WO1997048797A1 - Novel human chromosome 16 genes, compositions, methods of making and using same - Google Patents

Abstract

In accordance with the present invention, there are provided isolated nucleic acids encoding a human netrin, a human ATP binding cassette transporter, a human ribosomal L3 subtype, and a human augmenter of liver regeneration as well as isolated protein products encoded thereby. The present invention provides nucleic acid probes that hybridize to invention nucleic acids as well as isolated nucleic acids comprising unique gene sequences located on chromosome 16. Further provided are vectors containing invention nucleic acids, host cells transformed therewith, as well as transgenic non-human mammals that express invention polypeptides. The present invention includes antisense oligonucleotides, antibodies and compositions containing same. Additionally, the invention provides methods for identifying compounds that bind to invention polypeptides.

Description

NOVEL HUMAN CHROMOSOME 16 GENES. COMPOSITIONS. METHODS OF MAKING AND USING SAME

BACKGROUND OF THE INVENTION

The assembly of contiguous cloned genomic reagents is a necessary step in the process of disease-gene identification using a positional cloning approach. The rapid development of high density genetic maps based on polymorphic simple sequence repeats has facilitated contig assembly using sequence tagged site (STS) content mapping. Most contig construction efforts have relied on yeast artificial chromosomes (YACs) , since their large insert size uses the current STS map density more advantageously than bacterial-hosted systems. This approach has been validated for multiple human chromosomes with YAC coverage ranging from 65-95% for many chromosomes and contigs of 11 to 36 Mb being described (Chumakov et al . , Nature 377 (Supp. ) : 175-297, 1995; Doggett et al . , Nature 377 (Supp. ) :335-365, 1995b; Gemmill et al . , Nature 377 (Supp.) :299-319, 1995; Krauter et al . , Nature 377 (Supp. ) :321-333, 1995; Shimizu et al . , Cytogenet . Cell Genet . 70:147-182, 1995; van-Heyningen et al . , Cytogenet . Cell Genet . 69:127-158, 1995) .

Despite numerous successes, the YAC cloning system is not a panacea for cloning the entire genome of complex organisms due to intrinsic limitations that result in substantial proportions of chimeric clones (Green et al . , Genomics 11:658-669, 1991; Bellanne-Chantelot et al . , Cell 70:1059-1068, 1992; Nagaraja et al . , Nuc . Acids Res . 22:3406-3411, 1994), as well as clones that are rearranged, deleted or unstable (Neil et al . , Nuc . Acids Res . 18:1421- 1428, 1990; Wada et al . , Am. J. Hum. Genet . 46:95-106, 1990; Zuo et al . , Hum. Mol . Genet . 1:149-159, 1992; Szepetowski et al . , Cytogenet . Cell Genet . 69:101-107, 1995) . At least some of these cloned artifacts are a product of the recombinational machinery of yeast acting on the various types of repetitive elements in mammalian DNA (Neil et al . , supra . 1990; Green et al . , supra . 1991; Schlessinger et al . , Genomics 11:783-793, 1991; Ling et al . , Nuc . Acids Res . 21:6045-6046, 1993; Kouprina et al . , Genomics 21:7-17, 1994; Larionov et al . , Nuc . Acids Res . 22:4154-4162, 1994) .

Accordingly, alternative cloning systems must be used in concert with YAC-based approaches to complement localized YAC cloning deficiencies, to enhance the resolution of the physical map, and to provide a sequence-ready resource for genome-wide DNA sequencing. Several exon trapping methodologies and vectors have been described for the rapid and efficient isolation of coding regions from genomic DNA (Auch et al . , Nuc . Acids Res . 18:6743-6744, 1990; Duyk et al . , Proc . Natl . Acad. Sci . , USA 87:8995-8999, 1990; Buckler et al . , Proc . Natl . Acad. Sci . , USA 88:4005-4009, 1991; Church et al . , Nature Genet . 6:98-105, 1994) . The major advantage of exon trapping is that the expression of cloned genomic DNAs (cosmid, PI or YAC) is driven by a heterologous promoter in tissue culture cells. This allows for coding sequences to be identified without prior knowledge of their tissue distribution or developmental stage of expression. A second advantage of exon trapping is that exon trapping allows for the identification of coding sequences from only the cloned template of interest, which eliminates the risk of characterizing highly conserved transcripts from duplicated loci. This is not the case for either cDNA selection or direct library screening.

Exon trapping has been used successfully to identify transcribed sequences in the Huntington' s disease locus (Ambrose et al . , Hum . Mol . Genet . 1:697-703, 1992; Taylor et al . , Nature Genet . 2:223-227, 1992; Duyao et al . , Hum . Mol . Genet . 2:673-676, 1993) and BRCA1 locus (Brody et al . , Genomics 25:238-247 , 1995; Brown et al . , Proc . Natl . Acad. Sci . , USA 92:4362-4366, 1995) . In addition, a number of disease-causing genes have been identified using exon trapping, including the genes for Huntington's disease (The Huntington's Disease Collaborative Research Group, Cell 72:971-983, 1993), neurofibromatosis type 2 (Trofatter et al . , Cell 72:791-800, 1993), Menkes disease (Vulpe et al . , Nature Genet . 3:7-13, 1993), Batten Disease (The International Batten Disease Consortium, Cell 82:949-957, 1995) , and the gene responsible for the majority of Long-QT syndrome cases (Wang et al . , Nature Genet . 12:17-23, 1996) .

