Abstract:
This invention relates to a novel and seventh member of the subtilisin-kexin family isolated from rat, which has been named rPC7. The rat spleen cDNA has been totally sequenced. A shorter DNA sequence has been obtained for human, which corresponds to a portion of the catalytic region of a human pro-hormone convertase corresponding to the rat pro-hormone convertase. PC7 clearly distinguishes from the other mammalian members of the subtilisin-kexin family. Its tissue distribution is ubiquitous, but its presence is particularly remarkable in lymphoid tissues. It is present in LoVo cells that are able to cleave the HIV gp160 protein into active gp120/gp41 proteins and that are deficient in other effective pro-hormone convertases known up to date. Therefore, it is proposed that PC7 is a good candidate as a maturation enzyme responsible for the conversion of HIV gp160 protein in target CD +4  cells.

Description:
This application is a continuation-in-part of U.S. Ser. No. 08/510,347, filed Aug. 2, 1995, abandoned, and U.S. Ser. No. 08/517,015, filed Aug. 18, 1995, abandoned, both entitled Mammalian Pro-Hormone Convertase with inventors Nabil G. Seidah, Robert Day and Michel Chretien. Both U.S. Ser. Nos. 08/510,347 and 08/517,015 are incorporated by reference as if set forth herein. 
    
    
     FIELD OF THE INVENTION 
     This invention relates to proteases, particularly to maturation enzymes, more particularly those of the subtilisin-kexin family. 
     BACKGROUND OF THE INVENTION 
     Numerous enzymes of the subtilisin-kexin family are known and they all have the characteristics of being able to recognize and cleave basic residues on proteic precursors. They differ from each other by their ability to cleave specific sequences containing mono- and dibasic residues. They also differ from each other by their tissue and intra-cellular distribution. In mammalians, pro-hormone convertases 1 to 6 are already known. A partial amino acid sequence of a new pro-hormone convertase has been obtained from a human squamous carcinoma cell line BEN. This amino acid sequence has been disclosed by an Australian group during a Keystone meeting that one of the inventors organized which was held at lake Tahoe, Calif. on March 2-8, 1995. This group presented a poster (Abstract number B7-102, J. Cellular Biochemistry, supplement 19B, 1995 p243), wherein it has been shown that a new maturation enzyme was co-expressed in BEN cells with parathyroid hormone-related protein. No nucleotide sequence has been disclosed. 
     STATEMENT OF THE INVENTION 
     It is an object of the present invention to provide a new enzyme that has been isolated from rat cells which shows a considerable degree of homology with the partial amino acid sequence of the above-identified human enzyme and which will be called heretofore rat pro-hormone convertase 7 (rPC7). This enzyme is a new member of the subtilisin-kexin family. This enzyme has an ubiquitous cell distribution, but which presence is particularly remarkable in immune system cells. The cDNA obtained from rat spleen has been partially sequenced and the amino acid sequence of rPC7 has been deduced therefrom. Furthermore, a cDNA encoding the partial amino acid sequence of the human PC7 has also been obtained, which sequence encodes a peptidic sequence identical to the one presented by the Australian group. 
     It is further an object of this invention to provide antibodies directed to PC7. These antibodies are useful to detect the presence or amount of PC7 in cells or tissues of different mammalian species, assuming a conservation of proteic sequence between species, if one relies on the similarity of sequences existing between rat and human PC7 partial proteic sequences. These antibodies are useful as diagnostic reagents to detect the presence and/or amount of PC7. Therefore a kit and a method for detecting the presence and/or amount of PC7 in cells or tissues are also aspects of this invention. Kits and methods are conceived for different purposes: Western blots, immunochemistry and immunological assays. 
     Nucleic acid probes and oligonucleotides and methods and kits for detecting PC7 nucleic acids, particularly messenger RNAs present in cells or tissues of different mammalian species are also an object of this invention. Methods and kits are developed in different forms: for polymerase chain reaction (PCR), in situ hybridization, Northern blots and detection of DNA fragments separated by electrophoresis, transferred and hybridized to labelled probes and oligonucleotides. 
     Diagnostic reagents and probes are useful in the detection of this novel enzyme. Negative or positive results will provide information to the user as to whether a proteic precursor of a protein of interest present in a cell will be cleaved or not, if this precursor bears basic residues recognizable by PC7. Such utility has been already demonstrated for other members of this family. For example, in corticotroph cell line AtT-20, the absence of PC2 has been correlated with the lack of production of alpha-MSH and beta-End. As another example, reactive hypoglycemia has been correlated with a deficiency in PC1 expression. Due to the specificity of cleavage of each pro-hormone convertase towards proteic precursors, this new enzyme may be useful in the maturation of precursors that have been found to be poor substrates to the already known convertases. 
     The nucleic acid sequence encoding PC7 and sub-fragments thereof constitute an insert that can be cloned in plasmidic vectors in a sense or anti-sense fashion. These vectors may be bacterial plasmids, phages and expression vectors. Recombinant expression vectors comprising a PC7 sense insert are usable to produce PC7 gene product. Recombinant expression vectors comprising a PC7 antisense insert are usable to silence the expression of PC7 gene. 
     Antisense oligonucleotides that are specific for PC7 are also usable to silence PC7 gene expression. 
    
    
     DESCRIPTION OF THE INVENTION 
     This invention will be described in details hereinbelow and by way of the appended figures, which purpose is to illustrate the invention rather than to limit its scope. 
