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLA GGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFV TWIEGVMRNN* Sequence 32: Micro-plasminogen (pPLG7.1 and pPLG8.3) APSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQVSLRTRFGMHFCGGTL ISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEP TRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQGTF GAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSG GPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN* Sequence 33: Micro-plasminogen (pPLG9.1 and pPLGIO.l) SFDCGKPQVEPKKCPGRWG^CVAHPHSWPWQVSLRTRFGMHFCGGTLIS PEWVLTAAHCLEKSPRPSSylWILGAHQEVNLEPHVQEIEVSRLFLEPTR KDIALLKLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQGTFGA GLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGP LVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN* Sequence 34: DNA-sequence of the alpha factor from the yeast Saccharomyces cerevisiae in pPICZaA up to the Kex2-cleavage site. ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC TCGAG Sequence 35: Amino acid sequence of the alpha-factor from the yeast Saccharomyce! cerevisiae in pPICZaA up to the Kex2 cleavage site. MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLPFSNSTNN 54 GLLFINTTIASIAAKEEGVSLE Sequence 36: DNA-sequence of the Kex2 cleavage site AAAAGA Sequence 37: DNA-sequence of the Stel3 cleavage sites GAGGCTGAAGCT Sequence 38: Amino acid sequence of the Kex2 cleavage site KR Sequence 39: Amino acid sequence of the Stel3 cleavage sites EAEA Sequence 40: Amino acid sequences of the human mini-plasminogen as in pPLGl.l with Kex2 cleavage site and the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDV AVLPFSNSTNNGLLFINTTIASIAAKEEGVSLEKRAPPPWLLPDVETPS EEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLE KNYCRNPDGDVGGPWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKC PGRWGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEMVLTAAHCLEKS PRPSSYKVILGAHQEVN^EP^QEIEVSRLFLEPTRKDIALLKLSSPAVI TDKVIPACLPSPNYWADRTfftfFITGWGETQGTFGAGLLKEAQLPVIENK VCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGV TSWGLGCARPNKPGVYVRVSRFVTWI EGVMRNN* Sequence 41: Amino acid sequence of the human mini-plasminogen as in pPLG2.1 with Kex2 cleavage site and two Stel cleavage sites and the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDV AVLPFSNSTNNGLLFINTTIASIAAKEEGVSLEKREAEAAPPPWLLPDV ETPSEEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPR AGLEKNYCRNPDGDVGGPWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVE PKKCPGRWGGCVAHPHSWPWQVSLRTRPGMHFCGGTLISPEWVLTAAHC LEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSS PAVITDKVIPACLPSPNYWADRTECFITGWGETQGTFGAGLLKEAQLPV 55 IENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYI LQGVTSWGLGCARPNKPGVYVRVSRFVTWI EGVMRNN* Sequence 42: Amino acid sequence of the human micro-plasminogen as in pPLG3.2 with Kex2 cleavage site and the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLP FSNSTNNGLLFINTTIASIAAKEEGVSLEKRKLYDYCDVPQCAAPSFDCGKPQV EPKKCPGRWGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEK SPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDK VIPACLPSPNYWADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEF LNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPN KPGVYVRVS RFVTWIEGVMRNN* Sequence 43: Amino acid sequence of the human micro-plasminogen as in pPLG4.2 with Kex2 cleavage site and two Stel3 cleavage sites and the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSAIAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLPFS NSTNNGLLFINTTIASIAAKEEGVSLEKREAEAKLYDYCDVPQCAAPSFDCGKPQV EPKKCPGRWGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSP RPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPA CLPSPNYWADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQ STELCAGHLAGGTDSCQGDSGGPL.VCFEKDKYILQGVTSWGLGCARPNKPGVYVRV S RFVTWIEGVMRNN* Sequence 44: Amino acid sequence of the human micro-plasminogen as in pPLG5.3 with Kex2 cleavage site and the prepropeptide of the alpha-factor of the yeast Saccharomycvs cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLPFSNSTNN GLLFINTTIASIAAKEEGVSLEKRLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRWGGCVA HPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPH VQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQG TFGAGLLKEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKD KYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN* Sequence 45: Amino acid sequence of the human micro-plasminogen as in pPLG6.1 with Kex2 cleavage site and two Stel3 cleavage sites and the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLPFS NSTNNGLLFINTTIASIAAKEEGVSLEKREAEALYDYCDVPQCAAPSFDCGKPQVE 56 PKKCPGRWGGCVAHPHSWPWQVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPR PSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLSSPAVITDKVIPAC LPSPNYWADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQS TELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVS RFVTWIEGVMRNN* Sequence 46: Amino acid sequence of the human micro-plasminogen as in pPLG7.1 with Kex2 cleavage site and the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLPFSNSTNN GLLFINTTIASIAAKEEGVSLEKRAPSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQVSL RTRFGMHPCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFL EPTRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQGTFGAGLLKEAQ LPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEICDKYILQGVTSWG LGCARPNKPGVYVRVSRFVTWIEGVMRNN* Sequence 47: Amino acid sequence of the human micro-plasminogen as in pPLG8.3 with Kex2 cleavage site and two Stel3 cleavage sites and the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLPFSNSTNN GLLFINTTIASIAAKEEGVSLEKREAEAAPSFDCGKPQVEPKKCPGRWGGCVAHPHSWPW QVSLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVS RLFLEPTRKDIALLICLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQGTFGAGLL KEAQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGV TSWGLGCARPNKPGVYVRVSRFVTWIEGVMRNN* Sequence 48: Amino acid sequence of the human micro-plasminogen as in pP&ftl with Kex2 cleavage site and the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLPFSNSTNN GLLFINTTIASIAAKEEGVSLEKRSFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQVSLRT RFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEP TRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQGTFGAGLLKEAQLP VIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLG CARPNKPGVYVRVSRFVTWIEGVMRNN* Sequence 49: Amino acid sequence of the human micro-plasminogen as in pPLGlO.l with Kex2 cleavage site and two Stel3 cleavage sites and the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae MRFPSIFTAVLFAASSALAAPVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLPFSNSTNN GLLFINTTIASIAAKEEGVSLEKREAEASFDCGKPQVEPKKCPGRWGGCVAHPHSWPWQV 57 SLRTRFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRL FLEPTRKDIALLKLSSPAVITDKVIPACLPSPNYWADRTECFITGWGETQGTFGAGLLKE AQLPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTS WGLGCARPNKPGVYVRVSRFVTWIEGVMRNN* Sequence 50: Nucleic acid sequence of the human mini-plasminogen gene as in pPLGl.l with the codons for the Kex2 cleavage site and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC TCGAGAAAAGAGCACCTCCGCCTGTTGTCCTGCTTCCAGATGTAGAGACTCCTTCCGAAGA AGACTGTATGTTTGGGAATGGGAAAGGATACCGAGGCAAGAGGGCGACCACTGTTACTGGG ACGCCATGCCAGGACTGGGCTGCCCAGGAGCCCCATAGACACAGCATTTTCACTCCAGAGA CAAATCCACGGGCGGGTCTGGAAAAAAATTACTGCCGTAACCCTGATGGTGATGTAGGTGG TCCCTGGTGCTACACGACAAATCCAAGAAAACTTTACGACTACTGTGATGTCCCTCAGTGT GCGGCCCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGGG TTGTGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAG GTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTGCC CACTGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCAAG AAGTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCAC ACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATC CCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCACTG GCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCTGT GATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACCGAA CTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCCTC TGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGCTG TGCACGCCCCAATAAGCCTGgTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTGAG GGAGTGATGAGAAATAATTGA Sequence 51: Nucleic acid sequence of the human mini-plasminogen gene as in pPLG2.1 with the codons for the Kex2 cleavage site and the Stel3 cleavage sites and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC TCGAGAAAAGAGAGGCTGAAGCTGCACCTCCGCCTGTTGTCCTGCTTCCAGATGTAGAGAC TC CTTCCGAAGAAGACTGTATGTTTGGGAATGGGAAAGGATAC CGAGG CAAGAGGGCGAC C ACTGTTACTGGGACGCCATGCCAGGACTGGGCTGCCCAGGAGCCCCATAGACACAGCATTT TCACTCCAGAGACAAATCCACGGGCGGGTCTGGAAAAAAATTACTGCCGTAACCCTGATGG 58 rGATGTAGGTGGTCCCTGGTGCTACACGACAAATCCAAGAAAACTTTACGACTACTGTGAT GTCCCTCAGTGTGCGGCCCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAAT GTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAG TCTTAGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTG TTGACTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGG GTGCACACCAAGAAGTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTT CTTGGAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACT GACAAAGTAATCCCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAAT GTTTCATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGC CCAGCTCCCTGTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTC CAATCCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACA GTGGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTG GGGTCTTGGCTGTGCACGCCCCAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTT ACTTGGATTGAGGGAGTGATGAGAAATAATTGA Sequence 52: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG3.2 with the codons for the Kex2 cleavage site and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC TCGAGAAAAGAAAACTTTACGACTACTGTGATGTCCCTCAGTGTGCGGCCCCTTCATTTGA TTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTGGGGGGGTGTGTG GCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTGGAATGCACTTCT GTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTGCTTGGAGAAGTC CCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCAAGAAGTGAATCTCGAACCG CATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAAAAGATATTGCCT TGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCAGCTTGTCTGCCATC CCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCACTGGCTGGGGAGAAACCCAA GGTACTTTTGGAGCTGGQCT^CTCAAGGAAGCCCAGCTCCCTGTGATTGAGAATAAAGTGT GCAATCGCTATGAGTTTC^GffiaTGGAAGAGTCCAATCCACCGAACTCTGTGCTGGGCATTT GGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTTTGCTTCGAGAAG GACAAATACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCACGCCCCAATAAGC CTGGTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGTGATGAGAAATAA TTGA Sequence 53: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG4.2 with the codons for the Kex2 cleavage site and the Stel3 cleavage sites and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCtCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC 59 GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC TCGAGAAAAGAGAGGCTGAAGCTAAACTTTACGACTACTGTGATGTCCCTCAGTGTGCGGC CCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTG GGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTG GAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTG CTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCAAGAAGTG AATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAA AAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCAGC TTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCACTGGCTGG GGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCTGTGATTG AGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACCGAACTCTG TGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTT TGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCAC GCCCCAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGT GATGAGAAATAATTGA Sequence 54: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG5.3 with the codons for the Kex2 cleavage site and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC TCGAGAAAAGACTTTACGACTACTGTGATGTCCCTCAGTGTGCGGCCCCTTCATTTGATTG TGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCC CACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTGGAATGCACTTCTGTG GAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTGCTTGGAGAAGTCCCC AAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCAAGAAGTGAATCTCGAACCGCAT GTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAAAAGATATTGCCTTGC TAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCAGCTTGTCTGCCATCCCC AAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCACTGGCTGGGGAGAAACCCAAGGT ACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCTGTGATTGAGAATAAAGTGTGCA ATCGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACCGAACTCTGTGCTGGGCATTTGGC CGGAGGCACTGACAGTTQCC^GGTGACAGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGAC AAATACATTTTACAAGGAGT%?C'TTCTTGGGGTCTTGGCTGTGCACGCCCCAATAAGCCTG GTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGTGATGAGAAATAATTG Sequence 55: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG6.1 with the codons for the Kex2 cleavage site and the Stel3 cleavage sites and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC 60 GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC TCGAGAAAAGAGAGGCTGAAGCTCTTTACGACTACTGTGATGTCCCTCAGTGTGCGGCCCC TTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTGGGG GGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTGGAA TGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTGCTT GGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCAAGAAGTGAAT CTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAAAAG ATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCAGCTTG TCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCACTGGCTGGGGA GAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCTGTGATTGAGA ATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACCGAACTCTGTGC TGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTTTGC TTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCACGCC CCAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGTGAT GAGAAATAATTGA Sequence 56: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG7.1 with the codons for the Kex2 cleavage site and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC TCGAGAAAAGAGCCCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCC TGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTT AGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGA CTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGC ACACCAAGAAGTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTG GAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACA AAGTAATCCCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTT CATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAG CTCCCTGTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAAT CCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGG AGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGGGGT CTTGGCTGTGCACGCCCCAPOTAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTTACTT GGATTGAGGGAGTGATGAGAMTAATTGA Sequence 57: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG8.3 with the codons for the Kex2 cleavage site and the Stel3 cleavage sites and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC 61 GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGQGTATCTC TCGAGAAAAGAGAGGCTGAAGCTGCCCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCC GAAGAAATGTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGG CAAGTCAGTCTTAGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAG AGTGGGTGTTGACTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGT CATCCTGGGTGCACACCAAGAAGTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCT AGGCTGTTCTTGGAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCG TCATCACTGACAAAGTAATCCCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCG GACCGAATGTTTCATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTC AAGGAAGCCCAGCTCCCTGTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATG GAAGAGTCCAATCCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCA GGGTGACAGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTC ACTTCTTGGGGTCTTGGCTGTGCACGCCCCAATAAGCCTGGTGTCTATGTTCGTGTTTCAA GGTTTGTTACTTGGATTGAGGGAGTGATGAGAAATAATTGA Sequence 58: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG9.1 with the codons for the Kex2 cleavage site and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC TCGAGAAAAGATCATTTGATTGTQGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAG GGTTGTGGGGGGGTGTGTGG CC CAC C CACATTCCTGGCC CTGGCAAGTCAGTCTTAGAACA AGGTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTG CCCACTGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCA AGAAGTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCC ACACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAA TCCCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCAC TGGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCT GTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACCG AACTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCC TCTGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGC TGTGCACGCCCCAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTG AGGGAGTGATGAGAAATAATTGA Sequence 59: Nucleic add frequence of the human micro-plasminogen gene as in ^LG10.1 with the codons for the Kex2 cleavage site and the Stel3 cleavage sites and the gene of the prepropeptide of the alpha-factor of the yeast Saccharomyces cerevisiae ATGAGATTTCCTTCAATTTTTACTGCTGTTTTATTCGCAGCATCCTCCGCATTAGCTGCTC CAGTCAACACTACAACAGAAGATGAAACGGCACAAATTCCGGCTGAAGCTGTCATCGGTTA CTCAGATTTAGAAGGGGATTTCGATGTTGCTGTTTTGCCATTTTCCAACAGCACAAATAAC GGGTTATTGTTTATAAATACTACTATTGCCAGCATTGCTGCTAAAGAAGAAGGGGTATCTC 62 TCGAGAAAAGAGAGGCTGAAGCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAA ATGTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTC AGTCTTAGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGG TGTTGACTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCTTCAT'CCTACAAGGTCATCCT GGGTGCACACCAAGAAGTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTG TTCTTGGAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCA CTGACAAAGTAATCCCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGA ATGTTTCATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAA GCCCAGCTCCCTGTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAG TCCAATCCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGA CAGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCT TGGGGTCTTGGCTGTGCACGCCCCAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTG TTACTTGGATTGAGGGAGTGATGAGAAATAATTGA Sequence 60: Nucleic acid sequence of the human mini-plasminogen gene as in pPLGl.l and pPLG2.1 GCACCTCCGCCTGTTGTCCTGCTTCCAGATGTAGAGACTCCTTCCGAAGAAGACTGTATG TTTGGGAATGGGAAAGGATACCGAGGCAAGAGGGCGACCACTGTTACTGGGACGCCATGC CAGGACTGGGCTGCCCAGGAGCCCCATAGACACAGCATTTTCACTCCAGAGACAAATCCA CGGGCGGGTCTGGAAAAAAATTACTGCCGTAACCCTGATGGTGATGTAGGTGGTCCCTGG TGCTACACGACAAATCCAAGAAAACTTTACGACTACTGTGATGTCCCTCAGTGTGCGGCC CCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTG GGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTT GGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCAC TGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCAAGAA GTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACA CGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATC CCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCACT GGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCT GTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACC GAACTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGT CCTCTGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGGGGTCTT GGCTGTGCACGCCCCAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGG ATTGAGGGAGTGATGAGAAATAATTGA Sequence 61: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG3.2 and pPLG4.2 AAACTTTACGACTACTG?G^TGTCCCTCAGTGTGCGGCCCCTTCATTTGATTGTGGGAAGC CTCAAGTGGAGCCGAAGAA^^TCCTGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACA TTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACC TTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCTT CATCCTACAAGGTCATCCTGGGTGCACACCAAGAAGTGAATCTCGAACCGCATGTTCAGGA AATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTA AGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCAGCTTGTCTGCCATCCCCAAATTATG 63 TGGTCGCTGACCGGACCGAATGTTTCATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGG AGCTGGCCTTCTCAAGGAAGCCCAGCTCCCTGTGATTQAGAATAAAGTGTGCAATCGCTAT GAGTTTCTGAATGGAAGAGTCCAATCCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCA CTGACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACAT TTTACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCACGCCCCAATAAGCCTGGTGTCTAT GTTCGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGTGATGAGAAATAATTGA Sequence 62: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG5.3 and pPLG6.1 CTTTACGACTACTGTGATGTCCCTCAGTGTGCGGCCCCTTCATTTGATTGTGGGAAGCCTC AAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACATTC CTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACCTTG ATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCTTCAT CCTACAAGGTCATCCTGGGTGCACACCAAGAAGTGAATCTCGAACCGCATGTTCAGGAAAT AGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTAAGC AGTCCTGCCGTCATCACTGACAAAGTAATCCCAGCTTGTCTGCCATCCCCAAATTATGTGG TCGCTGACCGGACCGAATGTTTCATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGGAGC TGGCCTTCTCAAGGAAGCCCAGCTCCCTGTGATTGAGAATAAAGTGTGCAATCGCTATGAG TTTCTGAATGGAAGAGTCCAATCCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCACTG ACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACATTTT ACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCACGCCCCAATAAGCCTGGTGTCTATGTT CGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGTGATGAGAAATAATTGA Sequence 63: Nucleic acid sequence of the human micro-plasminogen gene as in pPLG7.1 and pPLG8.3 GCCCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTG TGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTT TGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCAC TGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCAAGAAG TGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACG AAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCA GCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCACTGGCT GGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCTGTGAT TGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACCGAACTC TGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGG nTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGC ACGCCCCAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTGAGGGA GTGATGAGAAATAATTGA Sequence 64: Nucleic acidAsequence of the human micro-plasminogen gene as in^P&GS.I and pPLGIO.l TCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGAAGGGTTGTGGGGG GGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGAACAAGGTTTGGAAT 64 GCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACTGCTGCCCACTGCTTG GAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCACACCAAGAAGTGAATC TCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTGGAGCCCACACGAAAAGA TATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGACAAAGTAATCCCAGCTTGT CTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGTTTCATCACTGGCTGGGGAG AAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCCCAGCTCCCTGTGATTGAGAA TAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTCCAATCCACCGAACTCTGTGCT GGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGACAGTGGAGGTCCTCTGGTTTGCT TCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCTTGGGGTCTTGGCTGTGCACGCCC CAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTTGTTACTTGGATTGAGGGAGTGATG AGAAATAATTGA Sequence 65: Nucleic acid sequence of the human Glu-plasminogen gene GAGCCTCTGGATGACTATGTGAATACCCAGGGGGCTTCACTGTTCAGTGTCACTAAGAAG CAGCTGGGAGCAGGAAGTATAGAAGAATGTGCAGCAAAATGTGAGGAGGACGAAGAATTC ACCTGCAGGGCATTCCAATATCACAGTAAAGAGCAACAATGTGTGATAATGGCTGAAAAC AGGAAGTCCTCCATAATCATTAGGATGAGAGATGTAGTTTTATTTGAAAAGAAAGTGTAT CTCTCAGAGTGCAAGACTGGGAATGGAAAGAACTACAGAGGGACGATGTCCAAAACAAAA AATGGCAT CAC CTGTCAAAAATGGAGTTCCACTTC TCC CCACAGACCTAGATTCTCACCT GCTACACACCCCTCAGAGGGACTGGAGGAGAACTACTGCAGGAATCCAGACAACGATCCG CAGGGGCCCTGGTGCTATACTACTGATCCAGAAAAGAGATATGACTACTGCGACATTCTT GAGTGTGAAGAGGAATGTATGCATTGCAGTGGAGAAAACTATGACGGCAAAATTTCCAAG ACCATGTCTGGACTGGAATGCCAGGCCTGGGACTCTCAGAGCCCACACGCTCATGGATAC ATTCCTTCCAAATTTCCAAACAAGAACCTGAAGAAGAATTACTGTCGTAACCCCGATAGG GAGCTGCGGCCTTGGTGTTTCACCACCGACCCCAACAAGCGCTGGGAACTTTGCGACATC CCCCGCTGCACAACACCTCCACCATCTTCTGGTCCCACCTACCAGTGTCTGAAGGGAACA GGTGAAAACTATCGCGGGAATGTGGCTGTTACCGTTTCCGGGCACACCTGTCAGCACTGG AGTGCACAGACCCCTCACACACATAACAGGACACCAGAAAACTTCCCCTGCAAAAATTTG GATGAAAACTACTGCCGCAATCCTGACGGAAAAAGGGCCCCATGGTGCCATACAACCAAC AGCCAAGTGCGGTGGGAGTACTGTAAGATACCGTCCTGTGACTCCTCCCCAGTATCCACG GAACAATTGGCTCCCACAGCACCACCTGAGCTAACCCCTGTGGTCCAGGACTGCTACCAT GGTGATGGACAGAGCTACCGAGGCACATCCTCCACCACCACCACAGGAAAGAAGTGTCAG TCTTGGTCATCTATGACACCACACCGGCACCAGAAGACCCCAGAAAACTACCCAAATGCT GGCCTGACAATGAACTACTGCAGGAATCCAGATGCCGATAAAGGCCCCTGGTGTTTTACC ACAGACCCCAGCGTCAGGTGGGAGTACTGCAACCTGAAAAAATGCTCAGGAACAGAAGCG AGTGTTGTAGCACCTCCGCCTGTTGTCCTGCTTCCAGATGTAGAGACTCCTTCCGAAGAA GACTGTATGTTTGGGAATGGGAAAGGATACCGAGGCAAGAGGGCGACCACTGTTACTGGG ACGCCATGCCAGGACTGGGCTGCCCAGGAGCCCCATAGACACAGCATTTTCACTCCAGAG