A 700 kb CpG-rich region in band 16pl3.3 has been shown to contain the disease gene for ~90% of the cases of autosomal dominant polycystic kidney disease (PKDl) (Germino et al . , Genomics 13:144-151, 1992; Somlo et al . , Genomics 13:152-158, 1992; The European Polycystic Kidney Disease Consortium, Cell 77:881-894, 1994) as well as the tuburin gene (TSC2), responsible for one form of tuberous sclerosis (The European Chromosome 16 Tuberous Sclerosis Consortium, Cell 75:1305-1315, 1993) . An estimated 20 genes are present in this region of chromosome 16 (Germino et al . , Kidney Int . Supp. 39:S20-S25, 1993) . Characterization of the region surrounding the PKDl gene in 16pl3.3, however, has been complicated by duplication of a portion of the genomic interval more proximally at 16pl3.1 (The European Polycystic Kidney Disease Consortium, supra . 1994) .

This chromosomal segment serves as a challenging test for large-insert cloning systems in E. coli and yeast since it resides in a GC-rich isochore (Saccone et al . , Proc . Natl . Acad. Sci . , USA 89:4913-4917, 1992) with an abundance of CpG islands (Harris et al . , Genomics 7:195- 206, 1990; Germino et al . , supra . 1992) , genes (Germino et al . , supra . 1993) and Alu repetitive sequences (Korenberg et al . , Cell 53:391-400, 1988) . Chromosome 16 also contains more low-copy repeats than other chromosomes with almost 25% of its cosmid contigs hybridizing to more than one chromosomal location when analyzed by fluorescence in si tu hybridization (FISH) (Okumura et al . , Cytogenet . Cell Genet . 67:61-67, 1994) . These types of repeats and sequence duplications interfere with "chromosome walking" techniques that are widely used for identification of genomic DNA and pose a challenge to hybridization-based methods of contig construction. This is because these techniques rely on hybridization to identify clones containing overlapping fragments of genomic DNA; thus, there is a high likelihood of "walking" into clones derived from homologues instead of clones derived from the authentic gene. In a similar manner, the sequence duplications and chromosome 16-specific repeats also interfere with the unambiguous determination of a complete cDNA sequence that encodes the corresponding protein. Furthermore, low copy repeats may lead to instability of this interval in bacteria, yeast and higher eukaryotes .

Thus, there is a need in the art for methods and compositions which enable accurate identification of genomic and cDNA sequences corresponding to authentic genes present on highly repetitive portions of chromosome 16, as well as genes similarly situated on other chromosomes. The present invention satisfies this need and provides related advantages as well.

SUMMARY OF THE INVENTION

In accordance with the present invention, there are provided isolated nucleic acids encoding a human netrin, a human ATP binding cassette transporter, a human ribosomal L3 subtype, and a human augmenter of liver regeneration.

The present invention further provides isolated protein products encoded by a human netrin gene, a human ATP binding cassette transporter gene, a human ribosomal L3 gene, and a human augmenter of liver regeneration gene.

Additionally, the present invention provides nucleic acid probes that hybridize to invention nucleic acids as well as isolated nucleic acids comprising unique gene sequences located on chromosome 16.

Further provided are vectors containing invention nucleic acids as well as host cells transformed with invention vectors.

Transgenic non-human mammals that express invention polypeptides are provided by the present invention.

The present invention includes antisense oligonucleotides, antibodies and compositions containing same.

Additionally, the invention provides methods for identifying compounds that bind to invention polypeptides. Such compounds are useful for modulating the activity of invention polypeptides. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a schematic diagram of the Pi contig and trapped exons.

Figures 2A and 2B show an alignment of selected exon traps with sequences in the databases.

Figures 3A through 3C show 6803 bp of hNET genomic sequence from Pi clone 53.8B (SEQ ID NO:19) .

Figures 4A and 4B show 1743 bp of hNET cDNA and deduced amino acid sequence coding for a human homologue of chicken netrin genes (SEQ ID NOs:20 and 21) .

Figures 4C and 4D show the nucleotide sequence of the 1.9 kb hNET cDNA including both 5' and 3' UTRs (SEQ ID NO:78) .

Figure 5 shows an amino acid comparison between chicken netrin-1 (SEQ ID NO:22), chicken netrin-2 (SEQ ID NO:23) and hNET (SEQ ID NO:21) . Shaded boxes denote regions of identical homology. The laminin domains V and VI and the C-terminal domain (C) are indicated by arrows with domain V divided into three sub-components (V-1 to V- 3) . The asterisks identify a motif for adhesion/signaling receptors.

Figure 6 shows a graphical representation of the homology between domains of chicken netrin-1, chicken netrin-2 and hNET.

Figure 7 shows exon traps, RT-PCR products and cDNA from the ABCgt.l clone. Exon traps are shown above. ABCgt.l DNA is shown below the exon traps with the position of the Genetrapper selection (S) and repair (R) oligonucleotides indicated. The position of the RT-PCR clones are shown below the cDNA. Figures 8A-8G show 5.8 kb of cDNA and deduced amino acid sequence encoding ABCgt.l clone (SEQ ID NOs:24 and 25) .

Figure 9A-9D show an amino acid alignment of murine ABC1 (SEQ ID NO:26) and ABC2 (SEQ ID NO:27) with clone ABCgt.l (SEQ ID NO:25) . Hyphens denote gaps; asterisks denote identical residues, while periods denote conservative substitutions. The location of the ATP binding cassettes is shown by the boxed regions. Numbers at the right show the relative position of the proteins.

Figure 10 shows the region of the transcriptional map of the PKDl locus from which Pi clones 49.10D, 109.8C and 47.2H were isolated. The open boxes represent trapped exons with their relative position indicated below the RPL3L (SEM L3) gene. c, r and h identify the location of the capture, repair and hybridization oligonucleotides, respectively.