     BRIEF DESCRIPTION OF THE FIGURES 
     FIGS. 1A and 1B represent Northern blot analyses of PC7 in rat, mouse and human cell lines (FIG. 1A) and across rat tissues (FIG. 1B). The estimated approximate size of PC7 mRNA is between 4.0-4.2 kb. The 22 established cell lines shown are  A! 12 constitutively secreting cells: HepG2 (hepatocellular carcinoma, human), Cos-1, (kidney, African green monkey), BSC40 (African green monkey kidney epithelial cells), BRL-3A (liver cells, Buffalo rat), Y1 (adrenal cortex, mouse), LoVo (colon adenocarcinoma, human), NIH/3T3 (embryo, mouse), Ltk -  (connective tissue, mouse), TM3 (testicular Leydig cells, mouse), TM4 (testicular Sertoli cells, mouse), Caco-2 (colon adenocarcinoma, human) and LLC-PK 1  (proximal kidney tubule epithelial cells, pig).  B! 10 regulated cells containing endogenous secretory granules:. Neuro2A (neuroblastoma, mouse), NG-108 (neuroblastomaglioma hybrids, rat-mouse), SK-N-MIXC (neuroepithelioma, human), GH4Cl (somatomammotroph, rat), GH3 (somatomammotroph, rat), AtT-20 (corticotroph, mouse), αT3-1 (gonadotrophs, mouse), Rin m5F (insulinoma, rat), PC12 (pheochromocytoma, rat) and βTC-3 (insulinoma, mouse). 
     FIGS. 2a) to f) shows the results of in situ hybridization histochemistry demonstrating the mRNA distribution of PC7 in the rat (2A) thymus, (2C) spleen and (2E) lymph nodes. The specificity of the hybridization signal is demonstrated when compared to the adjacent controls shown in 2B, 2D and 2F, which were hybridized with the sense strand RNA probe. These data demonstrate that PC7 is expressed in various lymphocyte subpopulations including CD4 +   and CD8 +   cells. The CD4 +  cells are the targets of infection by the HIV retrovirus and hence the presence of PC7 may well be important for the activation of the surface glycoprotein gp160 needed for viral infectivity. 
     FIG. 3A-3C illustrate the partial cDNA and deduced amino acid sequences of rat PC7 (SEQ ID NOs: 6 and 5, respectively) (this sequence covers the entire structure of the active enzyme). FIG. 3A illustrates amino acid residues -36 to 269; FIG. 3B illustrates amino acid residues 270 to 617; FIG. 3C illustrate amino acid residues 618 to 747. 
     FIG. 4 shows alignment of partial nucleotidic sequences of rat (top) and human (bottom) PC7 (SEQ ID NO: 6 and SEQ ID NO: 4, respectively), wherein identical sequences are connected by a vertical line. 
     FIG. 5 shows alignment of partial amino acid sequences of human (top) and rat (bottom) active PC7 (SEQ ID NO: 5 (a.a. 198-347) and SEQ ID NO: 1, respectively), wherein sequences susceptible to be PC7 specific epitopes are underlined. 
    
    
     History of the discovery of PC7: 
     During a recent Keystone meeting that one of the inventors organized which was held at lake Tahoe, Calif. on March 2-8, 1995, an Australian group presented a poster (Abstract number B7-102, J. Cellular Biochemistry, supplement 19B, 1995 p243) in which they showed a deduced partial amino acid sequence of a novel subtilisin-kexin-like convertase based on a PCR fragment isolated from a human squamous carcinoma cell line BEN. No nucleotidic sequence was presented. 
     
         ______________________________________Amino acid data presented by the Australian group______________________________________ ##STR1##______________________________________ 
    
     Underlined amino acids represent the sequences which permitted the development of consensus degenerate sense and antisense oligonucleotides. 
     Strategy of the choice of degenerate oligonucleotides based on human protein sequence of PC7 
     Based on this amino acid sequence, degenerate oligonucleotides were developed, which allowed the inventors to isolate a cDNA encoding the same amino acid sequence from total RNA of BEN cells as well as the equivalent mRNA from rat pituitary mRNA. 
     
         ______________________________________ ##STR2## 
    
     
         ______________________________________Sense Oligonucleotide for hPCZ ##STR3## ##STR4##hPACE421TGCATCGTGGGCATAGCGTACAATmPACE422TGCATCGTGGGCATCGCATATAATrPACE423TGCATCGTGGGCATAGCATATAAThFurin24TGTGGTGTAGGTGTGGCCTACAACmFurin25TGTGGCGTAGGTGTAGCTTACAAT25rFurin26TGTGGTGTAGGTGTAGCTTACAATmPC527TGCACCGTCGGGATCGCTTTCAACrPC528TGCACCGTTGGAATCGCTTTCAACmPC429TGTGGTGCCGGTGTGGCCTTCAATrPC430TGTGGTGCCGGTGTGGCCTTCAATmPC131TGTGGGGTTGGAGTTGCATATAATrPC132TGTGGAGTTGGAGTTGCATATAAThPC133TGCGGGGTTGGAGTTGCATACAATmPC234TGTGGAGTCGGCGTAGCATACAACrPC235TGTGGAGTCGGTGTAGCATACAACpPC236TGCGGGGTTGGAGTGGCCTACAGChPC237TGTGGAGTTGGAGTAGCATACAACAntisense Oligonucleotide for hPC7 ##STR5## ##STR6## ##STR7##hPACE447GGCGGGAGAGAGGGGGACTACTGCTCGTGCmPACE448GGTGGGAGAGAAGGGGACCACTGCTCCTGTrPACE449GGTGGGAGAGAAGGGGACCACTGCTCCTGThFurin50GGGGGCCGGGAACATGACAGCTGCAACTGCmFurin51GGGGGCCGGGAACATGACAGCTGCAACTGTrFurin52GGGGGCCGGGAACATGACAGCTGTAACTGTmPC553GGTGGACGGAGCAAGGATCACTGTTCTTGTrPC554GGTGGACGGAGTAAGGACCACTGCTCTTGTmPC455GGTGGCCTCCATTACGACAACTGCAATTGTrPC456GGTGGCCTCCACTACGACAACTGCAATTGTmPC157GGGGGTCGTCAGGGAGATAACTGTGACTGTrPC158GGGGGTCGTCAAGGAGATAACTGTGACTGThPC159GGGGGGCGTCAGGGAGATAATTGTGACTGTmPC260GGTGGCAGCTACGATGAC---TGCAACTGTrPC261GGTGGCAGCTACGATGAC---TGCAACTGTpPC262GGTGGCAGCTACGACGAC---TGCAACTGThPC263GGCGGCAGCTATGACGAC---TGCAACTGC______________________________________ 
    
     Deduced nucleotide and amino acid sequences of rat and human PC7 derived from PCR clones 
     Using reverse-transcriptase PCR on rat pituitary total RNA and oligo-dT, the inventors amplified first strand cDNAs. These were then primed with the sense and antisense consensus oligonucleotides in a typical PCR reaction of 30 cycles with 20 sec at 94° C., 1 min at 52° C. and 2 min at 72° C. The amplified cDNA of 285 nts was subcloned into the vector PCRII and several positive clones were sequenced by the automated ALF sequencer. One clone called R14 gave the rat PC7 sequence which was used for Northern blot analyses, in situ hybridization and to screen a lambda gt11 cDNA library from rat spleen. Two positive clones were isolated which permitted the identification of an extended rat cDNA sequence which encodes the complete protein. The active enzyme is encoded by amino acid residues 126 to 781 of SEQ ID NO: 5. The same strategy was used to isolate the cDNA sequence of human PC7 starting from RNA obtained from BEN cells. A fragment of 285 bp has been obtained and sequenced. A partial cDNA sequence of human PC7 is defined in SEQ ID NO: 4. The amino acid sequence deduced from SEQ ID NO: 4 is entirely comprised within the sequence disclosed by the Australian group. 