ACAAATCCACGGGCGGGTCTGGAAAAAAATTACTGCCGTAACCCTGATGGTGATGTAGGT GGTCCCTGGTGCTACACGACAAATCCAAGAAAACTTTACGACTACTGTGATGTCCCTCAG TGTGCGGCCCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAATGTCCTGGA AGGGTTGTGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTCAGTCTTAGA ACAAGGTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGGGTGTTGACT GCTGCCCACTGCTTGGAGA^TCCCCAAGGCCTTCATCCTACAAGGTCATCCTGGGTGCA CACCAAGAAGTGAATCT^GSftCCGCATGTTCAGGAAATAGAAGTGTCTAGGCTGTTCTTG GAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTCATCACTGAC 65 AAAGTAATCCCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGGACCGAATGT TTCATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTCAAGGAAGCC CAGCTCCCTGTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAATGGAAGAGTC CAATCCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGCCAGGGTGAC AGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGAGTCACTTCT TGGGGTCTTGGCTGTGCACGCCCCAATAAGCCTGGTGTCTATGTTCGTGTTTCAAGGTTT GTTACTTGGATTGAGGGAGTGATGAGAAATAATTGA Sequence 66: Nucleic acid sequence of the human Lys-plasminogen gene AAAGTGTATCTCTCAGAGTGCAAGACTGGGAATGGAAAGAACTACAGAGGGACGATGTCC AAAACAAAAAATGGCATCACCTGTCAAAAATGGAGTTCCACTTCTCCCCACAGACCTAGA TTCTCACCTGCTACACACCCCTCAGAGGGACTGGAGGAGAACTACTGCAGGAATCCAGAC AACGATCCGCAGGGGCCCTGGTGCTATACTACTGATCCAGAAAAGAGATATGACTACTGC GACATTCTTGAGTGTGAAGAGGAATGTATGCATTGCAGTGGAGAAAACTATGACGGCAAA ATTTCCAAGACCATGTCTGGACTGGAATGCCAGGCCTGGGACTCTCAGAGCCCACACGCT CATGGATACATTCCTTCCAAATTTCCAAACAAGAACCTGAAGAAGAATTACTGTCGTAAC CCCGATAOGGAGCTGCGGCCTTGGTGTTTCACCACCGACCCCAACAAGCGCTGGGAACTT TGCGACATCCCCCGCTGCACAACACCTCCACCATCTTCTGGTCCCACCTACCAGTGTCTG AAGGGAACAGGTGAAAACTATCGCGGGAATGTGGCTGTTACCGTTTCCGGGCACACCTGT CAGCACTGGAGTGCACAGACCCCTCACACACATAACAGGACACCAGAAAACTTCCCCTGC AAAAATTTGGATGAAAACTACTGC CGCAATC CTGACGGAAAAAGGGC CCCATGGTGC CAT ACAACCAACAGCCAAGTGCGGTGGGAGTACTGTAAGATACCGTCCTGTGACTCCTCCCCA GTATCCACGGAACAATTGGCTCCCACAGCACCACCTGAGCTAACCCCTGTGGTCCAGGAC TGCTACCATGGTGATGGACAGAGCTACCGAGGCACATCCTCCACCACCACCACAGGAAAG AAGTGTCAGTCTTGGTCATCTATGACACCACACCGGCACCAGAAGACCCCAGAAAACTAC CCAAATGCTGGCCTGACAATGAACTACTGCAGGAATCCAGATGCCGATAAAGGCCCCTGG TGTTTTACCACAGACCCCAGCGTCAGGTGGGAGTACTGCAACCTGAAAAAATGCTCAGGA ACAGAAGCGAGTGTTGTAGCACCTCCGCCTGTTGTCCTGCTTCCAGATGTAGAGACTCCT TCCGAAGAAGACTGTATGTTTGGGAATGGGAAAGGATACCGAGGCAAGAGGGCGACCACT GTTACTGGGACGCCATGCCAGGACTGGGCTGCCCAGGAGCCCCATAGACACAGCATTTTC ACTCCAGAGACAAATCCACGGGCGGGTCTGGAAAAAAATTACTGCCGTAACCCTGATGGT GATGTAGGTGGTCCCTGGTGCTACACGACAAATCCAAGAAAACTTTACGACTACTGTGAT GTCCCTCAGTGTGCGGCCCCTTCATTTGATTGTGGGAAGCCTCAAGTGGAGCCGAAGAAA TGTCCTGGAAGGGTTGTGGGGGGGTGTGTGGCCCACCCACATTCCTGGCCCTGGCAAGTC AGTCTTAGAACAAGGTTTGGAATGCACTTCTGTGGAGGCACCTTGATATCCCCAGAGTGG GTGTTGACTGCTGCCCACTGCTTGGAGAAGTCCCCAAGGCCTTCATCCTACAAGGTCATC CTGGGTGCACACCAAGAAGTGAATCTCGAACCGCATGTTCAGGAAATAGAAGTGTCTAGG CTGTTCTTGGAGCCCACACGAAAAGATATTGCCTTGCTAAAGCTAAGCAGTCCTGCCGTC ATCACTGACAAAGTAATCCCAGCTTGTCTGCCATCCCCAAATTATGTGGTCGCTGACCGG ACCGAATGTTTCATCACTGGCTGGGGAGAAACCCAAGGTACTTTTGGAGCTGGCCTTCTC AAGGAAGCCCAGCTCCCTGTGATTGAGAATAAAGTGTGCAATCGCTATGAGTTTCTGAAT GGAAGAGTCCAATCCACCGAACTCTGTGCTGGGCATTTGGCCGGAGGCACTGACAGTTGC CAGGGTGACAGTGGAGGTCCTCTGGTTTGCTTCGAGAAGGACAAATACATTTTACAAGGA GTCACTTCTTGGGGTCTTGGCTGTGCACGCCCCAATAAGCCTGGTGTCTATGTTCGTGTT TCAAGGTTTGTTACTTGGATTGAGGGAGTGATGAGAAATAATTGA 66 Bibliography (1) = Desire Collen, Thrombosis and Haemosfasis. 82,1999 (2) = Forsgren et al., FEBS Lett. 213.1987 (3) = Petersen et a!., J. Biol. Chem.. 265,1990 (4) = Duman et al., Biotechnol. Appl. Biochem. 28; 39-45,1998 (5) = Guan et al., Sheng Wu Gong Cheng Xue Bao, 17, 2001 (6) = Gonzalez-Gronow et al., Biochimica et Biophysica Acta, 1039,1990 (7) = Whitefleet-Smith etal., Arch. Biochem. Biophys., 271,1989 (8) = Nilsen und Castellino, Protein Expression and Purification, 16,1999 (9) = Busby et al. J. Biol. Chem., 266,1991 (10) = Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor press, 1989 (11) = Gassen & Schrimpf, Gentechnische Methoden, Spektrum Akademischer Verlag, Heidelberg, 1999 (12) = Malinowski et al, Biochemistry, 23,1984 (13) = Stack et al., Biochem. J. 284.1992 67 WE CLAIM: 1. A method for production of dressing materials, plasters or for use in vulnery drugs comprising incorporating a functional plasminogen produced in microorganisms wherein said functional plasminogen is produced by steps of: a) Fusing a nucleic acid of sequence coding for at least the functional part of the plasminogen with a nucleic acid sequence coding for at least one signal peptide, where in functional part of the plasminogen comprises the proteolytic domain of plasminogen or a mutant or a fragment thereof, which codes for at least 20 mg/1 of functional Glu- or Lys-plasminogen, wherein said nucleic acid sequence coding for the functional plasminogen and the nucleic acid sequence coding for at least the signal peptide being coupled with codons for cleavage sites of proteases providing for the cleavage of the signal peptide; b) incorporating the fusion product of step a) into an expression vector being suitable for microorganism like fungi comprises inducible or constitutive promoter like GPA-promoter from P. Pastoris; and c) transforming a host accounted to the microorganisms with thus obtained nucleic acid, which is a plasmid preferably selected from the group pPLG11.2, pPLG12.1, pPLG13.1, pPLG14.2, pPLG15.1, PPLGl6.3, pPLG17.2, pPLG18.1, pPLG19.2, pPLG20.1, pAC37.1, pJW9.1, pMHS476.1, pSM54.2, pSM49.8, pSM82.1, and pSM58.1. 2. Method for production of dressing materials, plasters or for use in vulnery drugs as claimed in claim 1, wherein the nucleic acid sequence coding for at least one signal peptide codes for a prepropeptide, a prepeptide or a propeptide and/or wherein the codons code for cleavage sites of proteases for the protease Kex2 and/or Stel3. 3. Method for production of dressing materials, plasters or for use in vulnery drugs as claimed in claim 2, wherein the nucleic acid molecule coding for at least one signal peptide 68 SEQUENCE PROTOCOL Trommsdorff GmPH & Co. KG Arzneimittel Method of production of recombinant proteins in microorganisms TRD-P01057WO EP 02 00:2 716.5 2002-02-06 US 60/357,809 2002-02-21 66 Patentln Ver. 2.1 1 33 DNA Homo sapiens 1 aaaaaccgcg gtcaattatt tctcatcact ccc 33 2 37 DNA Homo sapiens 2 aaaaactcga gaaaagaaaa gtgtatctct cagagtg 3 49 DNA Homo sapiens 3 aaaaactcga gaaaagagag gctgaagcta aagtgtatct ctcagagtg 4 32 DNA Homo sapiens 4 aaaaattcga aaaatggaac ataaggaagt gg 5 35 76 DNA Homo sapiens 5 aaaaactcga gaaaagagag cctctggatg 6 47 DNA Homo sapiens 6 aaaaactcga gaaaagagag gctgaagctg 7 2400 DNA Homo sapiens 7 atgagatttc cttcaatttt tactgctgtt ccagtcaaca ctacaacaga agatgaaacg tactcagatt tagaagggga tttcgatgtt aacgggttat tgtttataaa tactactatt tctctcgaga aaagaaaagt gtatctctca agagggacga tgtccaaaac aaaaaatggc ccccacagac ctagattctc acctgctaca tgcaggaatc cagacaacga tccgcagggg agatatgact actgcgacat tcttgagtgt aactatgacg gcaaaatttc caagaccatg cagagcccac acgctcatgg atacattcct aattactgtc gtaaccccga tagggagctg aagcgctggg aactttgcga catcccccgc acctaccagt gtctgaaggg aacaggtgaa tccgggcaca cctgtcagca ctggagtgca gaaaacttcc cctgcaaaaa tttggatgaa gccccatggt gccatacaac caacagccaa tgtgactcct ccccagtatc cacggaacaa cctgtggtcc aggactgcta ccatggtgat accaccacag gaaagaagtg tcagtcttgg accccagaaa actacccaaa tgctggcctg gataaaggcc cctggtgttt taccacagac aaaaaatgct caggaacaga agcgagtgtt gatgtagaga ctccttccga agaagactgt aagagggcga ccactgttac tgggacgcca agacacagca ttttcactcc agagacaaat cgtaaccctg atggtgatgt aggtggtccc tacgactact gtgatgtccc tcagtgtgcg gtggagccga agaaatgtcc tggaagggtt tggccctggc aagtcagtct tagaacaagg atatccccag agtgggtgtt gactgctgcc tcctacaagg tcatcctggg tgcacaccaa atagaagtgt ctaggctgtt cttggagccc agcagccctg ccgtcatcac cgacaaagta gtggtcgctg accggaccga atgtCtcatc gqaqctqqcc r.tcticaaqqa aqcccagctc actat 35 agcctctgga tgactat 47 Ctattcgcag catcctccgc attagctgct 60 gcacaaattc cggctgaagc tgtcatcggt 120 gctgttttgc cattttccaa cagcacaaat 180 gccagcattg ctgctaaaga agaaggggta 240 gagtgcaaga ctgggaatgg aaagaactac 300 atcacctgtc aaaaatggag ttccacttct 360 cacccctcag agggactgga ggagaactac 420 ccctggtgct atactactga tccagaaaag 480 gaagaggaat gtatgcattg cagtggagaa 540 tctggactgg aatgccaggc ctgggactct 600 tccaaatttc caaacaagaa cctgaagaag 660 cggccttggt gtttcaccac cgaccccaac 720 tgcacaacac ctccaccatc ttctggtccc 780 aactatcgcg ggaatgtggc tgttaccgtt 840 cagacccctc acacacaCaa caggacacca 900 aactactgcc gcaatcctga cggaaaaagg 960 gtgcggtggg agtactgtaa gataccgtcc 1020 ttggctccca cagcaccacc tgagctaacc 1080 ggacagagct accgaggcac atcctccacc 114 0 tcatctatga caccacaccg gcaccagaag 1200 acaatgaact actgcaggaa tccagatgcc 1260 cccagcgtca ggtgggagta ctgcaacctg 1320 gtagcacctc cgcctgttgt cctgcttcca 1380 atgtttggga atgggaaagg ataccgaggc 144 0 tgccaggact gggctgccca ggagccccat 1500 ccacgggcgg gtctggaaaa aaattactgc 1560 tggtgctaca cgacaaatcc aagaaaactt 1620 gccccttcat ttgattgtgg gaagcctcaa 1680 gtgggggggt gtgtggccca cccacattcc 174 0 tttggaatgc acttctgtgg aggcaccttg 1800 cactgcttgg agaagtcccc aaggccttca 1860 gaagcgaatc tcgaaccgca tgttcaggaa 1920 acacgaaaag atattgcctt gctaaagcta 1980 atcccagctt gtctgccatc cccaaactat 2040 actggctggg gagaaaccca aggtactttt 2100 cctgcgattq agaataaagt gtgcaaccgc 2160 77 ggcactgaca gttgccaggg tgacagcgga ggtcctctgg tttgcttcga gaaggacaaa 2280 tacattttac aaggagtcac ttcttggggt cttggctgtg cacgccccaa taagcctggt 2340 gtctatgttc gtgtttcaag gtttgttact tggattgagg gagtgatgag aaataattga 2400 8 799 PRT Homo sapiens 8 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser l 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 Ile Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe rle Asn Thr Thr rle Ala Ser rle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Lys Val Tyr Leu Ser Glu Cys Lys Thr Gly Asn 85 90 95 Gly Lys Asn Tyr Arg Gly Thr Met Ser Lys Thr Lys Asn Gly rle Thr 100 105 110 Cys Gln Lys Trp Ser Ser Thr Ser Pro His Arg Pro Arg Phe Ser Pro 115 120 125 Ala Thr His Pro Ser Glu Gly Leu Glu Glu Asn Tyr Cys Arg Asn Pro 130 135 140 Asp Asn Asp Pro Gln Gly Pro Trp Cys Tyr Thr Thr Asp Pro Glu Lys 145 150 155 160 Arg Tyr Asp Tyr Cys Asp rle Leu Glu Cys Glu Glu Glu Cys Met His 165 170 175 Cys Ser Gly Glu Asn Tyr Asp Gly Lys rle Ser Lys Thr Met Ser Gly 180 185 190 Leu Glu Cys Gln Ala Trp Asp Ser Gln Ser Pro His Ala His Gly Tyr 195 200 205 He Pro Ser Lys Phe Pro Asn Lys Asn Leu Lys Lys Asn Tyr Cys Arg 210 215 220 Asn Pro Asp Arg Glu Leu Arg Pro Trp Cys Phe Thr Thr Asp Pro Asn 225 230 235 240 Lys Arg Trp Glu Leu Cys Asp rle Pro Arg Cys Thr Thr Pro Pro Pro 245 250 255 78 Ser Ser Gly Pro 260 Arg Gly Asn Val 275 Ser Ala Gln Thr 290 Cys Lys Asn Leu 305 Ala Pro Trp Cys Lys Ile Pro Ser 340 Pro Thr Ala Pro 355 Gly Asp Gly Gln 370 Lys Lys Cys Gln 385 Thr Pro Glu Asn Asn Pro Asp Ala 420 Val Arg Trp Glu 435 Ser Val val Ala 450 Pro Ser Glu Glu 465 Lys Arg Ala Thr Gln Glu Pro His 500 Ala Gly Leu Glu 515 Gly Pro Trp Cys 530 Asp Val Pro Gln 545 Val Glu Pro Lys Thr Tyr Gln Cys Ala Val Thr Val 280 Pro His Thr His 295 Asp Glu Asn Tyr 310 His Thr Thr Asn 325 Cys Asp Ser Ser Pro Glu Leu Thr 360 Ser Tyr Arg Gly 375 Ser Trp Ser Ser 390 Tyr Pro Asn Ala 405 Asp Lys Gly Pro Tyr Cys Asn Leu 440 Pro Pro Pro Val 455 Asp Cys Met Phe 470 Thr Val Thr Gly 485 Arg His Ser Ile Lys Asn Tyr Cys 520 Tyr Thr Thr Asn 535 Cys Ala Ala Pro 550 Lys Cys Pro Gly 5 6 5 Leu Lys Gly Thr 265 Ser Gly His Thr Asn Arg Thr Pro 300 Cys Arg Asn Pro 315 Ser Gln Val Arg 330 Pro Val Ser Thr 345 Pro Val Val Gln Thr Ser Ser Thr 380 Met Thr Pro His 395 Gly Leu Thr Met 410 Trp Cys Phe Thr 425 Lys Lys Cys Ser Val Leu Leu Pro 460 Gly Asn Gly Lys 475 Thr Pro Cys Gln 490 Phe Thr Pro Glu 505 Arg Asn Pro Asp Pro Arg Lys Leu 540 Ser Phe Asp Cys 555 Arg VAL Val Gly 57 0 Gly Glu Asn Tyr 270 Cys Gln His Trp 285 Glu Asn Phe Pro Asp Gly Lys Arg 320 Trp Glu Tyr Cys 335 Glu Gln Leu Ala 350 Asp Cys Tyr His 365 Thr Thr Thr Gly Arg His Gln Lys 400 Asn Tyr Cys Arg 415 Thr Asp Pro Ser 430 Gly Thr Glu Ala 445 Asp Val Glu Thr Gly Tyr Arg Gly 480 Asp Trp Ala Ala 495 Thr Asn Pro Arg 510 Gly Asp Val Gly 525 Tyr Asp Tyr Cys Gly Lys Pro Gin 560 Gly Cys Val Ala 575 79 His Pro His Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly 580 585 590 Met His Phe Cys Gly Gly Thr Leu lle Ser Pro Glu Trp Val Leu Thr 595 600 605 Ala Ala Hls Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val 610 615 620 lle Leu Gly Ala His Gln Glu Val Asn Leu Glu Pro His Val Gln Glu 625 630 635 640 lle Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp lle Ala 645 650 655 Leu Leu Lys Leu Ser Ser Pro Ala Val lle Thr Asp Lys Val lle Pro 660 665 670 Ala Cys Leu Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys 675 680 685 Phe lle Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu 690 695 700 Leu Lys Glu Ala Gln Leu Pro Val lle Glu Asn Lys Val Cys Asn Arg 705 710 715 720 Tyr Glu Phe Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly 725 730 735 His Leu Ala Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro 740 745 750 Leu Val Cys Phe Glu Lys Asp Lys Tyr lle Leu Gln Gly Val Thr Ser 7S5 760 765 Trp Gly Leu Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg 770 775 780 Val Ser Arg Phe Val Thr Trp lle Glu Gly Val Met Arg Asn Asn 785 790 795 9 2412 DNA Homo sapiens 9 atgagatttc cttcaatttt tactgctgtt ttattcgcag catcctccgc attagctgct 60 ccagtcaaca ctacaacaga agatgaaacg gcacaaattc cggctgaagc tgtcatcggt 120 tactcagatt tagaagggga tttcgatgtt gctgttttgc cattttccaa cagcacaaat 180 aacgggttat tgtttataaa tactactatt gccagcattg ctgctaaaga agaaggggta 240 tctctcgaga aaagagaggc cgaagctaaa gtgtatctct cagagtgcaa gactgggaat 300 ggaaagaact acagagggac gatgtccaaa acaaaaaatg gcatcacctg tcaaaaatgg 360 agttccactt ccccccacag acctagattc tcacctgcta cacacccctc agagggactg 420 gaggagaact actgcaqqaa tccaqacaac qar.ccqcaqq qqccctqqtq ctatactact 480 80 tgcagtggag aaaactatga cggcaaaatt tccaagacca tgtctggact ggaatgccag 600 gcctgggact ctcagagccc acacgctcat ggatacattc cttccaaatt tccaaacaag 660 aacctgaaga agaattactg tcgtaacccc gatagggagc tgcggccttg gtgtttcacc 720 accgacccca acaagcgctg ggaactttgc gacatccccc gctgcacaac acctccacca 780 tcttctggtc ccacctacca gtgtctgaag ggaacaggtg aaaactatcg cgggaatgtg 840 gctgttaccg tttccgggca cacctgtcag cactggagtg cacagacccc tcacacacat 900 aacaggacac cagaaaactt cccctgcaaa aatttggatg aaaactactg ccgcaatcct 960 gacggaaaaa gggccccatg gcgccacaca accaacagcc aagtgcggtg ggagtactgt 1020 aagataccgt cctgtgactc ctccccagta tccacggaac aattggctcc cacagcacca 1080 cctgagctaa cccctgtggt ccaggactgc taccatggtg atggacagag ctaccgaggc 114 0 acatcctcca ccaccaccac aggaaagaag tgtcagtctt ggtcatctat gacaccacac 1200 cggcaccaga agaccccaga aaactaccca aatgctggcc tgacaatgaa ctactgcagg 1260 aatccagatg ccgataaagg cccctggtgt tttaccacag accccagcgt caggtgggag 1320 tactgcaacc tgaaaaaatg ctcaggaaca gaagcgagtg ttgtagcacc tccgcctgtt 1380 gtcctgcttc cagatgtaga gactccttcc gaagaagact gtatgtttgg gaatgggaaa 1440 ggataccgag gcaagagggc gaccactgtt actgggacgc catgccagga ctgggctgcc 1500 caggagcccc atagacacag cattttcact ccagagacaa atccacgggc gggtctggaa 1560 aaaaattact gccgtaaccc tgatggtgat gtaggtggtc cctggtgcta cacgacaaat 1620 ccaagaaaac tttacgacta ctgtgatgtc cctcagtgtg cggccccttc atttgattgt 1680 gggaagcctc aagtggagcc gaagaaatgt cctggaaggg ttgtgggggg gtgtgtggcc 1740 cacccacatt cctggccctg gcaagtcagt cttagaacaa ggtttggaat gcacttctgt 1800 ggaggcacct tgatatcccc agagtgggtg ttgactgctg cccactgctt ggagaagtcc 1860 ccaaggcctt catcctacaa ggtcatcctg ggtgcacacc aagaagtgaa tctcgaaccg 1920 catgttcagg aaatagaagt gtctaggctg ttcttggagc ccacacgaaa agatattgcc 1980 ttgctaaagc taagcagtcc tgccgtcatc actgacaaag taatcccagc ttgtctgcca 204 0 tccccaaatt atgtggtcgc tgaccggacc gaatgtttca tcactggctg gggagaaacc 2100 caaggtactt ttggagctgg ccttctcaag gaagcccagc tccctgtgat tgagaataaa 2160 gtgtgcaatc gctatgagtt tctgaatgga agagtccaat ccaccgaact ctgtgctggg 2220 catttggccg gaggcactga cagttgccag ggtgacagtg gaggtcctct ggtttgcttc 2280 gagaaggaca aatacatttt acaaggagtc acttcttggg gtcttggctg tgcacgcccc 2340 aataagcctg gtgtctatgt tcgtgtttca aggtttgtta cttggattga gggagtgatg 2400 agaaataatt ga 2412 10 803 PRT Homo sapiens 10 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 81 Ser Leu Glu Lys Arg Glu Ala Glu Ala Lys Val Tyr Leu Ser Glu Cys 85 90 95 100 105 110 Asn Gly lle Thr 115 Arg Phe Ser Pro 130 Cys Arg Asn Pro 145 Asp Pro Glu Lys Glu Cys Met His 180 Thr Met Ser Gly 195 Ala His Gly Tyr 210 Asn Tyr Cys Arg 225 Thr Asp Pro Asn Thr Pro Pro Pro 260 Gly Glu Asn Tyr 275 Cys Gln His Trp 290 Glu Asn Phe Pro 305 Asp Gly Lys Arg Trp Glu Tyr Cys 340 Glu Gln Leu Ala 355 Asp Cys Tyr His 370 Thr Thr Thr Gly 385 Arg H1s Gln Lys Cys Gln Lys Trp 120 Ala Thr His Pro 135 Asp Asn Asp Pro 150 Arg Tyr Asp Tyr 165 Cys Ser Gly Glu Leu Glu Cys Gln 200 lle Pro Ser Lys 215 Asn Pro Asp Arg 230 Lys Arg Trp Glu 245 Ser Ser Gly Pro Arg Gly Asn Val 280 Ser Ala Gln Thr 295 Cys Lys Asn Leu 310 Ala Pro Trp Cys 325 Lys lle Pro Ser Pro Thr Ala Pro 360 Gly Asp Gly Gln 375 Lys Lys Cys Gln 390 Thr Pro Glu Asn 405 Ser Ser Thr Ser Ser Glu Gly Leu 140 Gln Gly Pro Trp 155 Cys Asp lle Leu 170 Asn Tyr Asp Gly 185 Ala Trp Asp Ser Phe Pro Asn Lys 220 Glu Leu Arg Pro 235 Leu Cys Asp lle 250 Thr Tyr Gln Cys 265 Ala Val Thr Val Pro His Thr His 300 Asp Glu Asn Tyr 315 His Thr Thr Asn 330 Cys Asp Ser Ser 345 Pro Glu Leu Thr Ser Tyr Arg Gly 380 Ser Trp Ser Ser 395 Tyr Pro Asn Ala 410 Pro His Arg Pro 125 Glu Glu Asn Tyr Cys Tyr Thr Thr 160 Glu Cys Glu Glu 175 Lys lle Ser Lys 190 Gln Ser Pro His 205 Asn Leu Lys Lys Trp Cys Phe Thr 240 Pro Arg Cys Thr 255 Leu Lys Gly Thr 270 Ser Gly His Thr 285 Asn Arg Thr Pro Cys Arg Asn Pro 320 Ser Gln Val Arg 335 Pro Val Ser Thr 350 Pro Val Val Gln 365 Thr Ser Ser Thr Met Thr Pro His 400 Gly Leu Thr Mot 415 82- Asn Tyr Cys Arg 420 Thr Asp Pro Ser 435 Gly Thr Glu Ala 450 Asp Val Glu Thr 465 Gly Tyr Arg Gly Asp Trp Ala Ala 500 Thr Asn Pro Arg 515 Gly Asp Val Gly 530 Tyr Asp Tyr Cys 545 Gly Lys Pro Gln Gly Cys Val Ala 580 Thr Arg Phe Gly 595 Trp Val Leu Thr 610 Ser Tyr Lys Val 625 His Val Gln Glu Lys Asp lle Ala 660 Lys Val lle Pro 675 Arg Thr Glu Cys 690 Gly Ala Gly Leu 705 Val Cys Asn Arg Asn Pro Asp Ala Val Arg Trp Glu 440 Ser Val Val Ala 455 Pro Ser Glu Glu 470 Lys Arg Ala Thr 485 Gln Glu Pro His Ala Gly Leu Glu 520 Gly Pro Trp Cys 535 Asp Val Pro Gln 550 Val Glu Pro Lys 565 His Pro His Ser Met His Phe Cys 600 Ala Ala His Cys 615 lle Leu Gly Ala 630 lle Glu Val Ser 645 Leu Leu Lys Leu Ala Cys Leu Pro 680 Phe lle Thr Gly 695 Leu Lys Glu Ala 710 Tyr Glu Phe Lr-u 725 Asp Lys Gly Pro 425 Tyr Cys Asn Leu Pro Pro Pro Val 460 Asp Cys Met Phe 475 Thr Val Thr Gly 490 Arg His Ser lle 505 Lys Asn Tyr Cys Tyr Thr Thr Asn 540 Cys Ala Ala Pro 555 Lys Cys Pro Gly 570 Trp Pro Trp Gln 585 Gly Gly Thr Leu Leu Glu Lys Ser 620 His Gln Glu Val 635 Arg Leu Phe Leu 650 Ser Ser Pro Ala 665 Ser Pro Asn Tyr Trp Gly Glu Thr 700 Gln Leu Pro Val 715 Asn Gly Arq Val 710 Trp Cys Phe Thr 430 Lys Lys Cys Ser 445 Val Leu Leu Pro Gly Asn Gly Lys 480 Thr Pro Cys Gln 495 Phe Thr Pro Glu 510 Arg Asn Pro Asp 525 Pro Arg Lys Leu Ser Phe Asp Cys 560 Arg Val Val Gly 575 Val Ser Leu Arg 590 lle Ser Pro Glu 605 Pro Arg Pro Ser Asn Leu Glu Pro 640 Glu Pro Thr Arg 655 Val He Thr Asp 670 Val Val Ala Asp 685 Gln Gly Thr Phe lle Glu Asn Lys 720 Gln Ser Thr Glu 735 83 11 2433 DNA Homo sapiens 11 atggaacata aggaagtggt tcttctactt cttttatttc tgaaatcagg tcaaggagag 60 cctctggatg actatgtgaa tacccagggg gcttcactgt tcagtgtcac taagaagcag 120 ctgggagcag gaagtataga agaatgtgca gcaaaatgtg aggaggacga agaattcacc 180 tgcagggcat tccaatatca cagtaaagag caacaatgtg tgataatggc tgaaaacagg 240 aagtcctcca taatcattag gatgagagat gtagttttat ttgaaaagaa agtgtatctc 300 tcagagtgca agactgggaa tggaaagaac tacagaggga cgatgtccaa aacaaaaaat 360 ggcatcacct gtcaaaaatg gagttccact tctccccaca gacctagatt ctcacctgct 420 acacacccct cagagggact ggaggagaac tactgcagga atccagacaa cgatccgcag 480 gggccctggt gctatactac tgatccagaa aagagatatg actactgcga cattcttgag 540 tgtgaagagg aatgtatgca ttgcagtgga gaaaactatg acggcaaaat ttccaagacc 600 atgtctggac tggaatgcca ggcctgggac tctcagagcc cacacgctca tggatacatt 660 ccttccaaat ttccaaacaa gaacctgaag aagaattact gtcgtaaccc cgatagggag 720 ctgcggcctt ggtgtttcac caccgacccc aacaagcgct gggaacttcg cgacatcccc 780 cgctgcacaa cacctccacc atcttctggt cccacctacc agtgtctgaa gggaacaggt 840 gaaaactatc gcgggaatgt ggctgttacc gtttccgggc acacctgtca gcactggagt 900 gcacagaccc ctcacacaca taacaggaca ccagaaaact tcccctgcaa aaatttggat 960 gaaaactact gccgcaatcc Cgacggaaaa agggccccat ggtgccatac aaccaacagc 1020 caagtgcggt gggagtactg taagataccg tcctgtgact cctccccagt atccacggaa 1080 caattggctc ccacagcacc acctgagcta acccctgtgg tccaggactg ctaccatggt 1140 gatggacaga gctaccgagg cacatcctcc accaccacca caggaaagaa gtgtcagtct 1200 tggtcatcta tgacaccaca ccggcaccag aagaccccag aaaactaccc aaatgctggc 1260 ctgacaatga actactgcaq qaatccaqat gccgataaaq gcccctqqtq ttttaccaca 1320 ctccctgtga ttgagaataa agtgtgcaat cgctatgagt ttctgaatgg aagagtccaa 2220 tccaccgaac tctgtgctgg gcatttggcc ggaggcactg acagttgcca gggtgacagt 2280 ggaggtcctc tggtttgctt cgagaaggac aaatacattt tacaaggagt cacttcttgg 2340 ggtcttggct gtgcacgccc caataagcct ggtgtctatg ttcgtgtttc aaggtttgtt 2400 acttggattg agggagtgat gagaaataat tga 2433 12 810 PRT Homo sapiens 12 Met Glu His Lys Glu Val Val Leu Leu Leu Leu Leu Phe Leu Lys Ser 1 5 10 15 Gly Gin Gly Glu Pro Leu Asp Asp Tyr Val Asn Thr Gln Gly Ala Ser 20 25 30 Leu Phe Ser Val Thr Lys Lys Gln Leu Gly Ala Gly Ser lle Glu Glu 35 40 45 Cys Ala Ala Lys Cys Glu Glu Asp Glu Glu Phe Thr Cys Arg Ala Phe 50 55 60 Gln Tyr His Ser Lys Glu Gln Gln Cys Val lle Met Ala Glu Asn Arg 65 70 75 80 Lys Ser Ser lle He lle Arg Met Arg Asp Val Val Leu Phe Glu Lys 85 90 95 Lys Val Tyr Leu Ser Glu Cys Lys Thr Gly Asn Gly Lys Asn Tyr Arg 100 105 110 Gly Thr Met Ser Lys Thr Lys Asn Gly lle Thr Cys Gln Lys Trp Ser 115 120 125 Ser Thr Ser Pro His Arg Pro Arg Phe Ser Pro Ala Thr His Pro Ser 130 135 140 Glu Gly Leu Glu Glu Asn Tyr Cys Arg Asn Pro Asp Asn Asp Pro Gin 145 150 155 160 245 250 255 Cys Asp He Pro Arg Cys Thr Thr Pro Pro Pro Ser Ser Gly Pro Thr 260 265 270 Tyr Gln Cys Leu Lys Gly Thr Gly Glu Asn Tyr Arg Gly Asn Val Ala 275 280 285 Val Thr Val Ser Gly His Thr Cys Gln His Trp Ser Ala Gln Thr Pro 290 295 300 Hls Thr His Asn Arg Thr Pro Glu Asn Phe Pro Cys Lys Asn Leu Asp 305 310 315 320 325 330 Glu Asn Tyr Cys Arg Asn Pro Asp Gly Lys Arg Ala Pro Trp Cys His 335 Thr Thr Asn Ser Gln Val Arg Trp Glu Tyr Cys Lys lle Pro Ser Cys 340 345 350 Asp Ser Ser Pro Val Ser Thr Glu Gln Leu Ala Pro Thr Ala Pro Pro 355 360 365 Glu Leu Thr Pro Val Val Gln Asp Cys Tyr His Gly Asp Gly Gln Ser 370 375 380 Tyr Arg Gly Thr Ser Ser Thr Thr Thr Thr Gly Lys Lys Cys Gln Ser 385 390 395 400 Trp Ser Ser Met Thr Pro His Arg His Gln Lys Thr Pro Glu Asn Tyr 405 410 415 Pro Asn Ala Gly Leu Thr Met Asn Tyr Cys Arg Asn Pro Asp Ala Asp 420 425 430 Lys Gly Pro Trp Cys Phe Thr Thr Asp Pro Ser Val Arg Trp Glu Tyr 435 440 445 Cys Asn Leu Lys Lys Cys Ser Gly Thr Glu Ala Ser Val Val Ala Pro 450 455 460 Pro Pro Val Val Leu Leu Pro Asp Val Glu Thr Pro Ser Glu Glu Asp 465 470 475 480 Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg Gly Lys Arg Ala Thr Thr 485 490 495 Val Thr Gly Thr Pro Cys Gln Asp Trp Ala Ala Gln Glu Pro His Arg 500 505 510 His Ser lle Phe Thr Pro Glu Thr Asn Pro Arg Ala Gly Leu Glu Lys 515 520 525 Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Cys Tyr 530 535 540 Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gin Cys 545 550 555 560 86 Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gin Val Glu Pro Lys Lys 565 570 575 Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His Ser Trp 580 585 590 Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met Hls Phe Cys Gly 595 600 605 Gly Thr Leu lle Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu 610 615 620 Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly Ala His 625 630 635 640 Gln Glu Val Asn Leu Glu Pro His Val Gln Glu lle Glu Val Ser Arg 645 650 655 Leu Phe Leu Glu Pro Thr Arg Lys Asp lle Ala Leu Leu Lys Leu Ser 660 665 670 Ser Pro Ala Val lle Thr Asp Lys Val lle Pro Ala Cys Leu Pro Ser 675 680 685 Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe lle Thr Gly Trp 690 695 700 Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln 705 710 715 720 Leu pro Val lle Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn 725 730 735 Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly 740 745 750 Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu 755 760 765 Lys Asp Lys Tyr lle Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys 770 775 780 Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val 785 790 795 800 Thr Trp He Glu Gly Val Met Arg Asn Asn 805 810 tctctcgaga aaagagagcc tctggatgac tatgtgaata cccagggggc ttcactgttc 300 agtgtcacta agaagcagcC gggagcagga agtatagaag aatgtgcagc aaaatgtgag 360 gaggacgaag aattcacctg cagggcattc caatatcaca gtaaagagca acaatgtgtg 420 ataatggctg aaaacaggaa gtcctccata atcattagga tgagagatgt agttttattt 480 gaaaagaaag tgtatctctc agagtgcaag actgggaatg gaaagaacta cagagggacg 540 atgtccaaaa caaaaaatgg catcacctgt caaaaatgga gttccacttc tccccacaga 600 cctagattct cacctgctac acacccctca gagggactgg aggagaacta ctgcaggaat 660 ccagacaacg atccgcaggg gccctggtgc tatactactg atccagaaaa gagatatgac 720 tactgcgaca ttcttgagtg tgaagaggaa tgtatgcatt gcagtggaga aaactatgac 780 ggcaaaatct ccaagaccat gtctggactg gaatgccagg cctgggactc tcagagccca 840 cacgctcatg