Figures 11A-11B show the nucleotide and deduced amino acid sequence of the SEM L3 cDNA, now designated RPL3L (SEQ ID NOs:28 and 29) . The 5' upstream inframe stop codon is underlined and the arrows indicate the site of the polyA tract of the two shorter cDNA clones that were also isolated.

Figure 12 shows a comparison of the deduced amino acid sequences from human (SEQ ID NO:30), bovine (SEQ ID NO:31) , murine (SEQ ID NO:32) and the RPL3L (SEM L3) (SEQ ID NO:29) genes. Dashes indicate sequence identity to the human L3 gene. The nuclear targeting sequence at the N-terminal end is shaded and the bipartite motif is boxed.

Figure 13 shows the nucleotide and deduced amino acid sequence of the hALR cDNA (SEQ ID NO:33 and 34) . Figure 14 shows a comparison of the deduced amino acid sequences from rat ALR and human ALR (SEQ ID NOs:35 and 34) , respectively.

Figures 15A-15J show the nucleotide and deduced amino acid sequence of full-length hABC3 cDNA (SEQ ID NOs:74 and 75) .

Figure 16 shows a physical map of the region containing the hABC3 gene.

Figure 17A shows the deduced amino acid sequence for hABC3 (SEQ ID NO:75) aligned to the murine ABCl (SEQ ID NO:26) and ABC2 (SEQ ID NO:27) sequences (Luciani et al . , Genomics 21:150-159, 1994) and sequence predicted to be encoded by C. elegans cosmid C.48B4.4 (SEQ ID NO:77) (Wilson et al . , Nature 368:32-38, 1994) . Sequence identity is shown by letters, with mismatches denoted as periods. Gaps inserted during the alignment are also shown (=) . For ABCl, ABC2 and C.48B4.4, only those sequences included in, and C-terminal to, the first ATP-binding domain are shown. Boxes denote the ATP binding cassettes (I and III) and the HH1 domain (II) .

Figure 17B shows a schematic diagram of the ABC3 protein showing the transmembrane (TM) domains, ATP binding cassette (ABC) domains, Linker and HHl domains.

Figure 18 shows a map of the genomic interval surrounding the human netrin gene.

Figure 19A shows a GRAIL2 analysis of coding sequences in the 6.8 kb genomic sequence from 53.8B PI.

Figure 19B shows the results of a Pustell DNA/protein matrix comparing genomic sequence to chicken netrin-2. Figure 20A shows alignment of the human netrin with chicken netrin-1, chicken netrin-2 and UNC-6 (SEQ ID NO: 79) .

Figure 2OB shows a schematic of the genomic sequence with boxes representing exons and lines denoting the introns . Untranslated region is shown in black, with the location of the start codon indicated by the arrow. The domain structure of the human netrin protein is shown below the gene structure. The position of introns in the Drosophila netrin genes is shown by arrows, with the non-conserved intron being denoted by the open arrow.

DETAILED DESCRIPTION OF THE INVENTION

All patent applications, patents, and literature references cited in this specification are hereby incorporated by reference in their entirety. In case of conflict or inconsistency, the present description, including definitions, will control.

Definitions:

1. "complementary DNA (cDNA) " is defined herein as a single-stranded or double-stranded intronless DNA molecule that is derived from the authentic gene and whose sequence, or complement thereof, encodes a protein.

2. As referred to herein, a "contig" is a continuous stretch of DNA or DNA sequence, which may be represented by multiple, overlapping, clones or sequences.

3. As referred to herein, a "cosmid" is a DNA plasmid that can replicate in bacterial cells and that accommodates large DNA inserts from about 30 to about 51 kb in length.

4. The term "PI clones" refers to genomic DNAs cloned into vectors based on the PI phage replication mechanisms. These vectors generally accommodate inserts of about 70 to about 105 kb (Pierce et al . , Proc . Natl . Acad. Sci . , USA, 89:2056-2060, 1992) .

5. As used herein, the term "exon trapping" refers to a method for isolating genomic DNA sequences that are flanked by donor and acceptor splice sites for RNA processing.

6. "Amplification" of DNA as used herein denotes a reaction that serves to increase the concentration of a particular DNA sequence within a mixture ot DNA sequences. Amplification may be carried out using polymerase chain reaction (PCR) (Saiki et al . , Science, 239:487, 1988), ligase chain reaction (LCR) , nucleic acid- specific based amplification (NSBA) , or any method known in the art.

7. "RT-PCR" as used herein refers to coupled reverse transcription and polymerase chain reaction. This method of amplification uses an initial step in which a specific oligonucleotide, oligo dT, or a mixture of random primers is used to prime reverse transcription of RNA into single-stranded cDNA; this cDNA is then amplified using standard amplification techniques e.g. PCR.

A Pi contig containing approximately 700 kb of DNA surrounding the PKDl and TSC2 gene was assembled from a set of 12 unique chromosome 16-derived PI clones obtained by screening a 3 genome equivalent PI library (Shepherd et al . , Proc . Na tl . Acad. Sci . , USA 91:2629-2633 , 1994) with 15 distinct probes. Exon trapping was used to identify transcribed sequences from this region in 16pl3.3.

96 novel exon traps have been obtained containing sequences from a minimum of eighteen genes in this interval. The eighteen identified genes include five previously reported genes from the interval and a previously characterized gene whose location was unknown (Table I) . Additional exon traps have been mapped to genes based on their presence in cDNAs, RT-PCR products, or their hybridization to distinct mRNA species on Northern blots.

TABLE I: Database Ilomolυgics

a Gene as denoted in Fig I . b Number of the trapped exon present in cloned cDNA or PCR product. c Size of clone with type of clone indicated in parentheses. d Significant homology in databases as determined by BLASTX. e Accession Number of best hit. f. Smallest sum probability for the best database match.