     The rat 285 bp probe was then used to perform Northern blot of a multiplicity of cell lines as well as in situ hybridization studies in rat tissues and cells. Results on Northern blot are represented in FIG. 1 while those obtained from in situ hybridization are shown in FIG. 2. The data clearly show the following properties of this novel mRNA which was called PC7: 
     1) From Northern blot analyses, it appears that PC7 transcripts are ubiquitously expressed in all tissues and cells examined, suggesting a widespread distribution, similar to furin, as it is expressed in cells with constitutive and regulated secretory pathways. 
     2) The sum of the in situ and Northern data suggest that PC7 is most abundantly expressed in the colon, the spleen, the thymus and the lymph nodes, all of which are lymphoid-associated tissues. 
     3) Analysis of the cellular expression of PC7 in established cell lines confirmed the ubiquitous expression of PC7 in all cells but also demonstrated its conservation of sequence in various species such as mouse, rat, human and pig. The richest source of PC7 was the mouse pituitary alpha-T3-1 cell line derived from the gonadotrophs and the beta-TC3 cells line derived from a mouse insulinoma, the mouse fibroblast cell line Ltk -  and the rat pheochromocytoma cell line PC12. 
     4) Furthermore, the expression of PC7 in the human colon carcinoma LoVo cell line is significant since this cell line is deficient in furin activity. This cell line is indeed known to express PACE4 and furin  Seidah, N. G., Chretien, M. and Day, R. (1994) Biochimie 76, 197-209!. However, the LoVo furin has a point mutation which effectively makes it an inactive enzyme in this cell line  Takahashi, S., Kasai, K., Hatsuzawa, K., Kitamura, N., Misumi, Y., Ikehara, Y., Murakami, K. and Nakayama, K. (1993) Biochem. Biophys. Res. Commun. 195, 1019-1026.!. 
     5) Evidence has been presented that an enzyme other than furin is capable of processing the HIV gp160 surface glycoprotein, based on  1! the ability of LoVo cells to activate this precursor into gp120/gp41  Ohnishi, Y., Shioda, T., Nakayama, K., Iwata, S., Gotoh, B., Hamaguchi, M. and Nagai, Y. (1994) J. Virol. 68, 4075-4079!, and  2! the results presented the inventors which demonstrated that in vitro gp160 is processed by both furin and PC1 into gp120/gp41  Decroly, E., Vandenbranden, M., Ruysschaert, J. M., Cogniaux, J., Jacob, G. S., Howard, S. C., Marshall, G., Kompelli, A., Basak, A., Jean, F., Lazure, C., Benjannet, S., Chretien, M., Day, R. and Seidah, N. G. (1994) J Biol Chem 269(16), 12240-12247!. However, in the inventors&#39; laboratory, when gp160 was co-expressed in various cell lines with either PACE4, PC1, PC2, PC5 and its isoform PC5/6-B, furin was found to be by far the best processing enzyme of gp160. Yet, LoVo cells can efficiently process this precursor even though it is deficient in furin activity. This suggests that although furin is a good candidate processing enzyme of the AIDS virus gp160, another as yet undefined enzyme present in LoVo cells can also do the job. It is proposed that PC7 may well be the sought second candidate enzyme and not PACE4 which is a weak processor of gp160. 
     Deduced nucleotide and amino acid sequences of rat spleen PC7 
     This sequence is shown in FIG. 3 and the amino acid and nucleotidic sequences are defined in SEQ ID. NO: 5 and 6, respectively. Referring to FIG. 3, the active sites Asp 150 , His 191  and Ser 369  (bold, underlined), the oxyanion hole Asn 292  (bold)  ♦♦!, as well as the putative zymogen activation site ArgAlaLysArg  ↓! are emphasized (SEQ ID NO: 65). The three putative Asn 130 ,138,204,474 glycosylation sites are also shown  !. The other Asn 163  site is not acceptable for N-glycosylation in view of the Pro 166  residue. The predicted Ser, Thr phosphorylation  ★★! and Tyr sulfatation  ★! sites are depicted and the variant ArgArgGlySerLeu (amino acids 537-541 of SEQ ID NO: 5) sequence with its expected Ser phosphorylation site is also shown. Finally, the hydrophobic sequence, representing a putative transmembrane anchoring domain is underlined as: LeuValLeuValGlyCysPheSerValPheTrpThrIleTyrTyrMetLeu (SEQ ID NO: 64 The predicted polyadenylation signal AATAAA is also emphasized. The initiator methionine chosen occurs at nucleotide 218 giving a 36 amino acid signal peptide (-36 to -1). The presence of an in-phase ATG as well as the stop codon TAA is to be noted. 