gatacattcc ttccaaattt ccaaacaaga acctgaagaa gaattactgt 900 cgtaaccccg atagggagct gcggccttgg tgtttcacca ccgaccccaa caagcgctgg 960 gaactttgcg acatcccccg ctgcacaaca cctccaccat cttctggtcc cacctaccag 1020 tgtctgaagg gaacaggtga aaactatcgc gggaatgtgg ctgttaccgt ttccgggcac 1080 acctgtcagc actggagtgc acagacccct cacacacata acaggacacc agaaaacttc 114 0 ccctgcaaaa atttggatga aaactactgc cgcaatcctg acggaaaaag ggccccatgg 1200 tgccatacaa ccaacagcca agtgcggtgg gagtactgta agataccgtc ctgtgactcc 1260 tccccagtat ccacggaaca attggctccc acagcaccac ctgagctaac ccctgtggtc 1320 caggactgct accatggtga tggacagagc taccgaggca catcctccac caccaccaca 1380 ggaaagaagt gtcagtcttg gtcatctatg acaccacacc ggcaccagaa gaccccagaa 144 0 aactacccaa atgctggcct gacaatgaac tactgcagga atccagatgc cgataaaggc 1500 ccctggtgtt ttaccacaga ccccagcgtc aggtgggagt actgcaacct gaaaaaatgc 1560 tcaggaacag aagcgagtgt tgtagcacct ccgcctgttg tcctgcttcc agatgtagag 1620 actccttccg aagaagactg tatgtttggg aatgggaaag gataccgagg caagagggcg 1680 accactgtta ctgggacgcc atgccaggac tgggctgccc aggagcccca tagacacagc 174 0 attttcactc cagagacaaa tccacgggcg ggtctggaaa aaaattactg ccgtaaccct 1800 gatggtgatg taggtggtcc ctggtgctac acgacaaatc caagaaaact ttacgactac 1860 tgtgatgtcc ctcagtgtgc ggccccttca tttgattgtg ggaagcctca agtggagccg 1920 aagaaatgtc ctggaagggt tgtggggggg tgtgtggccc acccacattc ctggccctgg 1980 caagtcagtc ttagaacaag gtttggaatg cacttctgtg gaggcacctt gatatcccca 2040 gagtgggtgt tgactgctgc ccactgcttg gagaagtccc caaggccttc atcctacaag 2100 gtcatcctgg gtgcacacca agaagtgaat ctcgaaccgc atgttcagga aatagaagtg 2160 tctaggctgt tcttggagcc cacacgaaaa gatattgcct tgctaaagct aagcagtcct 222 0 gccgtcatca ctgacaaagt aatcccagct tgtctgccat ccccaaatta tgtggtcgct 2280 gaccggaccg aatgtttcat cactggctgg ggagaaaccc aaggtacttt tggagctggc 234 0 cttctcaagg aagcccagct ccctgtgatt gagaataaag tgtgcaatcg ctatgagttt 2400 ctgaatggaa gagtccaatc caccgaactc tgtgctgggc atttggccgg aggcactgac 2460 agttgccagg gtgacagtgg aggtcctctg gtttgcttcg agaaggacaa atacatttta 2520 caaggagtca cttcttgggg tcttggctgt gcacgcccca ataagcctgg tgtctatgtt 2580 cgtgtttcaa ggtttgttac ttggattgag ggagtgatga gaaataattg a 2631 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Glu Pro Leu Asp Asp Tyr Val Asn Thr Gln Gly 85 90 95 Ala Ser Leu Phe Ser Val Thr Lys Lys Gln Leu Gly Ala Gly Ser lle 100 105 110 Glu Glu Cys Ala Ala Lys Cys Glu Glu Asp Glu Glu Phe Thr Cys Arg 115 120 125 Ala Phe Gln Tyr His Ser Lys Glu Gln Gln Cys Val lle Met Ala Glu 130 135 140 Asn Arg Lys Ser Ser lle lle lle Arg Met Arg Asp Val Val Leu Phe 145 150 155 160 Glu Lys Lys Val Tyr Leu Ser Glu Cys Lys Thr Gly Asn Gly Lys Asn 165 170 175 Tyr Arg Gly Thr Met Ser Lys Thr Lys Asn Gly lle Thr Cys Gln Lys 180 185 190 Trp Ser Ser Thr Ser Pro His Arg Pro Arg Phe Ser Pro Ala Thr His 195 200 205 Pro Ser Glu Gly Leu Glu Glu Asn Tyr Cys Arg Asn Pro Asp Asn Asp 210 215 220 Pro Gln Gly Pro Trp Cys Tyr Thr Thr Asp Pro Glu Lys Arg Tyr Asp 225 230 235 240 Tyr Cys Asp lle Leu Glu Cys Glu Glu Glu Cys Met His Cys Ser Gly 245 250 255 Glu Asn Tyr Asp Gly Lys lle Ser Lys Thr Met Ser Gly Leu Glu Cys 260 265 270 Gln Ala Trp Asp Ser Gln Ser Pro His Ala His Gly Tyr lle Pro Ser 275 280 285 Lys Phe Pro Asn Lys Asn Leu Lys Lys Asn Tyr Cys Arg Asn Pro Asp 290 295 300 Arg Glu Leu Arg Pro Trp Cys Phe Thr Thr Asp Pro Asn Lys Arg Trp 305 310 315 320 Glu Leu Cys Asp lle Pro Arg Cys Thr Thr Pro Pro Pro Ser Ser Gly 325 330 335 89 370 375 380 Leu Asp Glu Asn Tyr Cys Arg Asn Pro Asp Gly Lys Arg Ala Pro Trp 385 390 395 400 Cys His Thr Thr Asn Ser Gln Val Arg Trp Glu Tyr Cys Lys lle Pro 405 410 415 Ser Cys Asp Ser Ser Pro Val Ser Thr Glu Gln Leu Ala Pro Thr Ala 420 425 430 Pro Pro Glu Leu Thr Pro Val Val Gln Asp Cys Tyr His Gly Asp Gly 435 440 445 Gln Ser Tyr Arg Gly Thr Ser Ser Thr Thr Thr Thr Gly Lys Lys Cys 450 455 460 Gln Ser Trp Ser Ser Met Thr Pro His Arg His Gln Lys Thr Pro Glu 465 470 475 480 Asn Tyr Pro Asn Ala Gly Leu Thr Met Asn Tyr Cys Arg Asn Pro Asp 485 490 495 Ala Asp Lys Gly Pro Trp Cys Phe Thr Thr Asp Pro Ser Val Arg Trp 500 505 510 Glu Tyr Cys Asn Leu Lys Lys Cys Ser Gly Thr Glu Ala Ser Val Val 515 520 525 Ala Pro Pro Pro Val Val Leu Leu Pro Asp Val Glu Thr Pro Ser Glu 530 535 540 Glu Asp Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg Gly Lys Arg Ala 545 550 555 560 Thr Thr Val Thr Gly Thr Pro Cys Gln Asp Trp Ala Ala Gln Glu Pro 565 570 575 His Arg His Ser lle Phe Thr Pro Glu Thr Asn Pro Arg Ala Gly Leu 580 585 590 Glu Lys Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp 595 600 605 Cys Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro 610 615 620 Gln Cys Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro 625 630 635 640 Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His 645 650 655 Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe 660 665 670 Cys Gly Gly Thr Leu lle Ser Pro Glu Trp Val Leu Thr Ala Ala His 675 680 685 90 Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly 690 695 700 Ala His Gln Glu Val Asn Leu Glu Pro His Val Gin Glu He Glu Val 705 710 715 720 Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp lie Ala Leu Leu Lys 735 725 730 Leu Ser Ser Pro Ala Val He Thr Asp Lys Val lle Pro Ala Cys Leu 740 745 750 Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe lle Thr 755 760 765 Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu 770 775 780 Ala Gln Leu Pro Val lle Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe 785 790 795 800 Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala 805 810 815 Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys 820 825 830 Phe Glu Lys Asp Lys Tyr lle Leu Gln Gly Val Thr Ser Trp Gly Leu 835 840 845 Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg 850 855 860 Phe Val Thr Trp lle Glu Gly Val Met Arg Asn Asn 865 870 87S 15 2643 DNA 91 Homo sapiens aacaagcgct gggaactttg cgacatcccc cgctgcacaa cacctccacc atcttctggt 1020 cccacctacc agtgtctgaa gggaacaggt gaaaactatc gcgggaatgt ggctgttacc 1080 gtttccgggc acacccgtca gcactggagt gcacagaccc ctcacacaca taacaggaca 114 0 ccagaaaact tcccctgcaa aaatttggat gaaaactact gccgcaatcc tgacggaaaa 1200 agggccccat ggtgccatac aaccaacagc caagtgcggt gggagtactg taagataccg 1260 tcctgtgact cctccccagt atccacggaa caattggctc ccacagcacc acctgagcta 1320 acccctgcgg tccaggactg ctaccacggt gatggacaga gctaccgagg cacatcctcc 1380 accaccacca caggaaagaa gtgtcagtct tggtcatcta tgacaccaca ccggcaccag 1440 aagaccccag aaaactaccc aaatgctggc ctgacaatga actactgcag gaatccagat 1500 gccgataaag gcccctggtg ttttaccaca gaccccagcg tcaggtggga gtactgcaac 1560 ctgaaaaaat gctcaggaac agaagcgagt gttgtagcac ctccgcctgt tgtcctgctt 1620 ccagatgtag agactccttc cgaagaagac tgtatgtttg ggaatgggaa aggataccga 1680 ggcaagaggg cgaccactgt tactgggacg ccatgccagg actgggctgc ccaggagccc 174 0 catagacaca gcattttcac tccagagaca aatccacggg cgggtctgga aaaaaattac 1800 tgccgtaacc ctgatggtga tgtaggtggt ccctggtgct acacgacaaa tccaagaaaa i860 ctttacgact actgtgatgt ccctcagtgt gcggcccctt catttgattg tgggaagcct 1920 caagtggagc cgaagaaatg tcctggaagg gttgtggggg ggtgtgtggc ccacccacat 198 0 tcctggccct ggcaagtcag tcttagaaca aggtttggaa tgcacttctg tggaggcacc 2040 ttgatatccc cagagtgggt gttgactgct gcccactgct tggagaagtc cccaaggcct 2100 tcatcctaca aggtcatcct gggtgcacac caagaagtga atctcgaacc gcatgttcag 2160 gaaatagaag tgtctaggct gttcttggag cccacacgaa aagatattgc cttgctaaag 2220 ctaagcagtc ctgccgtcat cactgacaaa gtaatcccag cttgtctgcc atccccaaat 2280 tatgtggccg ctgaccggac cgaatgtttc atcactggct ggggagaaac ccaaggtact 2340 tttggagctg gccttctcaa ggaagcccag ctccctgtga ttgagaataa agtgtgcaat 2400 cgctatgagt ttctgaatgg aagagtccaa tccaccgaac tctgtgctgg gcatttggcc 2460 99a99cactg acagttgcca gggtgacagt ggaggtcctc tggtttgctt cgagaaggac 2520 aaatacattt tacaaggagt cacttcttgg ggtcttggct gtgcacgccc caataagcct 2580 ggtgtctatg ttcgtgtttc aaggtttgtt acttggattg agggagtgat gagaaataat 2640 tga 2643 16 880 PRT Homo sapiens 16 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 92 Ser Leu Glu Lys Arg Glu Ala Glu Ala Glu Pro Leu Asp Asp Tyr Val 85 90 95 115 120 125 Phe Thr Cys Arg Ala Phe Gln Tyr His Ser Lys Glu Gln Gln Cys Val 130 135 140 lle Met Ala Glu Asn Arg Lys Ser Ser lle lle lle Arg Met Arg Asp 145 150 155 160 Val Val Leu Phe Glu Lys Lys Val Tyr Leu Ser Glu Cys Lys Thr Gly 165 170 175 Asn Gly Lys Asn Tyr Arg Gly Thr Met Ser Lys Thr Lys Asn Gly He 180 185 190 Thr Cys Gln Lys Trp Ser Ser Thr Ser Pro His Arg Pro Arg Phe Ser 195 200 205 Pro Ala Thr His Pro Ser Glu Gly Leu Glu Glu Asn Tyr Cys Arg Asn 210 215 220. Pro Asp Asn Asp Pro Gln Gly Pro Trp Cys Tyr Thr Thr Asp Pro Glu 225 230 235 240 Lys Arg Tyr Asp Tyr Cys Asp lle Leu Glu Cys Glu Glu Glu Cys Met 245 250 255 His Cys Ser Gly Glu Asn Tyr Asp Gly Lys lle Ser Lys Thr Met Ser 260 265 270 Gly Leu Glu Cys Gln Ala Trp Asp Ser Gln Ser Pro His Ala His Gly 275 280 285 Tyr lle Pro Ser Lys Phe Pro Asn Lys Asn Leu Lys Lys Asn Tyr Cys 290 295 300 Arg Asn Pro Asp Arg Glu Leu Arg Pro Trp Cys Phe Thr Thr Asp Pro 305 310 315 320 Asn Lys Arg Trp Glu Leu Cys Asp lle Pro Arg Cys Thr Thr Pro Pro 325 330 335 Pro Ser Ser Gly Pro Thr Tyr Gln Cys Leu Lys Gly Thr Gly Glu Asn 340 345 350 Tyr Arg Gly Asn Val Ala Val Thr Val Ser Gly His Thr Cys Gln His 355 360 36S Trp Ser Ala Gln Thr Pro His Thr His Asn Arg Thr Pro Glu Asn Phe 370 375 380 Pro Cys Lys Asn Leu Asp Glu Asn Tyr Cys Arg Asn Pro Asp Gly Lys 385 390 395 400 Arg Ala Pro Trp Cys His Thr Thr Asn Ser Gln Val Arg Trp Glu Tyr 405 410 415 Cys Lys lle Pro Ser Cys Asp Ser Ser Pro Val Ser Thr Glu Gln Leu 420 425 430 93 Ala Pro Thr Ala Pro Pro Glu Leu Thr Pro Val Val Gln Asp Cys Tyr 435 440 445 His Gly Asp Gly Gln Ser Tyr Arg Gly Thr Ser Ser Thr Thr Thr Thr 450 455 460 Gly Lys Lys Cys Gln Ser Trp Ser Ser Met Thr Pro His Arg His Gln 465 470 475 480 Lys Thr Pro Glu Asn Tyr Pro Asn Ala Gly Leu Thr Met Asn Tyr Cys 485 490 495 Arg Asn Pro Asp Ala Asp Lys Gly Pro Trp Cys Phe Thr Thr Asp Pro 500 505 510 Ser Val Arg Trp Glu Tyr Cys Asn Leu Lys Lys Cys Ser Gly Thr Glu 515 520 525 Ala Ser Val Val Ala Pro Pro Pro Val Val Leu Leu Pro Asp Val Glu 530 535 540 Thr Pro Ser Glu Glu Asp Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg 545 550 555 560 Gly Lys Arg Ala Thr Thr Val Thr Gly Thr Pro Cys Gln Asp Trp Ala 565 570 575 Ala Gln Glu Pro His Arg His Ser lle Phe Thr Pro Glu Thr Asn Pro 580 585 590 Arg Ala Gly Leu Glu Lys Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val 595 600 605 Gly Gly Pro Trp Cys Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr 610 615 620 Cys Asp Val Pro Gln Cys Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro 625 630 635 640 Gln Val Glu Pro Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys Val 645 650 655 Ala His Pro His Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe 660 665 670 Gly Met His Phe Cys Gly Gly Thr Leu lle Ser Pro Glu Trp Val Leu 675 680 685 Thr Ala Ala His Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys 690 695 700 Val lle Leu Gly Ala His Gln Glu Val Asn Leu Glu Pro His Val Gln 705 710 715 720 Glu lle Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp lle 725 730 735 Ala Leu Leu Lys Leu Ser Ser Pro Ala Val lle Thr Asp Lys Val lle 7 4 0 745 750 94 Pro Ala Cys Leu 755 Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu 760 765 Cys Phe lle Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly 770 775 780 Leu Leu Lys Glu Ala Gln Leu Pro Val lle Glu Asn Lys Val Cys Asn 785 790 795 800 Arg Tyr Glu Phe Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys Ala 805 810 815 Gly His Leu Ala Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly 820 825 830 Pro Leu Val Cys Phe Glu Lys Asp Lys Tyr lle Leu Gln Gly Val Thr 835 840 845 Ser Trp Gly Leu Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr Val 850 855 860 Arg Val Ser Arg Phe Val Thr Trp lle Glu Gly Val Met Arg Asn Asn 865 870 875 880 17 791 PRT Homo sapiens 17 Glu Pro Leu Asp Asp Tyr Val Asn Thr Gln Gly Ala Ser Leu Phe Ser 15 10 15 Val Thr Lys Lys Gln Leu Gly Ala Gly Ser lle Glu Glu Cys Ala Ala 20 25 30 Lys Cys Glu Glu Asp Glu Glu Phe Thr Cys Arg Ala Phe Gln Tyr His 35 40 45 Ser Lys Glu Gln Gln Cys Val lle Met Ala Glu Asn Arg Lys Ser Ser 50 55 60 lle lle lle Arg Met Arg Asp Val Val Leu Phe Glu Lys Lys Val Tyr 65 70 75 80 Leu Ser Glu Cys Lys Thr Gly Asn Gly Lys Asn Tyr Arg Gly Thr Met 85 90 95 Ser Lys Thr Lys Asn Gly lle Thr Cys Gln Lys Trp Ser Ser Thr Ser 100 105 110 Pro His Arg Pro Arg Phe Ser Pro Ala Thr His Pro Ser Glu Gly Leu 115 120 125 95 Glu Glu Asn Tyr Cys Arg Asn Pro Asp Asn Asp Pro Gln Gly Pro Trp 130 135 140 Cys Tyr Thr Thr Asp Pro Glu Lys Arg Tyr Asp Tyr Cys Asp lle Leu 145 150 155 160 Glu Cys Glu Glu Glu Cys Met Hls Cys Ser Gly Glu Asn Tyr Asp Gly 165 170 175 Lys lle Ser Lys Thr Met Ser Gly Leu Glu Cys