Northern analysis was not performed due to the small size of the exon traps.

§• Up to 200 copies of LLREP3 are present in the genome.

Exon trapping was performed using an improved trapping vector (Burn et al . , Gene 161:183-187, 1995), with the resulting exon traps being characterized by DNA sequence analysis. In order to determine the relative efficiency of the exon trapping procedure, exon traps were compared to the cDNA sequences for those genes known to be in the interval around the PKDl gene (Figure 1) . Single exon traps were obtained from the human homologue of the ERV1 (Lisowsky et al . , Genomics 29:690-697, 1995) and the ATP6C proton pump genes (Gillespie et al . , Proc . Natl . Acad. Sci . , USA 88:4289-4293, 1991). The horizontal line at the top of Figure 1 shows the position of relevant DNA markers with the scale (in kilobases) . The position of NotI sites is shown below the horizontal line. The position and orientation of the known genes is indicated by arrows with the number of exon traps obtained from each gene shown in parentheses. The position of the transcription units described in this report (A through M) are shown below the known genes. The Genbank Accession numbers of corresponding exon traps are shown below each transcriptional unit. PI clones are indicated by the overlapping lines with the name of the clone shown above the line. The position of trapped exons which did not map to characterized transcripts are shown below the Pi contig. Vertical lines denote the interval within the PI clone(s) detected by the exon traps in hybridization studies.

In contrast, eight individual exon traps were isolated from the TSC2 gene and ten from the CCNF gene (The European Chromosome 16 Tuberous Sclerosis Consortium, supra . 1993; Kraus et al . , Genomics 24:27-33, 1994). Trapped sequences from three of the exons present in the PKDl gene were obtained (The American PKDl Consortium, Hum . Mol . Genet . 4:575-582, 1995; The International Polycystic Kidney Disease Consortium, Cell 81:289-298, 1995; Hughes et al . , Nature Genet . 10:151-160, 1995). 16 additional exon traps from the 109.8C and 47.2H PI clones were also obtained. Sequences present in two exon traps (Genbank Accession Nos. L75926 and L75927), localizing to the region of overlap between the 96.4B and 64.12C PI clones, were shown to contain sequences from the previously described human homologue to the murine RNPSl gene (Genbank Accession No. L37368) , encoding an S phase-prevalent DNA/RNA-binding protein (Schmidt et al . , Biochim . Biophys . Acta 1216:317- 320, 1993) . A comparison of these exon traps to the dbEST database indicated that they were also contained in cDNA 52161 from the I.M.A.G.E. Consortium (Lennon et al . , Genomics 33:151-152, 1996) . Based on these data, the hRNPSl gene can be mapped to 16pl3.3 near DNA marker D16S291 (transcript G in Figure 1) .

Two exon traps from the 1.8F Pi clone were found to have a high level of homology to the previously described murine ΦAP3 encoding a zinc finger-containing transcription factor (Fognani efc al . , EMBO J. 12:4985-4992,

1993) . The mΦAP3 protein, a zinc finger-containing transcription factor, is believed to function as a negative regulator for genes encoding proteins responsible for the inhibition of cell cycling (Fognani et al . , supra . ) . The two exon traps were linked by PCR, with the resulting 1.2 kb PCR product being 85% identical at the nucleotide level to the murine ΦAP3 cDNA. Hybridization of the ΦAP3-like exon traps to the dot blotted Pi contig indicated that the gene lies in the non-overlapping region of the 1.8F PI, between the DNA markers KLH7 and GGG12 (transcript H in Figure 1) .

Significant homology was also seen between two exon traps obtained from the 97.10G PI and the rat Rab26 gene encoding a ras-related GTP-binding protein involved in the regulation of vesicular transport (Nuoffer et al , Ann . Rev. Biochem. 63:949-990, 1994; Wagner et al . , Biochem . Biophys . Res . Comm. 207:950-956, 1995) . The Rab26-like exon traps were linked by RT-PCR (transcript J in Figure 1) witn the encoded sequences being 94% (83/88) identical at the protein level to Rab26. See, for example, Figure 2 showing an alignment of the following selected exon traps with sequences in the databases. An alignment of sequences encoded by exon trap L48741 (SEQ ID N0:1) and N-acetylglucosamine-6-phosphate deacetylase from C. Eleganε (SEQ ID N0:2), E. coli (SEQ ID N0:3) and Haemophiluε (SEQ ID NO:4) . The EGF repeat from netrin-1 (SEQ ID NO:7) , netrin-2 (SEQ ID NO:6) and UNC-6 (SEQ ID NO:8) are shown aligned to one of the translated netrin-like exon traps (Genbank Accession No. L75917) (SEQ ID N0:5) . An alignment of sequences from the second netrin-like exon trap (Genbank Accession No. L75916) (SEQ ID NO:9) and netrin-1 (SEQ ID NO:11) and netrin-2 (SEQ ID NO:10) is shown. An alignment of the translated Rab26-like RT-PCR product (Genbank Accession Nos. L48770-L48771) (SEQ ID NO:12) and rat Rab26 (SEQ ID NO:13) . Sequences encoded by exon trap L48792 (SEQ ID NO:14) are shown aligned to sequences from the pilB transcriptional repressor from Neisseria gonorrhoeae (SEQ ID NO:15), sequences predicted by computer analysis to be encoded by cosmid F44E2.6 from C. elegans (SEQ ID NO:17), the YCL33C gene product from yeast (Genbank Accession No. P25566) (SEQ ID NO:16), and a transcriptional repressor from Haemophilus (SEQ ID NO: 18) . Periods denote positions where gaps were inserted in the protein sequence in order to maintain alignment.