     The available data will have important implications in pathologies of the immune system and in viral infections. These considerations were based on the following: 
     a) The amino acid sequence of the catalytic domain of PC7 from both rat and human strongly suggest that PC7 will have a similar cleavage specificity to furin and would thus recognize both single basic residues and pairs of basic residues. Furthermore, based on the available specificity of furin  Siezen, R J, Creemers, J W M and Van de Ven, W J M. (1994) Eur. J. Biochem. 222, 255-266!, it is suggested that PC7 may be better suited to cleave precursors with a negatively charged amino acid present three residues before the cleavage site (at P3) such as the case of the HIV gp160 where the cleavage site is Arg-Glu-Lys-Arg-↓ (SEQ ID NO: 66) and Glu occupies the P3 position. 
     b) PC7 is ubiquitously distributed and its expression is particularly enriched in the immune system tissues and cells including the CD4+cells which are infectable by the HIV virus. PC7 is therefore a target of choice toward which future inhibitors may be developed to inhibit the conversion of HIV gp160 to gp120/gp41. 
     c) The unique presence of an RRGSL sequence in the P-domain of PC7 which in all other members of the family is RRGDL is notable. This would imply a uniqueness of PC7 and may negate its possible interactions with surface integrin receptors which recognize the RGD sequence. 
     Alignment of the sequence of PC7 with the other members of the subtilisin-kexin family 
     This alignment (not shown) demonstrates that PC7 represents an ancestral PC gene product as it best resembles the yeast kexin-like enzymes kex2, krp, kex1 and XRP-6 derived from four different yeast strains. In the mammalian PCs, the closest members are PC1 and PC2. 
     Nomenclature 
     This novel gene product is called PC7 since it represents the seventh member of the subtilisin-kexin family. It should be noted that the name PC7 was recently published to erroneously suggest that a reported rat sequence represents a seventh member of this family  Tsuji, AS. et al. Biochem Biophys. Res. Commun. 202, 1452-1459, 1994!. However, sequence alignment clearly demonstrated that the published rat PC7 sequence is nothing but rat PACE4 which also has been published  Johnson, R C et al. Endocrinology 135, 1178-1185, 1994!. Therefore, the present inventors have decided to keep the name PC7, as it accurately reflects the rank of this enzyme in order of discovery of the convertases. 
     Oligonucleotides useful as probes 
     Since nucleotidic sequences for rat and human PC7 have been obtained, it is now possible to deduce which are the conserved sequences that are usable to detect the presence and/or amount of PC7 in different species. Comparison of human and rat sequences are shown in FIG. 4. This alignment shows that a 38 nucleotide stretch (comprised between nucleotides 1043 and 1080 of SEQ ID NO: 6) is absolutely conserved between rat and human, suggesting that it could be used as an effective specific probe for the expression of PC7 in these species and presumably in other species. When this sequence was compared in both sense and anti sense orientations with the other six members of the mammalian family, the inventors calculated that the best alignment was with rat furin, PC4, PC2and PC5 at 63% identity. Therefore, it is believed that hybridization performed at high stringency will give a specific signal for PC7 in various mammalian species. The following oligonucleotides and part thereof that will give the same specific signal for PC7 in stringent conditions are 5&#39;CAC TAT CAG ATC AAT GAC ATC TAC AGC TGC AGC TGG GG3&#39;, 5&#39;CC CCA GCT GCA GCT GTA GAT GTC ATT GAT CTG ATA GTG3&#39;(SEQ ID NO: 7 AND 8, respectively). They are to be used as well as the oligonucleotides which have the SEQ ID NOs: 2 and 3 and their reverse sequence (SEQ ID NOs: 11 and 12) as diagnosing reagents or as components of diagnostic kits to detect the presence and/or amount of PC7 encoding nucleic acids, preferably mRNAs, in conventional detection procedures (Northern blot, in situ hybridization, for example). A method of detection of PC7 which comprises the steps of contacting a cell sample (cells, tissues, lysates or cellular fractions thereof) with one the above oligonucleotides in selected hybridization conditions and detecting the presence and/or amount of hybridized oligonuleotides as an indication of the presence of PC7 is also new. 
     Development of specific antibodies to PC7 
     Alignment of peptidic sequences of rat and human PC7 is shown in FIG. 5. The sequence HisGlnLueGlyLysAlaAlaLeuGlnHis (SEQ ID NO: 9 corresponding to amino acid residues 265 to 274 of SEQ ID NO: 5) is absolutely conserved between the two species. It has only two amino acid identities with the other PCs (underlined). This peptidic sequence is therefore considered as a sequence of choice to raise antibodies specific to PC7. Another 17 amino acid sequence which is unique to rat PC7 is also assumed to be an antigen susceptible to entail of the production of specific antibodies to PC7: AlaSerTyrValSerProMetLeuLysGluAsnLysAlaValProArgSer (SEQ ID NO: 10 corresponding to amino acids 485 to 501 of SEQ ID NO: 5). This sequence is located in the C-terminal region which shows the greatest degree of divergence between PC7 and the other members of the family. It is assumed that this region will show a sufficient degree of similarity between species to entail of the production of antibodies recognizing PC7 in tissues or cells of different species. The antibodies raised against these peptides by using techniques well known in the art are to be used as diagnosing reagents or as components of diagnostic kits to detect the presence and/or amount of PC7 in conventional detection procedures (Western blot, immunohistochemistry, immunoassays, for example). A method of detection of PC7 which comprises the steps of contacting a cell sample (cells, tissues, lysates or cellular fractions thereof) with a specific anti-PC7 antibody in conditions allowing the binding of the antibodies to PC7 and detecting the presence and/or amount of bound antibodies as an indication of the presence of PC7 is also new. 