Gln Ala Trp Asp Ser 180 18S 190 Gln Ser Pro His Ala His Gly Tyr lle Pro Ser Lys Phe Pro Asn Lys 195 200 205 Asn Leu Lys Lys Asn Tyr Cys Arg Asn Pro Asp Arg Glu Leu Arg Pro 210 215 220 Trp Cys Phe Thr Thr Asp Pro Asn Lys Arg Trp Glu Leu Cys Asp lle 225 230 235 240 Pro Arg Cys Thr Thr Pro Pro Pro Ser Ser Gly Pro Thr Tyr Gln Cys 245 250 255 Leu Lys Gly Thr Gly Glu Asn Tyr Arg Gly Asn Val Ala Val Thr Val 260 265 270 Ser Gly His Thr Cys Gln His Trp Ser Ala Gln Thr Pro His Thr His 275 280 285 Asn Arg Thr Pro Glu Asn Phe Pro Cys Lys Asn Leu Asp Glu Asn Tyr 290 295 300 Cys Arg Asn Pro Asp Gly Lys Arg Ala Pro Trp Cys His Thr Thr Asn 305 310 315 320 Ser Gln Val Arg Trp Glu Tyr Cys Lys lle Pro Ser Cys Asp Ser Ser 325 330 335 Pro Val Ser Thr Glu Gln Leu Ala Pro Thr Ala Pro Pro Glu Leu Thr 340 345 350 Pro Val Val Gln Asp Cys Tyr His Gly Asp Gly Gln Ser Tyr Arg Gly 355 360 365 Thr Ser Ser Thr Thr Thr Thr Gly Lys Lys Cys Gln Ser Trp Ser Ser 370 375 380 Met Thr Pro His Arg His Gln Lys Thr Pro Glu Asn Tyr Pro Asn Ala 385 390 395 400 Gly Leu Thr Met Asn Tyr Cys Arg Asn Pro Asp Ala Asp Lys Gly Pro 405 410 415 Trp Cys Phe Thr Thr Asp Pro Ser Val Arg Trp Glu Tyr Cys Asn Leu 420 425 430 Lys Lys Cys Set Gly Thr Glu Ala Ser Val Val Ala Pro Pro Pro Val 430 4 4 0 4 4 5 96 Val Leu Leu Pro Asp Val Glu Thr Pro Ser Glu Glu Asp Cys Met Phe 450 455 460 Gly Asn Gly Lys Gly Tyr Arg Gly Lys Arg Ala Thr Thr Val Thr Gly 465 470 475 480 Thr Pro Cys Gln Asp Trp Ala Ala Gln Glu Pro His Arg His Ser lle 485 490 495 Phe Thr Pro Glu Thr Asn Pro Arg Ala Gly Leu Glu Lys Asn Tyr Cys 500 505 510 Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Cys Tyr Thr Thr Asn 515 520 525 Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys Ala Ala Pro 530 535 540 Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys Cys Pro Gly 545 550 555 560 Arg Val Val Gly Gly Cys Val Ala His Pro His Ser Trp Pro Trp Gln 565 570 575 Val Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly Gly Thr Leu 580 585 590 lle Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu Glu Lys Ser 595 600 605 Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly Ala His Gln Glu Val 610 615 620 Asn Leu Glu Pro His Val Gln Glu lle Glu Val Ser Arg Leu Phe Leu 625 630 635 640 Glu Pro Thr Arg Lys Asp lle Ala Leu Leu Lys Leu Ser Ser Pro Ala 645 650 655 Val lle Thr Asp Lys Val lle Pro Ala Cys Leu Pro Ser Pro Asn Tyr 660 665 670 Val Val Ala Asp Arg Thr Glu Cys Phe He Thr Gly Trp Gly Glu Thr 675 680 685 Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln Leu Pro Val 690 695 700 lle Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn Gly Arg Val 705 710 715 720 Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly Thr Asp Ser 725 730 735 97 Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu Lys Asp Lys 740 745 750 755 760 765 Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val Thr Trp lle 770 775 780 Glu Gly Val Met Arg Asn Asn 765 790 18 714 PRT Homo sapiens 18 Lys Val Tyr Leu Ser Glu Cys Lys Thr Gly Asn Gly Lys Asn Tyr Arg 1 5 10 15 Gly Thr Met Ser Lys Thr Lys Asn Gly lle Thr Cys Gln Lys Trp Ser 20 25 3 0 Ser Thr Ser Pro His Arg Pro Arg Phe Ser Pro Ala Thr His Pro Ser 35 40 45 Glu Gly Leu Glu Glu Asn Tyr Cys Arg Asn Pro Asp Asn Asp Pro Gln 50 55 60 Gly Pro Trp Cys Tyr Thr Thr Asp Pro Glu Lys Arg Tyr Asp Tyr Cys 65 70 75 80 Asp lle Leu Glu Cys Glu Glu Glu Cys Met His Cys Ser Gly Glu Asn 85 90 95 Tyr Asp Gly Lys lle Ser Lys Thr Met Ser Gly Leu Glu Cys Gln Ala 100 105 110 Trp Asp Ser Gln Ser Pro His Ala His Gly Tyr lle Pro Ser Lys Phe 115 120 125 Pro Asn Lys Asn Leu Lys Lys Asn Tyr Cys Arg Asn Pro Asp Arg Glu 130 135 140 Leu Arg Pro Trp Cys Phe Thr Thr Asp Pro Asn Lys Arg Trp Glu Leu 145 150 155 160 Cys Asp lle Pro Arg Cys Thr Thr Pro Pro Pro Ser Ser Gly Pro Thr 165 170 175 Tyr Gln Cys Leu Lys Gly Thr Gly Glu Asn Tyr Arg Gly Asn Val Ala 180 185 190 Val Thr Val Ser Gly His Thr Cys Gln His Trp Ser Ala Gln Thr Pro 195 200 205 His Thr His Asn Arg Thr Pro Glu Asn Phe Pro Cys Lys Asn Leu Asp 210 215 220 Glu Asn Tyr Cys Arg Asn Pro Asp Gly Lys Arg Ala Pro Trp Cys His 225 230 235 240 % Thr Thr Asn Ser Gln Val Arg Trp Glu Tyr Cys Lys lle Pro Ser Cys 245 250 255 Asp Ser Ser Pro Val Ser Thr Glu Gln Leu Ala Pro Thr Ala Pro Pro 260 265 270 Glu Leu Thr Pro Val Val Gln Asp Cys Tyr His Gly Asp Gly Gln Ser 275 280 285 Tyr Arg Gly Thr Ser Ser Thr Thr Thr Thr Gly Lys Lys Cys Gln Ser 290 295 300 Trp Ser Ser Met Thr Pro His Arg His Gln Lys Thr Pro Glu Asn Tyr 305 310 315 ' 320 Pro Asn Ala Gly Leu Thr Met Asn Tyr Cys Arg Asn Pro Asp Ala Asp 325 330 335 Lys Gly Pro Trp Cys Phe Thr Thr Asp Pro Ser Val Arg Trp Glu Tyr 340 345 350 Cys Asn Leu Lys Lys Cys Ser Gly Thr Glu Ala Ser Val Val Ala Pro 355 360 365 Pro Pro Val Val Leu Leu Pro Asp Val Glu Thr Pro Ser Glu Glu Asp 370 375 380 Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg Gly Lys Arg Ala Thr Thr 385 390 395 400 Val Thr Gly Thr Pro Cys Gln Asp Trp Ala Ala Gln Glu Pro His Arg 405 410 415 His Ser lle Phe Thr Pro Glu Thr Asn Pro Arg Ala Gly Leu Glu Lys 420 425 430 Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Cys Tyr 435 440 445 Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys 450 455 460 Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys 465 470 475 480 Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His Ser Trp 485 490 495 Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly 500 505 510 Gly Thr Leu lle Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu 515 520 525 99 Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly Ala Hls 530 535 540 S4S 550 555 S60 Leu Phe Leu Glu Pro Thr Arg Lys Asp lle Ala Leu Leu Lys Leu Ser 565 570 575 Ser Pro Ala Val lle Thr Asp Lys Val lle Pro Ala Cys Leu Pro Ser 580 585 590 Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe lle Thr Gly Trp 595 600 605 Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln 610 615 620 Leu Pro Val lle Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn 625 630 635 640 Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly 645 650 655 Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu 660 665 670 Lys Asp Lys Tyr lle Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys 675 680 685 Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val 690 695 700 Thr Trp lle Glu Gly Val Met Arg Asn Asn 705 710 19 33 DNA Homo sapiens 19 aaaaactcga gaaaagagca cctccgcctg ttg 20 45 DNA Homo sapiens 20 aaaaactcga gaaaagagag gctgaagctg cacctccgcc tgttg 100 22 46 DNA Homo sapiens aaaaactcga gaaaagagag gctgaagcta aactttacga ctactg 46 23 33 DNA Homo sapiens 23 aaaaactcga gaaaagactt tacgactact gtg 24 45 DNA Homo sapiens 24 aaaaactcga gaaaagagag gctgaagctc tttacgacta ctgtg 25 36 Homo sapiens 25 aaaaactcga gaaaagagcc ccttcatttg attgtg 26 48 DNA Homo sapiens 26 aaaaactcga gaaaagagag gctgaagctg ccccttcatt tgattgtg 37 DNA Homo sapiens 27 aaaaactcga gaaaagatca tttgattgtg ggaagcc 101 28 aaaaactcga gaaaagagag gctgaagctt catttgatcg tgggaagcc 49 29 348 PRT Homo sapiens 29 Ala Pro Pro Pro Val Val Leu Leu Pro Asp Val Glu Thr Pro Ser Glu 15 10 15 Glu Asp Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg Gly Lys Arg Ala 20 25 30 Thr Thr Val Thr Gly Thr Pro Cys Gln Asp Trp Ala Ala Gln Glu Pro 35 40 45 His Arg His Ser lle Phe Thr Pro Glu Thr Asn Pro Arg Ala Gly Leu 50 55 60 Glu Lys Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp 65 70 75 80 Cys Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro 85 90 95 Gln Cys Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro 100 105 110 Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His 115 120 125 Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe 130 135 140 Cys Gly Gly Thr Leu lle Ser Pro Glu Trp Val Leu Thr Ala Ala His 145 150 155 160 Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly 165 170 175 Ala His Gln Glu Val Asn Leu Glu Pro His Val Gln Glu lle Glu Val 180 185 190 Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp lle Ala Leu Leu Lys 195 200 205 Leu Ser Ser Pro Ala Val lle Thr Asp Lys Val lle Pro Ala Cys Leu 210 215 220 Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe lle Thr 225 230 235 240 Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu 215 250 255 102 Ala Gln Leu Pro Val lle Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe 260 265 270 Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala 275 280 285 Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys 290 295 300 Phe Glu Lys Asp Lys Tyr lle Leu Gln Gly Val Thr Ser Trp Gly Leu 305 310 315 320 Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg- 325 330 335 Phe Val Thr Trp lle Glu Gly Val Met Arg Asn Asn 340 345 30 261 PRT Homo sapiens 30 Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys Ala Ala Pro Ser Phe 15 10 15 Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys Cys Pro Gly Arg Val 20 25 30 Val Gly Gly Cys Val Ala His Pro His Ser Trp Pro Trp Gin Val Ser 35 40 45 Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly Gly Thr Leu lle Ser 50 55 60 Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu Glu Lys Ser Pro Arg 65 70 75 80 Pro Ser Ser Tyr Lys Val lle Leu Gly Ala His Gln Glu Val Asn Leu 85 90 95 Glu Pro His Val Gln Glu lle Glu Val Ser Arg Leu Phe Leu Glu Pro 100 105 110 Thr Arg Lys Asp lle Ala Leu Leu Lys Leu Ser Ser Pro Ala Val lle 115 120 125 Thr Asp Lys Val lle Pro Ala Cys Leu Pro Ser Pro Asn Tyr Val Val 130 135 140 Ala Asp Arg Thr Glu Cys Phe lle Thr Gly Trp Gly Glu Thr Gln Gly 145 150 155 160 103 Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln Leu Pro Val lle Glu 165 170 175 180 185 190 Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly Thr Asp Ser Cys Gln 195 200 205 Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu Lys Asp Lys Tyr lle 210 215 220 Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys Ala Arg Pro Asn Lys 225 230 235 240 Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val Thr Trp lle Glu Gly 245 250 255 Val Met Arg Asn Asn 260 31 260 PRT Homo sapiens 31 Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys Ala Ala Pro Ser Phe Asp 15 10 15 Cys Gly Lys Pro Gln Val Glu Pro Lys Lys Cys Pro Gly Arg Val Val 20 25 30 Gly Gly Cys Val Ala His Pro His Ser Trp Pro Trp Gln Val Ser Leu 35 40 45 Arg Thr Arg Phe Gly Met His Phe Cys Gly Gly Thr Leu lle Ser Pro 50 55 60 Glu Trp Val Leu Thr Ala Ala His Cys Leu Glu Lys Ser Pro Arg Pro 65 70 75 80 Ser Ser Tyr Lys Val lle Leu Gly Ala His Gln Glu Val Asn Leu Glu 85 90 95 Pro His Val Gln Glu lle Glu Val Ser Arg Leu Phe Leu Glu Pro Thr 100 105 110 Arg Lys Asp lle Ala Leu Leu Lys Leu Ser Ser Pro Ala Val lle Thr 115 120 125 Asp Lys Val He Pro Ala Cys Leu Pro Ser Pro Asn Tyr Val Val Ala 130 135 140 Asp Arg Thr Glu Cys Phe lle Thr Gly Trp Gly Glu Thr Gln Gly Thr 145 150 155 160 Phe Gly Ala Gly Leu Leu Lys Glu Ala Gin Leu Pro Val He Glu Asn 165 17 0 175 Glu Leu Cys Ala Gly His Leu Ala Gly Gly Thr Asp Ser Cys Gln Gly 195 200 205 Asp Ser Gly Gly Pro Leu Val Cys Phe Glu Lys Asp Lys Tyr lle Leu 210 215 220 Gln Gly Val Thr Ser Trp Gly Leu Gly Cys Ala Arg Pro Asn Lys Pro 225 ' 230 235 240 Gly Val Tyr Val Arg Val Ser Arg Phe Val Thr Trp lle Glu Gly Val 245 250 255 Met Arg Asn Asn 260 32 249 PRT Homo sapiens 32 Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys Cys 15 10 15 Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His Ser Trp Pro 20 25 30 Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly Gly 35 40 45 Thr Leu lle Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu Glu 50 55 60 Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly Ala His Gln 65 70 75 80 Glu Val Asn Leu Glu Pro His Val Gln Glu lle Glu Val Ser Arg Leu 85 90 95 Phe Leu Glu Pro Thr Arg Lys Asp lle Ala Leu Leu Lys Leu Ser Ser 100 105 no Pro Ala Val lle Thr Asp Lys Val lle Pro Ala Cys Leu Pro Ser Pro 115 120 125 Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe lle Thr Gly Trp Gly 130 135 140 Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln Leu 145 150 155 160 105 Pro Val lle Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn Gly 165 170 175 Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu Lys 195 200 205 Asp Lys Tyr lle Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys Ala 210 215 220 Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val Thr 225 230 235 240 Trp lle Glu Gly Val Met Arg Asn Asn 245 33 247 PRT Homo sapiens 33 Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys Cys Pro Gly 15 10 15 Arg Val Val Gly Gly Cys Val Ala His Pro His Ser Trp Pro Trp Gln 20 25 30 Val Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly Gly Thr Leu 35 40 45 lle Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu Glu Lys Ser 50 55 60 Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly Ala His Gln Glu Val 65 70 75 80 Asn Leu Glu Pro His Val Gln Glu lle Glu Val Ser Arg Leu Phe Leu 85 90 95 Glu Pro Thr Arg Lys Asp lle Ala Leu Leu Lys Leu Ser Ser Pro Ala 100 105 110 Val lle Thr Asp Lys Val lle Pro Ala Cys Leu Pro Ser Pro Asn Tyr 115 120 125 Val Val Ala Asp Arg Thr Glu Cys Phe lle Thr Gly Trp Gly Glu Thr 130 135 140 Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln Leu Pro Val 145 150 155 160 lle Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn Gly Arg Val 165 170 175 210 215 220 Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val Thr Trp lle 225 230 235 240 Glu Gly Val Mec Arg Asn Asn 245 34 249 DNA Homo sapiens 34 atgagatttc cttcaatttt tactgctgtt ttattcgcag catcctccgc attagctgct 60 ccagtcaaca ctacaacaga agatgaaacg gcacaaattc cggctgaagc tgtcatcggt 120 tactcagatt tagaagggga tttcgatgtt gctgttttgc cattttccaa cagcacaaat 180 aacgggttat tgtttataaa tactactatt gccagcattg ctgctaaaga agaaggggta 240 tctctcgag 249 35 83 PRT Homo sapiens 35 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu 36 6 DNA Homo sapiens 36 aaaaga 37 12 DNA 107 12 40 433 PRT Homo sapiens 40 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 1 5 10 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 — iO 70 75 Ser Leu Glu Lys Arg Ala Pro Pro Pro Val Val Leu Leu Pro Asp Val 85 90 95 Glu Thr Pro Ser Glu Glu Asp Cys Met Phe Gly Asn Gly Lys Gly Tyr 100 105 110 108 Arg Gly Lys Arg Ala Thr Thr Val Thr Gly Thr Pro Cys Gln ASD Trp 115 120 125 Pro Arg Ala Gly Leu Glu Lys Asn Tyr Cys Arg Asn Pro Asp Gly Asp 145 150 155 160 Val Gly Gly Pro Trp Cys Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp 165 170 175 Tyr Cys Asp Val Pro Gln Cys Ala Ala Fro Set Fhe Asp Cys Gly Lys 180 185 190 Pro Gln Val Glu Pro Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys 195 200 205 Val Ala His Pro His Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg 210 215 220 Phe Gly Met His Phe Cys Gly Gly Thr Leu lle Ser Pro Glu Trp Val 225 230 235 240 Leu Thr Ala Ala His Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr 245 250 255 Lys Val lle Leu Gly Ala His Gln Glu Val Asn Leu Glu Pro His Val 260 265 270 Gln Glu lle Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp 275 280 285 lle Ala Leu Leu Lys Leu Ser Ser Pro Ala Val lle Thr Asp Lys Val 290 295 300 lle Pro Ala Cys Leu Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr 305 310 315 320 Glu Cys Phe lle Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala 325 330 335 Gly Leu Leu Lys Glu Ala Gln Leu Pro Val lle Glu Asn Lys Val Cys 340 345 350 Asn Arg Tyr Glu Phe Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys 355 360 365 Ala Gly His Leu Ala Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly 370 375 380 Gly Pro Leu Val Cys Phe Glu Lys Asp Lys Tyr lle Leu Gln Gly Val 385 390 395 400 Thr Ser Trp Gly Leu Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr 405 410 415 Val Arg Val Ser Arg Phe Val Thr Trp lle Glu Gly Val Met Arg Asn 420 425 430 Asn 4 1 109 437 PRT Homo sapiens 41 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 1 5 10 .15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Glu Ala Glu Ala Ala Pro Pro Pro Val Val Leu 85 90 95 Leu Pro Asp Val Glu Thr Pro Ser Glu Glu Asp Cys Met Phe Gly Asn 100 105 110 Gly Lys Gly Tyr Arg Gly Lys Arg Ala Thr Thr Val Thr Gly Thr Pro 115 120 125 Cys Gln Asp Trp Ala Ala Gln Glu Pro His Arg His Ser lle Phe Thr 130 135 140 Pro Glu Thr Asn Pro Arg Ala Gly Leu Glu Lys Asn Tyr Cys Arg Asn 145 150 155 160 Pro Asp Gly Asp Val Gly Gly Pro Trp Cys Tyr Thr Thr Asn Pro Arg 165 170 175 Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys Ala Ala Pro Ser Phe 180 185 190 Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys Cys Pro Gly Arg Val 195 200 205 Val Gly Gly Cys Val Ala His Pro His Ser Trp Pro Trp Gln Val Ser 210 215 220 Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly Gly Thr Leu He Ser 225 230 235 240 Pro Glu Trp Val Leu Thr Ala Ala Hls Cys Leu Glu Lys Ser Pro Arg 245 250 255 Pro Ser Ser Tyr Lys Val lle Leu Gly Ala His Gln Glu Val Asn Leu 260 265 270 Glu Pro His Val Gln Glu lle Glu Val Ser Arg Leu Phe Leu Glu Pro 275 230 285 110 Thr Arg Lys Asp lle Ala Leu Leu Lys Leu Ser Ser Pro Ala Val lle 290 295 300 Thr Asp Lys Val lle Pro Ala Cys Leu Pro Ser Pro Asn Tyr Val Val 305 310 315 320 Ala Asp Arg Thr Glu Cys Phe lle Thr Gly Trp Gly Glu Thr Gln Gly 325 330 335 Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln Leu Pro Val lle Glu 340 345 350 Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn Gly Arg Val Gln Ser 355 360 365 Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly Thr Asp Ser Cys Gln 370 375 380 Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu Lys Asp Lys Tyr lle 385 390 395 400 Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys Ala Arg Pro Asn Lys 405 410 415 Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val Thr Trp lle Glu Gly 420 425 430 Val Met Arg Asn Asn 435 42 346 PRT Homo sapiens 42 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys 85 90 95 111 Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys 100 105 HO 115 120 125 Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly 130 135 140 Gly Thr Leu lle Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu 145 150 155 160 Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly Ala His 165 170 175 Gln Glu Val Asn Leu Glu Pro His Val Gln Glu lle Glu Val Ser Arg 180 185 190 Leu Phe Leu Glu Pro Thr Arg Lys Asp lle Ala Leu Leu Lys Leu Ser 195 200 205 Ser Pro Ala Val lle Thr Asp Lys Val lle Pro Ala Cys Leu Pro Ser 210 215 220 Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe lle Thr Gly Trp 225 230 235 240 Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu Ala Gln 245 250 255 Leu Pro Val lle Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe Leu Asn 260 265 270 Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala Gly Gly 275 280 285 Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu 290 295 300 Lys Asp Lys Tyr lle Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys 305 310 315 320 Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val 325 330 335 Thr Trp lle Glu Gly Val Met Arg Asn Asn 340 345 43 350 PRT Homo sapiens 43 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 2 0 25 3 0 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe He Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Glu Ala Glu Ala Lys Leu Tyr Asp Tyr Cys Asp 85 90 95 Val Pro Gln Cys Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val 100 105 110 Glu Pro Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His 115 120 125 Pro His Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met 130 135 140 His Phe Cys Gly Gly Thr Leu lle Ser Pro Glu Trp Val Leu Thr Ala 145 150 155 160 Ala His Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle 165 170 175 Leu Gly Ala His Gln Glu Val Asn Leu Glu Pro His Val Gln Glu lle 180 185 190 Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp lle Ala Leu 195 200 205 Leu Lys Leu Ser Ser Pro Ala Val lle Thr Asp Lys Val lle Pro Ala 210 215 220 Cys Leu Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe 225 230 235 240 He Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu 245 250 255 Lys Glu Ala Gln Leu Pro Val lle Glu Asn Lys Val Cys Asn Arg Tyr 260 265 270 Glu Phe Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly Hls 275 280 285 Leu Ala Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu 290 295 300 Val Cys Phe Glu Lys Asp Lys Tyr lle Leu Gln Gly Val Thr Ser Trp 305 310 315 320 113 44 345 PRT Homo sapiens 44 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 1 5 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys Ala 85 90 95 Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro Lys Lys Cys 100 105 110 Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His Ser Trp Pro 115 120 125 Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe Cys Gly Gly 130 135 140 Thr Leu lle Ser Pro Glu Trp Val Leu Thr Ala Ala His Cys Leu Glu 145 150 155 160 Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly Ala His Gln 165 170 175 Glu Val Asn Leu Glu Pro His Val Gln Glu lle Glu Val Ser Arg Leu 180 185 190 Phe Leu Glu Pro Thr Arg Lys Asp He Ala Leu Leu Lys Leu Ser Ser 195 200 205 Pro Ala Val lle Thr Asp Lys Val lle Pro Ala Cys Leu Pro Ser Pro 210 215 220 114 Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe lle Thr Gly Trp Gly 225 230 235 240 Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Cys Phe Glu Lys 290 295 300 Asp Lys Tyr lle Leu Gln Gly Val Thr Ser Trp Gly Leu Gly Cys Ala 305 310 315 320 Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val Ser Arg Phe Val Thr 325 330 335 Trp lle Glu Gly Val Met Arg Asn Asn 340 345 45 349 PRT Homo sapiens 45 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Glu Ala Glu Ala Leu Tyr Asp Tyr Cys Asp Val 85 90 95 Pro Gln Cys Ala Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val Glu 100 105 110 Pro Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro 115 120 125 His Ser Trp Pro Trp Gin Val Ser Leu Arg Thr Arg Phe Gly Met His 130 135 140 Phe Cys Gly Gly Thr Leu He Ser Pro Glu Trp Val Leu Thr Ala Ala 145 150 155 160 Lys Leu Ser Ser Pro Ala Val lle Thr Asp Lys Val lle Pro Ala Cys 210 215 220 Leu Pro Ser Pro 225 Thr Gly Trp Gly Glu Ala Gln Leu 260 Phe Leu Asn Gly 275 Ala Gly Gly Thr 290 Cys Phe Glu Lys 305 Leu Gly Cys Ala Arg Phe Val Thr 340 Asn Tyr Val Val 230 Glu Thr Gln Gly 245 Pro Val lle Glu Arg Val Gln Ser 280 Asp Ser Cys Gln 295 Asp Lys Tyr lle 310 Arg Pro Asn Lys 325 Trp lle Glu Gly Ala Asp Arg Thr 235 Thr Phe Gly Ala 250 Asn Lys Val Cys 265 Thr Glu Leu Cys Gly Asp Ser Gly 300 Leu Gln Gly Val 315 Pro Gly Val Tyr 330 Val Met Arg Asn 345 Glu Cys Phe lle 240 Gly Leu Leu Lys 255 Asn Arg Tyr Glu 270 Ala Gly His Leu 285 Gly Pro Leu Val Thr Ser Trp Gly 320 Val Arg Val Ser 335 Asn 46 334 PRT Homo sapiens 46 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Ala Pro Ser Phe Asp Cys Gly Lys Pro Gln Val 85 90 95 114 130 135 140 Ala His Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle 145 150 155 160 Leu Gly Ala His Gln Glu Val Asn Leu Glu Pro His Val Gln Glu lle 165 170 175 Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp lle Ala Leu 180 185 190 Leu Lys Leu Ser Ser Pro Ala Val lle Thr Asp Lys Val lle Pro Ala 195 200 205 Cys Leu Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe 210 215 220 lle Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu 225 230 235 240 Lys Glu Ala Gln Leu Pro Val lle Glu Asn Lys Val Cys Asn Arg Tyr 245 250 255 Glu Phe Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His 260 265 270 Leu Ala Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu 275 280 285 Val Cys Phe Glu Lys Asp Lys Tyr lle Leu Gln Gly Val Thr Ser Trp 290 295 300 Gly Leu Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr Val Arg Val 305 310 315 320 Ser Arg Phe Val Thr Trp He Glu Gly Val Met Arg Asn Asn 325 330 Ser Leu Glu Lys Arg Glu Ala Glu Ala Ala Pro Ser Phe Asp Cys Gly 85 90 95 Lys Pro Gln Val Glu Pro Lys Lys Cys Pro Gly Arg Val Val Gly Gly 100 105 110 Cys Val Ala His Pro His Ser Trp Fro Trp Gln Val Ser Leu Arg Thr 115 120 125 Arg Phe Gly Met His Phe Cys Gly Gly Thr Leu lle Ser Pro Glu Trp 130 135 140 Val Leu Thr Ala Ala His Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser 145 150 155 160 Tyr Lys Val lle Leu Gly Ala His Gln Glu Val Asn Leu Glu Pro His 165 170 175 Val Gln Glu lle Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys 180 185 190 Asp lle Ala Leu Leu Lys Leu Ser Ser Pro Ala Val lle Thr Asp Lys 195 200 205 Val lle Pro Ala Cys Leu Pro Ser Pro Asn Tyr Val Val Ala Asp Arg 210 215 220 Thr Glu Cys Phe lle Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly 225 230 235 240 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr He Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Ser Phe Asp Cys Gly Lys Pro Gln Val Glu Pro 85 90 95 Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys Val Ala His Pro His 100 105 110 Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe Gly Met His Phe 115 120 125 Cys Gly Gly Thr Leu lle Ser Pro Glu Trp Val Leu Thr Ala Ala His 130 135 140 Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys Val lle Leu Gly 145 150 155 160 Ala His Gln Glu Val Asn Leu Glu Pro His Val Gln Glu lle Glu Val 165 170 175 Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp lle Ala Leu Leu Lys 180 185 190 Leu Ser Ser Pro Ala Val lle Thr Asp Lys Val lle Pro Ala Cys Leu 195 200 205 Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu Cys Phe lle Thr 210 215 220 Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly Leu Leu Lys