In order to correlate exon traps with individual transcripts, cDNA library screening and PCR based approaches were used to clone transcribed sequences containing selected exon traps. RT-PCR was used to link individual exon traps together in cases where the two exon traps had homology to similar sequences in the databases . In cases where only single exon traps were available, 3 ' RACE or cDNA library screening was used to obtain additional sequences. Sequences from the exon traps and cloned products were used to map the position, and when possible the orientation, of the corresponding transcription units. Six unique exon traps, containing sequences from at least eight exons, were shown to be from a transcriptional unit in the centromeric most Pi clone, 94.10H (transcript A in Figure 1) . A 2 kb cDNA linking the six exon traps was isolated and shown to hybridize to an 8 kb transcript. Additional hybridization studies indicated that the gene was oriented centromeric to telomeric, with at least 6 kb of the transcript originating from sequences centromeric of the Pi contig. Extensive homology was observed between the translated cDNA and a variety of protein kinases; however, the presence of the conserved HRDLKPEN motif (SEQ ID N0:71) encoded in exon trap L48734, as well as the partial cDNA, suggests that it encodes a serine/threonine kinase (van-der-Geer et al . , Ann . Rev. Cell Bio . 10:251-337, 1994) .

cDNAs were isolated using sequences derived from a separate 94.10H exon trap (Genbank Accession No. L48738) and the position and orientation of the corresponding transcription unit were determined. Two cDNA species were obtained using exon trap L48738 as a probe, with the only homology between the two species arising from the 109 bases contained in the exon trap. Using oligonucleotide probes, the transcription unit was mapped to a position near the 26-6DIS DNA marker, in a telomeric to centromeric orientation; however, only one of the cDNA species mapped to the PI contig (transcript B in Figure 1) . Based on these data, it is likely that the second cDNA species originated from a region outside of the PI contig, possibly from the duplicated 26-6PROX marker located further centromeric in 16pl3.3 (Gillespie et al . , Nuc . Acids Res . 18:7071-7075, 1990) .

The 110.IF Pi clone contains at least two genes in addition to the ATP6C gene. Using BLASTX to search the protein databases, significant homology was observed between sequences encoded by exon trap L48741 and the N-acetylglucosamine-6-phosphate deacetylase (nagA) proteins from C. elegans (Wilson et al . , supra . 1994), E. coli (Plumbridge, Mol . Microbiol . 3:505-515, 1989) and Haemophilus (Fleischmann et al . , Science 269:496-512, 1995) . An alignment of the nagA proteins to the translated exon trap revealed the presence of multiple conserved regions (Figure 2) , suggesting that the exon trap contains sequences from the human nagA gene. Additional sequences from the nagA-like transcript have been cloned using 3 ' RACE and the transcription unit mapped to a region between NotI sites 2 and 3 in Figure 1. The gene is oriented telomeric to centromeric with NotI site 2 being present in the 3' UTR of the RACE clone (transcript C in Figure 1) .

Two additional exon traps (Genbank Accession Nos. L75916 and L75917) , mapping to the region of overlap between the 110.IF and 53.8B PI clones (transcript D in Figure 1) , were shown to have homology with the chicken netrins (Kennedy et al. , Cell 78:425-435, 1994; Serafini et al . , Cell 78:409-424, 1994) and the C. elegans UNC-6 protein (Ishii et al . , Neuron 9:873-881, 1992) (Figures 2 and 20A) .

Sequences encoded by exon trap, L75917, were shown to have significant homology with the C-terminal most epidermal growth factor (EGF) repeat found in the netrin and UNC-6 proteins (Figures 2 and 20A) . Exon trap L75917 encodes sequences which are 98% identical to sequences from the third epidermal growth factor (EGF) repeat of chicken netrin-2 and 90% identical to sequences from the same region of netrin-1. The netrin-like trap, L75916, encodes sequences from the more divergent C-terminal domain of the netrins which are 43% identical to sequences contained in the C-terminal domain of netrin-1 and netrin-2 (Figures 2 and 20A) . This region is the least conserved between UNC-6 and the netrins, with sequences being 63% conserved between netrin-1 and netrin-2 and 29% conserved between netrin-2 and UNC-6 (Serafini et al .- , supra . ) .

Yl The netrins define a family of chemotropic factors which have been shown to play a central role in axon guidance. Axonal growth cones are guided to their target by both local cues, present in the extracellular matrix or on the surface of cells, and long-range cues in the form of diffusible chemoattractants and chemorepellents (Goodman and Shatz, Cell 72:77-98, 1993; Keynes and Cook, Curr. Opin . Neurobiol . 5:75-82, 1995) .

Chicken netrin-1 and netrin-2 have been shown to function as chemoattractants for developing spinal commissural axons (Serafini et al . , Cell 78:409-424, 1994; Kennedy et al . , Cell 78:425-435, 1994) with netrin-1 also acting as a chemorepellant for trochlear motor axons (Colamarino and Tessier-Lavigne, Cell 81:621-629, 1995) . Comparative analysis revealed the presence of extensive homology between the chicken netrins and C. elegans UNC-6 protein which is required for circumferential cell migration and axon guidance (Hedgecock et al . , Neuron 4:61-85, 1990; Ishii et al . , Neuron 9:873-881, 1992) . More recently, two Drosophila netrins, NETA and NETS, have been described and shown to be required for commissural axon guidance as well as for guidance of motor neurons to their target muscles (Harris et al . , Cell 17:217-228, 1996; Mitchell et al . , Cell 17:203-215, 1996) . These studies indicate that the netrin family of chemoattractant and chemorepellant proteins is conserved between invertebrates and vertebrates.