     Probing other mammalian PC7 enzymes 
     Part of totality of PC7 cDNA may be used to clone the same enzyme in other species, using either the cDNA as a probe to screen cDNA or genomic libraries or the PCR program outlined in this application. The oligonucleotides useful in the above diagnostic kit and method may be used as primers to initiate the PCR. 
     Recombinant plasmids and hosts 
     A variety of recombinant plasmids may now be constructed, using conventional techniques and commercially available plasmids. Expression vectors are particularly useful to produce PC7 in compatible host cells. It is also contemplated to insert the cDNA of PC7 in whole or in part in an antisense orientation in an expression vector such as pRcCMV or pcDNA-neo (InVitrogen) and to introduce these recombinant vectors in host cells by transfection or lipofection, for example, to silence the expression of PC7 gene in these cells. This procedure may be used in cell systems producing a proteic precursor wherein the presence of PC7 is undesirable, or to reveal pathologies correlated with a deficient production of PC7. Production of transgenic mice which are PC7deficient (silenced PC7) are particularly contemplated as &#34;knock-out&#34; animal models wherein associated pathologies will be revealed. 
     
         __________________________________________________________________________SEQUENCE LISTING(1) GENERAL INFORMATION:(iii) NUMBER OF SEQUENCES: 66(2) INFORMATION FOR SEQ ID NO:1:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 114 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:HisGlyThrArgCysAlaGlyGluSerAlaXaaSerSerProAsnAsn151015SerPheCysAlaValGlyValAlaTyrGlySerArgIleAlaGlyIle202530ArgValLeuAspGlyProLeuThrAspSerMetGluAlaValAlaPhe354045AsnLysHisTyrGlnIleAsnAspIleTyrSerCysSerTrpGlyPro505560AspAspAspGlyLysThrValAspGlyProHisGlnLeuGlyLysAla65707580AlaLeuGlnHisGlyValIleAlaGlyArgGlnGlyPheGluGlySer859095IlePheValValAlaSerGlyAsnGlyGlyGluHisAsnAspAsnCys100105110AsnCys(2) INFORMATION FOR SEQ ID NO:2:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 23 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;Oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:TGYGCYGTRGGYGTVGCWTAYGG23(2) INFORMATION FOR SEQ ID NO:3:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:RCAGTTRCARTTGTCRTTRTGYTCSCCMCC30(2) INFORMATION FOR SEQ ID NO:4:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 285 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: double(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:TGCGCTGTGGGCGTAGCATATGGGAGCCGCATCGCAGGTATCCGGGTACTGGATGGACCT60CTCACAGACAGCATGGAGGCGGTGGCGTTCAACAAGCACTATCAGATCAATGACATCTAC120AGTTGCAGCTGGGGACCAGATGACGATGGGAGGACAGTGGATGGCCCCCATCAGCTTGGA180AAGGCTGCCTTACAACATGGGGTGATTGCTGGTCGCCAGGGCTTTGGGAGCATCTTTGTG240GTAGCCAGTGGCAACGGTGGGGAGCATAACGACAACTGTAACTGT285(2) INFORMATION FOR SEQ ID NO:5:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 783 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:MetProLysGlyArgGlnLysValProArgLeuAspAlaArgLeuGly151015LeuProIleCysLeuCysLeuGluLeuAlaIlePhePheLeuValPro202530GlnValMetGlyLeuThrGluAlaGlyGlyLeuAspThrLeuGlyAla354045GlyGlyLeuSerTrpAlaValHisLeuAspSerLeuGluGlyGluArg505560LysGluGluSerLeuIleGlnGlnAlaAsnAlaValAlaGlnAlaAla65707580GlyLeuValAsnAlaGlyArgIleGlyGluLeuGlnGlyHisTyrLeu859095PheValGlnProAlaGlyHisGlyGlnAlaMetGluAlaGluAlaMet100105110ArgGlnGlnAlaGluAlaValLeuAlaLysHisGluAlaValArgTrp115120125HisSerGluGlnArgLeuLeuLysArgAlaLysArgSerIleHisPhe130135140AsnAspProLysTyrProGlnGlnTrpHisLeuAsnAsnArgArgSer145150155160ProGlyArgAspIleAsnValThrGlyValTrpGluArgAsnValThr165170175GlyArgGlyValThrValValValValAspAspGlyValGluHisThr180185190ValGlnAspIleAlaProAsnTyrSerProGluGlySerTyrAspLeu195200205AsnSerAsnAspProAspProMetProHisProAspGluGluAsnGly210215220AsnHisHisGlyThrArgCysAlaGlyGluIleAlaAlaValProAsn225230235240AsnSerPheCysAlaValGlyValAlaTyrGlySerArgIleAlaGly245250255IleArgValLeuAspGlyProLeuThrAspSerMetGluAlaValAla260265270PheAsnLysHisTyrGlnIleAsnAspIleTyrSerCysSerTrpGly275280285ProAspAspAspGlyLysThrValAspGlyProHisGlnLeuGlyLys290295300AlaAlaLeuGlnHisGlyValMetAlaGlyArgGlnGlyPheGlySer305310315320IlePheValValAlaSerGlyAsnGlyGlyGlnHisAsnAspAsnCys325330335AsnTyrAspGlyTyrAlaAsnSerIleTyrThrValThrIleGlyAla340345350ValAspGluGluGlyArgMetProPheTyrAlaGluGluCysAlaSer355360365MetLeuAlaValThrPheSerGlyGlyAspLysMetLeuArgSerIle370375380ValThrThrAspTrpAspLeuGlnLysGlyThrGlyCysThrGluGly385390395400HisThrGlyThrSerAlaAlaAlaProLeuAlaAlaGlyMetIleAla405410415LeuMetLeuGlnValArgProCysLeuThrTrpArgAspValGlnHis420425430IleIleValPheThrAlaThrGlnTyrGluAspHisArgAlaAspTrp435440445LeuThrAsnGluAlaGlyPheSerHisSerHisGlnHisGlyPheGly450455460LeuLeuAsnAlaTrpArgLeuValAsnAlaAlaLysIleTrpThrSer465470475480ValProTyrLeuAlaSerTyrValSerProMetLeuLysGluAsnLys485490495AlaValProArgSerProHisSerLeuGluValLeuTrpAsnValSer500505510ArgThrAspLeuGluMetSerGlyLeuLysThrLeuGluHisValAla515520525ValThrValSerIleThrHisProArgArgGlySerLeuGluLeuLys530535540LeuPheCysProSerGlyMetMetSerLeuIleGlyAlaProArgSer545550555560MetAspSerAspProAsnGlyPheAsnAspTrpThrPheSerThrVal565570575ArgCysTrpGlyGluArgAlaArgGlyValTyrArgLeuValIleArg580585590AspValGlyAspGluProLeuGlnValGlyIleLeuGlnGlnTrpGln595600605LeuThrLeuTyrGlySerThrTrpSerProValAspIleLysAspArg610615620GlnSerLeuLeuGluSerAlaMetSerGlyLysTyrLeuHisAspAsp625630635640PheThrLeuProCysProProGlyLeuLysIleProGluGluAspGly645650655TyrSerIleThrProAsnThrLeuLysThrLeuValLeuValGlyCys660665670PheSerValPheTrpThrIleTyrTyrMetLeuGluValCysLeuSer675680685GlnArgSerLysAlaSerThrHisGlyCysArgArgGlyCysCysPro690695700TrpProProGlnSerGlnAsnSerLysGluValGlyThrAlaLeuGlu705710715720SerMetProLeuCysSerSerLysAspLeuAspGlyValAspSerGlu725730735HisGlyAspCysThrThrAlaSerSerLeuLeuAlaProGluLeuLeu740745750GlyGluAlaAspTrpSerLeuSerGlnAsnSerLysSerAspLeuAsp755760765CysProProHisGlnProProAspLeuLysAspGlyGlnIleCys770775780(2) INFORMATION FOR SEQ ID NO:6:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 3450 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: double(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:CGGGGAAGCTGAGAGTTTCCGCAGGTGGCGGCTGCGGCGGCGGCGGCAGCGGTAGCAACT60GCAACAGTAGCAACGAAGGCTGTGGGTCTGCAGCTGTGTTCCCAGTCGACATTGCTCACG120GTGAAGGTGACATCTCCCTCCAGTTTCACAAAATGAGTGTGGTATGGTTACGAAGACCAG180GACCTAAACTTCACAGAGAGCCCAGCCTGCTGTTCTGATGCCGAAAGGGAGACAGAAAGT240CCCACGCTTGGATGCCCGCCTGGGCCTGCCTATCTGCCTCTGTCTGGAATTAGCCATCTT300CTTTCTGGTTCCCCAGGTCATGGGCCTAACAGAGGCAGGTGGTCTTGACACCTTGGGTGC360AGGGGGGCTAAGCTGGGCTGTACATCTGGACAGCCTAGAAGGTGAGAGGAAGGAAGAGAG420TCTGATACAACAGGCAAATGCTGTGGCCCAGGCAGCGGGGCTGGTGAATGCTGGGCGCAT480TGGAGAGCTCCAGGGGCACTACCTCTTTGTCCAGCCAGCTGGGCACGGGCAAGCCATGGA540GGCGGAGGCCATGCGGCAACAGGCAGAGGCTGTGTTAGCCAAGCATGAAGCTGTGCGCTG600GCACTCAGAGCAGAGGCTGCTGAAGAGGGCCAAGCGCAGCATCCACTTCAATGATCCCAA660GTATCCTCAACAGTGGCACCTGAATAATCGGCGGAGCCCAGGAAGAGACATCAATGTGAC720AGGTGTGTGGGAGAGAAATGTAACTGGGCGAGGGGTGACGGTGGTAGTGGTGGACGACGG780AGTGGAGCACACCGTCCAGGACATTGCACCCAACTATAGCCCAGAGGGAAGCTATGACCT840CAACTCTAATGACCCAGATCCTATGCCCCACCCTGATGAGGAGAACGGTAACCACCATGG900GACCCGGTGTGCAGGAGAAATTGCAGCTGTGCCCAACAACAGCTTCTGTGCAGTAGGTGT960GGCCTATGGGAGCCGAATAGCAGGTATCCGGGTGCTGGATGGACCACTCACAGACAGTAT1020GGAAGCTGTGGCATTCAACAAACACTATCAGATCAATGACATCTACAGCTGCAGCTGGGG1080CCCCGATGATGATGGGAAGACAGTGGATGGTCCTCATCAGCTTGGGAAGGCTGCCTTACA1140ACATGGAGTGATGGCTGGTCGCCAAGGCTTTGGAAGTATCTTTGTGGTTGCCAGTGGTAA1200TGGTGGCCAGCACAATGACAACTGCAACTATGATGGCTATGCCAACTCCATCTACACTGT1260CACCATAGGAGCTGTGGATGAGGAGGGACGGATGCCTTTTTATGCAGAGGAGTGTGCCTC1320CATGCTGGCAGTCACCTTCAGTGGAGGAGACAAGATGCTGCGGAGCATTGTGACTACTGA1380CTGGGACCTTCAGAAGGGCACTGGCTGCACTGAAGGCCACACAGGAACCTCAGCTGCAGC1440CCCTCTAGCAGCTGGCATGATAGCTCTCATGCTGCAGGTGCGGCCCTGCCTCACGTGGCG1500GGATGTCCAGCACATCATTGTCTTCACAGCCACTCAGTATGAAGATCATCGTGCAGACTG1560GCTCACTAATGAGGCTGGATTCAGCCACAGCCATCAGCATGGTTTCGGCCTGCTCAACGC1620CTGGAGACTTGTCAATGCAGCCAAGATCTGGACGTCTGTCCCTTACTTAGCTTCCTATGT1680CAGCCCCATGCTGAAAGAAAATAAGGCTGTTCCACGGTCCCCCCACTCTCTGGAGGTCCT1740ATGGAATGTCAGCAGGACGGACCTGGAGATGTCGGGGCTGAAGACCCTGGAACATGTGGC1800GGTGACAGTCTCCATCACTCACCCACGACGTGGCAGCTTAGAACTGAAACTGTTTTGTCC1860CAGTGGCATGATGTCTTTGATCGGCGCGCCCCGCAGCATGGACTCGGACCCTAACGGCTT1920CAATGACTGGACATTTTCCACTGTGCGGTGCTGGGGGGAAAGAGCAAGAGGAGTCTACAG1980ACTGGTTATCAGGGATGTAGGAGATGAGCCGCTCCAGGTGGGCATCCTCCAGCAGTGGCA2040GCTGACGCTGTATGGCTCCACGTGGAGTCCAGTAGACATCAAGGACAGACAAAGTCTCTT2100AGAAAGTGCTATGAGTGGAAAATACCTGCATGATGACTTCACTCTGCCTTGCCCACCTGG2160ACTGAAAATTCCTGAGGAGGATGGTTACAGCATTACCCCTAACACACTCAAGACCCTTGT2220GCTGGTTGGCTGCTTCAGTGTCTTCTGGACCATTTACTACATGCTAGAAGTGTGCCTGAG2280CCAGAGGAGCAAGGCTTCCACCCATGGCTGCAGGAGAGGATGCTGCCCCTGGCCCCCACA2340AAGCCAAAACTCCAAGGAAGTGGGGACAGCACTAGAATCAATGCCACTGTGCAGCAGCAA2400GGACCTGGATGGAGTGGATTCAGAGCACGGGGACTGCACAACTGCCTCTAGCTTGCTGGC2460CCCAGAGCTGCTGGGGGAAGCTGACTGGAGTCTGTCCCAGAACAGTAAGAGTGACCTGGA2520TTGTCCTCCCCACCAACCCCCAGACCTGAAGGATGGACAGATCTGCTGACCCCAGAGCCC2580AGCTTCTTCCATGTACAACAGGCTCTTCCTAAACTTGGTTATGAGGCTTTCAATCATGGA2640TGCTCAGGAGAGAATGGTCCTGATAGTGACATCTGCCACCCAAGGCCTCTGAAGCATTCT2700