Glu 225 230 235 240 Ala Gln Leu Pro Val lle Glu Asn Lys Val Cys Asn Arg Tyr Glu Phe 245 250 255 Leu Asn Gly Arg Val Gln Ser Thr Glu Leu Cys Ala Gly His Leu Ala 260 265 270 Phe Val Thr Trp lle Glu Gly Val Met Arg Asn Asn 325 330 49 336 PRT Homo sapiens 49 Met Arg Phe Pro Ser lle Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 1 5 10 15 Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Ala Gln 20 25 30 lle Pro Ala Glu Ala Val lle Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Ala Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lle Asn Thr Thr lle Ala Ser lle Ala Ala Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg Glu Ala Glu Ala Ser Phe Asp Cys Gly Lys Pro 85 90 95 Gln Val Glu Pro Lys Lys Cys Pro Gly Arg Val Val Gly Gly Cys Val 100 105 110 Ala His Pro His Ser Trp Pro Trp Gln Val Ser Leu Arg Thr Arg Phe 115 120 125 Gly Met His Phe Cys Gly Gly Thr Leu lle Ser Pro Glu Trp Val Leu 130 135 140 Thr Ala Ala His Cys Leu Glu Lys Ser Pro Arg Pro Ser Ser Tyr Lys 145 150 155 160 Val lle Leu Gly Ala His Gln Glu Val Asn Leu Glu Pro His Val Gln 165 170 17= Glu lle Glu Val Ser Arg Leu Phe Leu Glu Pro Thr Arg Lys Asp lle 180 185 190 Ala Leu Leu Lys Leu Ser Ser Pro Ala Val lle Thr Asp Lys Val lle 195 200 205 Pro Ala Cys Leu Pro Ser Pro Asn Tyr Val Val Ala Asp Arg Thr Glu 210 215 220 Cys Phe lle Thr Gly Trp Gly Glu Thr Gln Gly Thr Phe Gly Ala Gly 225 230 235 240 Leu Leu Lys Glu Ala Gln Leu Pro Val lle Glu Asn Lys Val Cys Asn 245 250 255 120 Arg Tyr Glu Phe 260 Leu Asn Gly Arg Val 265 Gln Ser Thr Glu Leu Cys Ala 270 Gly His Leu Ala Gly Gly Thr Asp Ser Cys Gln Gly Asp Ser Gly Gly 275 280 285 Pro Leu Val Cys Phe Glu Lys Asp Lys Tyr lle Leu Gln Gly Val Thr 290 295 300 Ser Trp Gly Leu Gly Cys Ala Arg Pro Asn Lys Pro Gly Val Tyr Val 305 310 315 320 Arg Val Ser Arg Phe Val Thr Trp lle Glu Gly Val Met Arg Asn Asn 325 330 335 tctctcgaga aaagagaggc tgaagctgca cctccgcctg ttgtcctgct tccagatgta 300 gagactcctt ccgaagaaga ctgtatgctt gggaatggga aaggataccg aggcaagagg 360 gcgaccacCg ttactgggac gccatgccag gactgggctg cccaggagcc ccatagacac 420 agcattttca ctccagagac aaatccacgg gcgggtctgg aaaaaaatta ctgccgtaac 480 cctgatggtg atgtaggtgg tccctggtgc tacacgacaa atccaagaaa actttacgac 540 tactgtgatg tccctcagtg tgcggcccct tcatttgatt gtgggaagcc tcaagtggag 600 ccgaagaaat gtcctggaag ggttgtgggg gggtgtgtgg cccacccaca ttcctggccc 660 tggcaagtca gtcttagaac aaggtttgga atgcacttct gtggaggcac cttgatatcc 720 ccagagtggg tgttgactgc tgcccactgc ttggagaagt ccccaaggcc ttcatcctac 780 aaggtcatcc tgggtgcaca ccaagaagtg aatctcgaac cgcatgttca ggaaatagaa 840 gtgtctaggc tgttcttgga gcccacacga aaagatattg ccttgctaaa gctaagcagt 900 cctgccgtca tcactgacaa agtaatccca gcttgtctgc catccccaaa ttatgtggtc 960 gctgaccgga ccgaatgttt catcactggc tggggagaaa cccaaggtac ttttggagct 1020 ggccttctca aggaagccca gctccctgtg attgagaata aagtgtgcaa tcgctatgag 1080 tttctgaatg gaagagtcca atccaccgaa ctctgtgctg ggcatttggc cggaggcact 1140 gacagttgcc agggtgacag tggaggtcct ctggtttgct tcgagaagga caaatacatt 1200 ttacaaggag tcacttcttg gggtcttggc tgtgcacgcc ccaataagcc tggtgtctat 1260 gttcgtgttt caaggtttgt tacttggatt gagggagtga tgagaaataa ttga 1314 52 1041 DNA Homo sapiens 52 atgagatttc cttcaatttt tactgctgtt ttattcgcag catcctccgc attagctgct 60 ccagtcaaca ctacaacaga agatgaaacg gcacaaattc cggctgaagc tgtcatcggt 120 tactcagatt tagaagggga tttcgatgtt gctgttttgc cattttccaa cagcacaaat 180 aacgggttat tgtttataaa tactactatt gccagcattg ctgctaaaga agaaggggta 240 tctctcgaga aaagaaaact ttacgactac tgtgatgtcc ctcagtgtgc ggccccttca 300 tttgattgtg ggaagcctca agtggagccg aagaaatgtc ctggaagggt tgtggggggg 360 tgtgtggccc acccacattc ctggccctgg caagtcagtc ttagaacaag gtttggaatg 420 cacttctgtg gaggcacctt gatatcccca gagtgggtgt tgactgctgc ccactgcttg 480 gagaagtccc caaggccttc atcctacaag gtcatcctgg gtgcacacca agaagtgaat 540 ctcgaaccgc atgttcagga aatagaagtg tctaggctgt tcttggagcc cacacgaaaa 600 gatattgcct tgctaaagct aagcagtcct gccgtcatca ctgacaaagt aatcccagct 660 tgtctgccat ccccaaatta tgtggtcgct gaccggaccg aatgtttcat cactggctgg 720 ggagaaaccc aaggtacttt tggagctggc cttctcaagg aagcccagct ccctgtgatt 780 gagaataaag tgtgcaatcg ctatgagttt ctgaatggaa gagtccaatc caccgaactc 840 tgtgctgggc atttggccgg aggcactgac agttgccagg gtgacagtgg aggtcctctg 900 gtttgcttcg agaaggacaa atacatttta caaggagtca cttcttgggg tcttggctgt 960 gcacgcccca ataagcctgg tgtctatgtt cgtgtttcaa ggtttgttac ttggattgag 1020 ggagtgatga gaaataattg a 104 1 53 1053 DNA 12-2- Homo sapiens \73 accgaactct gtgctgggca tttggccgga ggcactgaca gttgccaggg tgacagtgga 900 ggtcctctgg tttgcttcga gaaggacaaa tacattttac aaggagtcac ttcttggggt 960 cttggctgtg cacgccccaa taagcctggt gtctatgttc gtgtttcaag gtttgttact 1020 tggattgagg gagtgatgag aaataattga 1050 56 1005 Homo sapiens 56 atgagatttc cttcaatttt tactgctgtt ttattcgcag catcctccgc attagctgct 60 ccagtcaaca ctacaacaga agatgaaacg gcacaaattc cggctgaagc tgtcatcggt 120 tactcagatt tagaagggga tttcgatgtt gctgttttgc cattttccaa cagcacaaat 180 aacgggttat tgtttataaa tactactatt gccagcattg ctgctaaaga agaaggggta 240 tctctcgaga aaagagcccc ttcatttgat tgtgggaagc ctcaagtgga gccgaagaaa 300 tgtcctggaa gggttgtggg ggggtgtgtg gcccacccac attcctggcc ctggcaagtc 360 agtcttagaa caaggtttgg aatgcacttc tgtggaggca ccttgatatc cccagagtgg 420 gtgttgactg ctgcccactg cttggagaag tccccaaggc cttcatccta caaggtcatc 480 ctgggtgcac accaagaagt gaatctcgaa ccgcatgttc aggaaataga agtgtctagg 540 ctgttcttgg agcccacacg aaaagatatt gccttgctaa agctaagcag tcctgccgtc 600 atcactgaca aagtaatccc agcttgtctg ccatccccaa attatgtggt cgctgaccgg 660 accgaatgtt tcatcactgg ctggggagaa acccaaggta cttttggagc tggccttctc 720 aaggaagccc agctccctgt gattgagaat aaagtgtgca atcgctatga gtttctgaat 780 ggaagagtcc aatccaccga actctgtgct gggcatttgg ccggaggcac tgacagttgc 840 cagggtgaca gtggaggtcc tctggtttgc ttcgagaagg acaaatacat tttacaagga 900 gtcacttctt ggggtcttgg ctgtgcacgc cccaataagc ctggtgtcta tgttcgtgtt 960 tcaaggtttg ttacttggat tgagggagtg atgagaaata attga 1005 57 1017 DNA Homo sapiens 57 atgagatttc cttcaatttt tactgctgtt ttattcgcag catcctccgc attagctgct 60 ccagtcaaca ctacaacaga agatgaaacg gcacaaattc cggctgaagc tgtcatcggt 120 tactcagatt tagaagggga tttcgatgtt gctgttttgc cattttccaa cagcacaaat 180 aacgggttat tgtttataaa tactactatt gccagcattg ctgctaaaga agaaggggta 240 tctctcgaga aaagagaggc tgaagctgcc ccttcatttg attgtgggaa gcctcaagtg 300 gagccgaaga aatgtcctgg aagggttgtg ggggggtgtg tggcccaccc acattcctgg 360 ccctggcaag tcagtcttag aacaaggttt ggaatgcact tctgtggagg caccttgata 420 tccccagagt gggtgttgac tgctgcccac tgcttggaga agtccccaag gccttcatcc 480 tacaaggcca tcctgggtgc acaccaagaa gtgaatctcg aaccgcatgt tcaggaaata 540 gaagtgtcta ggctgttctt ggagcccaca cgaaaagata ttgccttgct aaagctaagc 600 agtcctgccg tcatcactga caaagtaatc ccagcttgtc tgccatcccc aaattatgtg 660 gtcgctgacc ggaccgaatg tttcatcact ggctggggag aaacccaagg tacttttgga 720 gctggccttc tcaaggaagc ccagctccct gtgattgaga ataaagtgtg caatcgctat 780 gagtttctga atggaagagt ccaatccacc gaactctgtg ctgggcattt ggccggaggc 840 actgacagtt gccagggtga cagtggaggt cctctggttt gcttcgagaa ggacaaatac 900 attttacaag gagtcacttc ttggggtctt ggctgtgcac gccccaataa gcctggtgtc 960 tatgttcgtg tttcaaggtt tgttacttgg attgagggag tgatgagaaa taattga 1017 124 Homo sapiens 62 783 DNA Homo sapiens 62 750 DNA Homo sapiens 63 gccccttcat ttgattgtgg gaagcctcaa gtggagccga agaaatgtcc tggaagggtt 60 gtgggggggt gtgtggccca cccacattcc tggccctggc aagtcagtct tagaacaagg 120 tttggaatgc acttctgtgg aggcaccttg atatccccag agtgggtgtt gactgctgcc 180 cactgcttgg agaagtcccc aaggccttca tcctacaagg tcatcctggg tgcacaccaa 240 gaagtgaatc tcgaaccgca cgttcaggaa atagaagtgt ctaggctgtt cttggagccc 300 acacgaaaag atattgcctt gctaaagcta agcagtcctg ccgtcatcac tgacaaagta 360 atcccagctt gtctgccatc cccaaattat gtggtcgctg accggaccga atgtttcatc 420 actggctggg gagaaaccca aggtactttt ggagctggcc ttctcaagga agcccagctc 480 cctgtgattg agaataaagt gtgcaatcgc Catgagtttc tgaatggaag agtccaatcc 540 accgaactct gtgctgggca tttggccgga ggcactgaca gttgccaggg tgacagtgga 600 ggtcctctgg tttgcttcga gaaggacaaa tacattttac aaggagtcac ttcttggggt 660 cttggctgtg cacgccccaa taagcctggt gtctatgttc gtgtttcaag gtttgttact 720 tggattgagg gagtgatgag aaataattga 750 64 744 DNA Homo sapiens 64 tcatttgatt gtgggaagcc tcaagtggag ccgaagaaat gtcctggaag ggttgtgggg 60 gggtgtgtgg cccacccaca ttcctggccc tggcaagtca gtcttagaac aaggtttgga 120 atgcacttct gtggaggcac cttgatatcc ccagagtggg tgttgactgc tgcccactgc 180 ttggagaagt ccccaaggcc ttcatcctac aaggtcatcc tgggtgcaca ccaagaagtg 240 aatctcgaac cgcatgttca ggaaatagaa gtgtctaggc tgttcttgga gcccacacga 300 aaagatattg ccttgctaaa gctaagcagt cctgccgtca tcactgacaa agtaatccca 360 gcttgtctgc catccccaaa ttatgtggtc gctgaccgga ccgaatgttt catcactggc 420 tggggagaaa cccaaggtac ttttggagct ggccttctca aggaagccca gctccctgtg 480 attgagaata aagtgtgcaa tcgctatgag tttctgaatg gaagagtcca atccaccgaa 540 ctctgtgctg ggcatttggc cggaggcact gacagttgcc agggtgacag tggaggtcct 600 ctggtttgct tcgagaagga caaatacatt ttacaaggag tcacttcttg gggtcttggc 660 tgtgcacgcc ccaataagcc tggtgtctat gttcgtgttt caaggtttgt tacttggatt 720 gagggagtga tgagaaataa ttga 744 65 DNA 127 Homo sapiens ccccgctgca caacacctcc accatcttct ggtcccacct accagtgtct gaagggaaca 780 ggtgaaaact atcgcgggaa tgtggctgtt accgtttccg ggcacacctg tcagcactgg 840 agtgcacaga cccctcacac acataacagg acaccagaaa acttcccctg caaaaatttg 900 gatgaaaact actgccgcaa tcctgacgga aaaagggccc catggtgcca tacaaccaac 960 agccaagtgc ggtgggagta ctgtaagata ccgtcctgtg actcctcccc agtatccacg 102 0 gaacaattgg ctcccacagc accacctgag ctaacccctg tggtccagga ctgctaccat 1080 ggtgatggac agagctaccg aggcacatcc tccaccacca ccacaggaaa gaagtgtcag 1140 tcttggtcat ctatgacacc acaccggcac cagaagaccc cagaaaacta cccaaatgct 1200 ggcctgacaa tgaactactg caggaatcca gatgccgata aaggcccctg gtgttttacc 1260 acagacccca gcgtcaggtg ggagtactgc aacctgaaaa aatgctcagg aacagaagcg 132 0 agtgttgtag cacctccgcc tgttgtcctg cctccagatg tagagactcc ttccgaagaa 1380 gactgtatgt ttgggaatgg gaaaggatac cgaggcaaga gggcgaccac tgttactggg 144 0 acgccatgcc aggactgggc tgcccaggag ccccatagac acagcatttt cactccagag 1500 acaaatccac gggcgggtct ggaaaaaaat tactgccgta accctgatgg tgatgtaggt 1560 ggtccctggt gctacacgac aaatccaaga aaactttacg actactgtga tgtccctcag 1620 tgtgcggccc cttcatttga ttgtgggaag cctcaagtgg agccgaagaa atgtcctgga 1680 agggttgtgg gggggtgtgt ggcccaccca cattcctggc cctggcaagt cagtcttaga 1740 acaaggtttg gaatgcactt ctgtggaggc accttgatat ccccagagtg ggtgttgact 1800 gctgcccact gcttggagaa gtccccaagg ccttcatcct acaaggtcat cctgggtgca 1860 caccaagaag tgaatctcga accgcatgtt caggaaatag aagtgtctag gctgttcttg 192 0 gagcccacac gaaaagatat tgccttgcta aagctaagca gtcctgccgt catcactgac 1980 aaagtaatcc cagcttgtct gccatcccca aattatgtgg tcgctgaccg gaccgaatgt 204 0 ttcatcactg gctggggaga aacccaaggt acttttggag ctggccttct caaggaagcc 2100 cagctccctg tgattgagaa taaagtgtgc aatcgctatg agtttctgaa tggaagagtc 2160 caatccaccg aactctgtgc tgggcatttg gccggaggca ctgacagttg ccagggtgac 222 0 agtggaggtc ctctggtttg cttcgagaag gacaaataca ttttacaagg agtcacttct 2280 tggggtcttg gctgtgcacg ccccaataag cctggtgtct atgttcgtgt ttcaaggttt 234 0 gttacttgga ttgagggagt gatgagaaat aattga 2376 66 2145 DNA Homo sapiens gtccctcagt gtgcggcccc ttcatttgat tgtcctggaa gggttgtggg ggggtgtgtg agtcttagaa caaggtttgg aatgcacttc gtgttgactg ctgcccactg cttggagaag ctgggtgcac accaagaagt gaatctcgaa ctgttcttgg agcccacacg aaaagatatt atcactgaca aagtaatccc agcttgtctg accgaatgtt tcatcactgg ctggggagaa aaggaagccc agctccctgt gattgagaat ggaagagtcc aatccaccga actctgtgct cagggtgaca gtggaggtcc tctggtttgc gtcacttctt ggggtcttgg ctgtgcacgc tcaaggtttg ttacttggat tgagggagtg tgtgggaagc ctcaagtgga gccgaagaaa 1440 gcccacccac attcctggcc ctggcaagtc 1500 tgtggaggca ccttgatatc cccagagtgg 1560 tccccaaggc cttcatccta caaggtcatc 1620 ccgcatgttc aggaaataga agtgtctagg 1680 gccttgctaa agctaagcag tcctgccgtc 1740 ccatccccaa attatgtggt cgctgaccgg 1800 acccaaggta cttttggagc tggccttctc 1860 aaagtgtgca atcgctatga gtttctgaat 1920 gggcatttgg ccggaggcac tgacagttgc 1980 ttcgagaagg acaaatacat tttacaagga 2040 cccaataagc ctggtgtcta tgttcgtgtt 2100 atgagaaata attga 2145 129

Documents:

423-mumnp-2004-cancelled pages(17-11-2005).pdf

423-mumnp-2004-claims(granted)-(17-11-2005).doc

423-mumnp-2004-claims(granted)-(17-11-2005).pdf

423-mumnp-2004-correspondence(17-11-2005).pdf

423-mumnp-2004-correspondence(ipo)-(17-5-2006).pdf

423-mumnp-2004-drawing(31-10-2005).pdf

423-mumnp-2004-form 19(3-8-2004).pdf

423-mumnp-2004-form 1a(3-5-2004).pdf

423-mumnp-2004-form 2(granted)-(17-11-2005).doc

423-mumnp-2004-form 2(granted)-(17-11-2005).pdf

423-mumnp-2004-form 3(23-1-2004).pdf

423-mumnp-2004-form 3(31-10-2005).pdf

423-mumnp-2004-form 5(31-10-2005).pdf

423-mumnp-2004-form-pct-isa-210(31-10-2005).pdf

423-mumnp-2004-power of attorney(31-10-2005).pdf

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