The genomic interval containing the netrin-like exon traps was sequenced in order to obtain additional sequence information from the gene and to rule out the possibility that the exon traps were derived from a pseudogene. In preliminary studies using the 53.8B genomic Pi clone, the netrin-like exon traps were mapped to a 6 kb Xhol fragment. See, for example, Figure 18 wherein relevant DNA markers are shown on top of the horizontal line, with Notl sites (N) being shown below the line. The location and orientation of the ATP6C, CCNF, and nagA transcriptional units have been previously described (Gillespie et al . , Proc . Na tl . Acad . Sci . , USA 88: 4289-4293, 1991; Kraus et al . , Genomics 24: 27-33, 1994; Burn et al . , Genome Research 6: 525-537, 1996) and are shown below the genomic interval. The two PI clones containing the netrin gene are shown below the schematic diagram of the interval. The location of the 6.8 kb of genomic sequence is enlarged below the PI clones. The position of the two exon traps in the 6.8 kb of genomic sequence is also indicated.

The 6 kb fragment, and the adjacent 3.5 kb Xhol fragment, were subcloned and used to screen a random shotgun library from the 53.8B PI clone. Subclones which were positive by hybridization were sequenced with forward and reverse vector primers. A total of 88 subclones were sequenced in this manner.

Additional sequence was obtained using internal primers as well as end sequence from the parental Xhol fragments. A total of 6.8 kb of genomic sequence with an overall redundancy of 7-fold was sequenced. The GC-content for the sequenced region was found to be 68.9%, which is slightly higher than the 62.8% observed for the 53 kb of genomic sequence from the PKDl gene, located 350 kb further telomeric (The American PKDl Consortium, 1995, supra ; Burn et al . , 1996, supra) .

Computer analyses were performed to identify putative exons. GRAIL2 analysis predicted six exons within the 6.8 kb of genomic sequence with database analysis indicating that all but one exon (exon 1) , encoded sequences with homology to the chicken netrins . Figure 19A shows a GRAIL2 analysis of coding sequences in the 6.8 kb of genomic sequence from the 53.8B PI, with the gray scale denoting GC-content (white to light gray is GC rich and gray to black is AT rich) , vertical boxes indicating relative quality of the predicted exons . A graphical depiction of the predicted exons is shown above the vertical boxes with light colored boxes denoting exons with a score of "excellent" ( >80% probability) and dark colored boxes denoting exons with a score of "good" (>60% probability) . The position of exon traps L75917 and L75916 (left to right, respectively) are shown above the GRAIL2 predicted exons. The structure of the gene based on comparison of the RT-PCR products and genomic sequence is shown at the top, the position of the exons in the genomic sequence is shown by the numbers above the exons. The 5' and 3' untranslated regions are also shown.

Additionally, the 6.8 kb of genomic sequence was compared to the protein sequences of the chicken netrins using a Pustell DNA/protein matrix. The genomic sequence (translated in all six frames) was compared to chicken netrin-2 in Figure 19B, using a PAM250 matrix with the minimum homology set at 50% and the window set at 20. Regions of homology are shown by heavy diagonal lines. Five exons were predicted by this analysis, with only the first GRAIL2 predicted exon not appearing to be bona fide . Sequences from the two exon traps were also predicted by GRAIL2; however, there were noteworthy differences ( cf Figure 19A) . In predicting sequences present in exon trap L75917, GRAIL2 included an additional 55 bp at the 5' end of the exon. The first of the two exons present in exon trap L75916 was not predicted by GRAIL2, while GRAIL2 added additional bases to the 5 ' and 3 ' ends of the second exon present in this exon trap.

A search of the Expressed Sequence Tags (EST) database did not reveal the presence of any ESTs from the human netrin gene. Nor was the human netrin message detected by Northern and/or RNA dot blot analysis using mRNA from over fifty different adult and fetal tissues, suggesting that hNET has an extremely restricted pattern of expression and when expressed is present in low abundance. Two murine ESTs, however, were identified from a brain library and a whole fetus library (Genbank Accession Nos. W59766 and AA048205, respectively) which have significant homology to hNET. The murine ESTs contain overlapping sequence with a total of 477 bp of contiguous sequence being represented. This 477 bp contiguous sequence aligns to the 5 ' end of the human netrin cDNA and includes 47 bp of 5 ' UTR and sequences encoding the N-terminal 143 amino acids. A comparison of the deduced human and murine protein sequence indicated that the two proteins were 89.5% (128/143) identical.

Characterization of the Human Netrin Transcript

In order to confirm the structure of the netrin gene, RT-PCR was performed using primers designed from the predicted exons. Since the predicted human netrin appeared to slightly more homologous to netrin-2 than netrin-1 (57% versus 54%, respectively) and netrin-2 is expressed in the spinal cord of chicken, adult human spinal cord polyA+ RNA was utilized as a template. RT-PCR products were obtained with only a portion of the primer pairs; however, even this required the use of nested primers and two rounds of PCR, with low yields making it necessary to use hybridization and radiolabeled probes to visualize the products. The low yield, and lack of RT-PCR products in some cases, was attributed to the high GC-content of the products (70-80%) . The addition of betaine to a final concentration of 2.5 M in the PCR reactions was found to dramatically improve yield and purity of the RT-PCR products. (International Publication No. WO 96/12041; Reeves et al . (1994) Am. J. Hum . Genet . 55:A238; Baskaran et al . (1996) Genome Research 6:633-638) .