CAGCCTTCTCAAGAGGGTGAGGGCCATCTTAATTAAGCGCAGTGGTAAGGGACTGGTGTT2760CATGGCTCCTCTAGCTGAGCTTTGCTGAGAGCCTTTCGACAAGGGGTTGGCGCCCAGGCC2820AGGCAGCCCTTGATTTCATCTCTCTCGGGCTAGTCACTGTCCTCGGCCATCAGGACCTCC2880ACCCCTTCACAAGTTATGCAGCAGGTGCCTGTATACCTAGGAACACTCTCAACAGAAGTG2940CCGCTGTACCGAGGGCCCAGAGAGAGGCTGGCAAGAGCCTAGACATGCCTACCCTGAAAG3000CAGCTGCCTTCATTACCCTTTCCTGTGTGCCTGTTCTGAAGCCCGTACCTTCACTACCAC3060TCACCCTTCCTGCTGAAGGAATGGTGGCGTGTCCCAGGAAAACTGGGAGGCACAGGATTC3120CCAGCCAGCACCCTTGCTGCCTCACTGGGGAAGTTGGCCTGCTGGGCTGCAGAGAGCTGA3180GACACAGTGTTGTCTAAGATAGCATGGGAGCCCCTGCCTATGACCACCTGTCTTCCTCTG3240CAAAGTGCTCAGGGAAATGGCCTTCATTCCAGAGGCCAGCTGTCCGCCTGACTTTTCCTC3300CATTCTTGGCCTTCTCCCCTTCCCATCTTTGGAGCTAATTGTTAATATGAATTTTTTAAT3360GCTTAAGATTTGATTTTTACTTTTCAAAGCAACATTTTGTTGAATTTTTTTCTGCACAGC3420TTTCCAAAATAAAAAGCAGAAGTAAAAAAA3450(2) INFORMATION FOR SEQ ID NO:7:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 38 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:CACTATCAGATCAATGACATCTACAGCTGCAGCTGGGG38(2) INFORMATION FOR SEQ ID NO:8:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 38 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:CCCCAGCTGCAGCTGTAGATGTCATTGATCTGATAGTG38(2) INFORMATION FOR SEQ ID NO:9:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 10 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:HisGlnLeuGlyLysAlaAlaLeuGlnHis1510(2) INFORMATION FOR SEQ ID NO:10:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 17 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:AlaSerTyrValSerProMetLeuLysGluAsnLysAlaValProArg151015Ser(2) INFORMATION FOR SEQ ID NO:11:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 23 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:CCRTAWGCBACRCCYACRGCRCA23(2) INFORMATION FOR SEQ ID NO:12:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:GGKGGSGARCAYAAYGACAAYTGYAACTGY30(2) INFORMATION FOR SEQ ID NO:13:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 8 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:CysAlaValGlyValAlaTyrGly15(2) INFORMATION FOR SEQ ID NO:14:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:TGTGCTGTGGGCGTGGCTTACGGT24(2) INFORMATION FOR SEQ ID NO:15:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:TGCGCCGTCGGTGTCGCCTATGGC24(2) INFORMATION FOR SEQ ID NO:16:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:TGTGCGGTTGGGGTGGCGTACGGG24(2) INFORMATION FOR SEQ ID NO:17:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:TGTGCAGTAGGAGTAGCATACGGA24(2) INFORMATION FOR SEQ ID NO:18:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 23 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:TGCGCCGTGGGCGTAGCATACGG23(2) INFORMATION FOR SEQ ID NO:19:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 23 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:TGTGCTGTAGGTGTCGCTTATGG23(2) INFORMATION FOR SEQ ID NO:20:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 23 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:TGCGCCGTGGGCGTGGCATACGG23(2) INFORMATION FOR SEQ ID NO:21:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:TGCATCGTGGGCATAGCGTACAAT24(2) INFORMATION FOR SEQ ID NO:22:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:TGCATCGTGGGCATCGCATATAAT24(2) INFORMATION FOR SEQ ID NO:23:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:TGCATCGTGGGCATAGCATATAAT24(2) INFORMATION FOR SEQ ID NO:24:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:TGTGGTGTAGGTGTGGCCTACAAC24(2) INFORMATION FOR SEQ ID NO:25:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:TGTGGCGTAGGTGTAGCTTACAAT24(2) INFORMATION FOR SEQ ID NO:26:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:TGTGGTGTAGGTGTAGCTTACAAT24(2) INFORMATION FOR SEQ ID NO:27:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:TGCACCGTCGGGATCGCTTTCAAC24(2) INFORMATION FOR SEQ ID NO:28:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:TGCACCGTTGGAATCGCTTTCAAC24(2) INFORMATION FOR SEQ ID NO:29:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:TGTGGTGCCGGTGTGGCCTTCAAT24(2) INFORMATION FOR SEQ ID NO:30:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:TGTGGTGCCGGTGTGGCCTTCAAT24(2) INFORMATION FOR SEQ ID NO:31:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:TGTGGGGTTGGAGTTGCATATAAT24(2) INFORMATION FOR SEQ ID NO:32:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:TGTGGAGTTGGAGTTGCATATAAT24(2) INFORMATION FOR SEQ ID NO:33:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:TGCGGGGTTGGAGTTGCATACAAT24(2) INFORMATION FOR SEQ ID NO:34:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:TGTGGAGTCGGCGTAGCATACAAC24(2) INFORMATION FOR SEQ ID NO:35:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:TGTGGAGTCGGTGTAGCATACAAC24(2) INFORMATION FOR SEQ ID NO:36:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:TGCGGGGTTGGAGTGGCCTACAGC24(2) INFORMATION FOR SEQ ID NO:37:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:TGTGGAGTTGGAGTAGCATACAAC24(2) INFORMATION FOR SEQ ID NO:38:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 10 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:GlyGlyGluHisAsnAspAsnCysAsnCys1510(2) INFORMATION FOR SEQ ID NO:39:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:GGCGGCGAGCACAATGATAATTGTAATTGT30(2) INFORMATION FOR SEQ ID NO:40:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:GGAGGAGAACATAACGACAACTGCAACTGC30(2) INFORMATION FOR SEQ ID NO:41:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:GGTGGTGAGCACAATGATAATTGTAATTGT30(2) INFORMATION FOR SEQ ID NO:42:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:GGGGGGGAGCACAATGATAATTGTAATTGT30(2) INFORMATION FOR SEQ ID NO:43:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:GGTGGCGAGCACAATGACAATTGTAACTGT30(2) INFORMATION FOR SEQ ID NO:44:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:GGGGGGGAACATAACGACAACTGCAACTGC30(2) INFORMATION FOR SEQ ID NO:45:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:ACAGTTACAATTGTCATTGTGCTCGCCACC30(2) INFORMATION FOR SEQ ID NO:46:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:GCAGTTGCAGTTGTCGTTATGTTCCCCCCC30(2) INFORMATION FOR SEQ ID NO:47:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:GGCGGGAGAGAGGGGGACTACTGCTCGTGC30(2) INFORMATION FOR SEQ ID NO:48:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:GGTGGGAGAGAAGGGGACCACTGCTCCTGT30(2) INFORMATION FOR SEQ ID NO:49:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:GGTGGGAGAGAAGGGGACCACTGCTCCTGT30(2) INFORMATION FOR SEQ ID NO:50:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:GGGGGCCGGGAACATGACAGCTGCAACTGC30(2) INFORMATION FOR SEQ ID NO:51:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:GGGGGCCGGGAACATGACAGCTGCAACTGT30(2) INFORMATION FOR SEQ ID NO:52:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:GGGGGCCGGGAACATGACAGCTGTAACTGT30(2) INFORMATION FOR SEQ ID NO:53:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:GGTGGACGGAGCAAGGATCACTGTTCTTGT30(2) INFORMATION FOR SEQ ID NO:54:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:GGTGGACGGAGTAAGGACCACTGCTCTTGT30(2) INFORMATION FOR SEQ ID NO:55:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:GGTGGCCTCCATTACGACAACTGCAATTGT30(2) INFORMATION FOR SEQ ID NO:56:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:GGTGGCCTCCACTACGACAACTGCAATTGT30(2) INFORMATION FOR SEQ ID NO:57:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:GGGGGTCGTCAGGGAGATAACTGTGACTGT30(2) INFORMATION FOR SEQ ID NO:58:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:GGGGGTCGTCAAGGAGATAACTGTGACTGT30(2) INFORMATION FOR SEQ ID NO:59:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:GGGGGGCGTCAGGGAGATAATTGTGACTGT30(2) INFORMATION FOR SEQ ID NO:60:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 27 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:GGTGGCAGCTACGATGACTGCAACTGT27(2) INFORMATION FOR SEQ ID NO:61:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 27 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:GGTGGCAGCTACGATGACTGCAACTGT27(2) INFORMATION FOR SEQ ID NO:62:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 27 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:GGTGGCAGCTACGACGACTGCAACTGT27(2) INFORMATION FOR SEQ ID NO:63:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 27 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: other nucleic acid(A) DESCRIPTION: /desc = &#34;oligonucleotide&#34;(xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:GGCGGCAGCTATGACGACTGCAACTGC27(2) INFORMATION FOR SEQ ID NO:64:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 17 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:LeuValLeuValGlyCysPheSerValPheTrpThrIleTyrTyrMet151015Leu(2) INFORMATION FOR SEQ ID NO:65:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:ArgAlaLysArg(2) INFORMATION FOR SEQ ID NO:66:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:ArgGluLysArg1__________________________________________________________________________