Assembly of the RT-PCR products revealed a 1743 bp open reading frame (ORF) with an in-frame stop codon upstream of the proposed start methionine. In verifying the start and stop codons, a 209 bp 5' UTR and a 22 bp 3 ' UTR were cloned. Additional sequences from the respective UTRs were not cloned, however, since the goal of the RT-PCR experiments was to only confirm the predicted protein sequence and not to assemble a full-length cDNA. The position of the intron-exon boundaries was determined based on the comparison of the genomic sequence and the RT-PCR clones (Figure 19A) .

A 1.9 kb cDNA, hNET, was cloned by performing nested PCR using spinal cord cDNA as template and standard PCR conditions with the addition of betaine. The human netrin protein is predicted to be 580 amino acids in size, with the common domain structure of the netrin family being conserved. In Figure 20A positions where the chicken netrins and UNC-6 sequences match the human sequence are denoted by periods while gaps introduced during the alignment are shown by hyphens. Arrows above the sequence alignment show the boundaries of the laminin VI and V domains, and C-terminal region (C) as described (Serafini et al . , Cell 78: 409-424, 1994) . The signal sequence (S) is also shown. V-1, V-2, and V-3 designate each of the EGF domains that constitute domain V.

The hNET coding sequence and its predicted protein product are shown in Figures 4A and 4B. Figures 4C and 4D show full length hNET cDNA including both 5' and 3' UTR sequence.

Several lines of evidence rule against the possibility that the human netrin gene described herein represents a pseudogene. First, none of the exons in the coding region contain stop codons. Secondly, the overall gene structure described is highly conserved when compared to other members of the netrin/UNC-6 family. Third, despite the lack of signal in the Northern and RNA blot analysis, a mature transcript was isolated by RT-PCR. Finally, sequences in the murine EST database have been identified which are highly conserved. Taken together, these data indicate that a novel human netrin gene with a restricted pattern of expression has been identified.

Human netrins may have a significant role in neural regeneration. Though netrins do not by themselves promote axon growth, they do play a role in the orientation of axon growth. The combination of growth promoting activities with axon guidance cues would be a necessary requisite for directed neural regeneration.

The ability to clone a gene with such a restricted pattern of expression points out one of the strengths of the exon trapping procedure, since it is unlikely that the netrin gene would have been identified using cDNA selection or direct library screening. These results highlight the need for using a variety of approaches to identify and clone sequences from a large genomic contig.

Exon trapping results further show that there is a novel ATP Binding Cassette (ABC) transporter in the PKDl locus located between the LCN1 and D16S291 markers in a centromeric to telomeric orientation. Database searches with the exon trap sequences show homology to the murine ABCl and ABC2 genes (Luciani et al . , supra . 1994) . The human homologs of murine ABCl and ABC2 have been cloned and mapped to human chromosome 9 (Luciani et al . supra . 1994) . Sequences derived from the trapped exons along with those from cDNA selection and SAmple SEquencing (SASE) were used to recover overlapping partial cDNA clones.

Seven exon traps with homology to ABC transporters were isolated from PI clones 30.IF, 64.12C and 96.4B. Additional sequences encoded by the ABC3 gene were obtained by RT-PCR (placenta and brain RNA as template) and library PCR (using commercially available lung cDNA library as template) using custom primers designed from the exon traps (Tables II and III) . Three exon traps (L48758, L48759 and L48760) were obtained from the region of overlap between the 30. IF, 64.12C and 96.4B PI clones (transcript F Figure 1), while a fourth exon (L48753) maps to the 79.2A PI clone, exclusively (transcript E in Figure 1) . TABLE II: Oligonucleotides Used to Clone Additional Sequences

<0

CD

H C H

m a. Gene as denoted in Figure 1. x m Method used to clone additional sequences. Lifetechnologies Genetrapper system, 3 'RACE and RT-PCR . m Sequence of oligonucleotides used to obtain additional sequences. For the Genetrapper system, this oligonucleotide was used in the direct selection step. In the case of 3 'RACE experiments, this oligonucleotide was the external prime. In the case of RT-

3D c PCR experiments, the designated oligonucleotide was used as a sense primer. r m d. Sequence of oligonucleotides. In the Genetrapper experiments, this oligonucleotide was used in the repair step. For 3 'RACE to experiments,- this was the internal primer. For RT-PCR experiments, this was the anitsense primer. Size of clone obtained using the primer pair.

TABLE Ilia: Oligonucleotides Used to Clone Additional Sequences from human AB C3

Method used to clone additional sequences Lifetechnologics Genetrapper system and RT-PCR.

Sequence of oligonucleotides used to obtain additional sequences. For the Genetrapper system, this oligonucleotide was used in the diiect selection step. In the case of RT-PCR experiments, the designated oligonucleotide was used as a sense primer.

(Λ Sequence of oligonucleotides. In the Genetrapper experiments, this oligonucleotide was used in the repair step, For RT-PCR

03 experiments, this was the anitsense pi imcr. 0⁾ Assigned name of the isolated clone.

H Siv.c, of clone obtained using the primer pair. m

(A

X m m 'ABLE 111 b : Oligonucleotides Used to Clone Additional Sequences from human ΛB C3

H

33 c r- m ro

Clone used to derive the 5' primer.

Sequence of the sense primer used in the RT-PCR reaction.

Clone used to derive the 3' primer.

Sequence of the anttsense primer used in the RT-PCR reaction.

Assigned name of the isolated clone.

Size of clone obtained using the primer pair

Exon traps from the hABC3 transporter encoded by transcript F encode sequences with homology to the R-domain of the murine ABCl and ABC2 genes. The R-domain is believed to play a regulatory role based on the comparison to a conserved region in CFTR. To date, only ABCl, ABC2 and CFTR have been shown to contain an R-domain (Luciani et al . , supra . 1994) .

Additionally, a 1.1 kb RT-PCR product which links the three exon traps from transcript F, with the RT-PCR product detecting a 7 kb message on Northern blots has been obtained. Based on a search of the dbEST database, a cDNA from this region was obtained with sequences from exon traps L75924 and L75925 being contained in cDNA 49233 from the I.M.A.G.E. Consortium (Lennon et al . , supra . ) . The presence of both cloned reagents in the same transcription unit has been confirmed using RT-PCR.

The ATP binding cassette (ABC) transporters, or traffic ATPs, comprise a family of more than 100 proteins responsible for the transport of a wide variety of substrates across cell membranes in both prokaryotic and eukaryotic cells (Higgins, C. F., Annu . Rev. Cell . Biol . 8:67-113, 1992; Higgins, C. F. Cell 82:693-696, 1995) . Proteins belonging to the ABC transporter superfamily are linked by strong structural similarities . Typically ABC transporters have four conserved domains, two hydrophobic domains which may impart substrate specificity (Payne et al . , Mol . Gen . Genet . 200:493-496, 1985; Foote et al . , Nature 345:255-258, 1990; Anderson et al . , Science 253:202- 205, 1991; Shustik et al . , Br. J. Haema tol . 79:50-56, 1991; Covitz et al . , EMBO J. 13:1752-1759, 1994) , and two highly conserved domains associated with ATP binding and hydrolysis (Higgins, supra . 1992) . ABC transporters govern unidirectional transport of molecules into or out of cells and across subcellular membranes (Higgins, supra . 1992) . Their substrates range from heavy metals (Ouellette et al . , Res . Microbiol . 142:737-746 1991) to peptides and full size proteins (Gartner et al . , Nature Genet . 1:16-23 1992) . In eukaryotic cells, ABC transporters exist either as single large symmetrical proteins containing all four domains or as dimers resulting from the association of two smaller polypeptides each containing a hydrophobic and ATP-binding domain. Examples of this multimeric structural form are human TAP proteins (Kelly et al . , Nature 355:641- 644 1992) and the functional PMP70 protein (Kamijo et al . , J. Biol . Chem . 265:4534-40 1990) . This multimeric structure is also found in numerous prokaryotic ABC transporters. The hydrophobic regions are comprised of up to six transmembrane spanning segments. Each ATP binding domain operates independently and may or may not be functionally equivalent (Kerem et al . , Science 245:1073-80 1989; Mimmack et al . , Proc . Na tl . Acad. Sci . , USA 86:8257- 61 1989; Cutting et al . , Nature 346:366-369 1990; Kerppola et al . , J. Biol . Chem. 266:9857-65 1991) .

Several of the ABC transporters thus far identified in humans have been shown to be clinically important. For example, overexpression of P-glycoproteins is responsible for multi-drug resistance in tumors (Gottesman et al . , Ann . Rev. Biochem . 62:385-427 1993) . Classical cystic fibrosis (CF) as well as a large proportion of cases of bilateral congenital disease of the vas deferens (CBAVD) are caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) , an ABC transporter (Kerem et al . , supra . ; Cutting et al . , supra . ) . Defects in ABC transporters have also been implicated in Zellweger syndrome (Gartner et al . , supra . ) , and adrenoleukodystrophy (Mosser et al . , Nature 361:726-730 1993) .

Two members of a novel ABC transporter subgroup (murine ABCl and ABC2) have been shown to contain domains similar to the regulatory R-domain of CFTR (Luciani et al . , supra . 1994) . Functionally, the mouse ABCl protein has been shown to play a role in macrophage engulfment of apoptotic cells (Luciani et al . , EMBO J. 16:226-235, 1996), while the function of ABC2 remains unknown. All three proteins contain a large charged region containing several potential phosphorylation sites (Kerem et al . , supra . ; Luciani et al . , supra . 1994) . The charged amino acid residues within this region are sequentially arranged in blocks of alternating positive and negative charge.

A common feature of these particular ABC transporters, including hABC3, is the presence of a large linker domain between the two ATP binding cassettes. The presence of numerous polar residues and potential phosphorylation sites in the linker domain suggest that this region may play a regulatory role perhaps similar to that of the R-domain of CFTR (Kerem et al . , supra . ) . In addition, the four proteins also contain a hydrophobic region, the HHl domain (Luciani et al . , supra . 1994), within the conserved linker domain. Although there is little homology at the sequence level between the HHl domains of hABC3 and the murine ABCs, they appear to be structurally conserved with each domain predicted to have S-sheet conformation. The similarity between these proteins would suggest that they all belong to the same ABC subfamily, originally defined by ABCl and ABC2 (Luciani et al . , supra . 1994) . The genes encoding the human homologues of ABCl and ABC2 have been mapped to human chromosome 9 at q22-q31 and q34, respectively (Luciani et al . , supra . 1994) .

Despite being members of the same subfamily, it is likely that ABCl, ABC2 and hABC3 have different functional roles. The differences present in the transmembrane and linker domains of ABCl, ABC2 and hABC3 may confer each with a unique substrate specificity. For example, alterations and mutations in the transmembrane domains of both prokaryotic and eukaryotic ABC transporters have been shown to alter substrate specificity (Payne et al . , supra . ; Foote et al . , supra . ; Covitz et al . , supra . ) while changes to the R-domain of CFTR have been shown to alter its ion selectivity (Anderson et al . , supra . ; Rich et al . , Science 253:205-207 1991) . The differences in the expression patterns of ABCl, ABC2 and hABC3 also suggest that the proteins may be functionally distinct. Murine ABCl and ABC2 have been shown to be expressed at varying levels in a wide variety of adult and embryonic tissues, with the highest levels of ABCl expression being seen in pregnant uterus and regions rich in monocytic cells while highest levels of ABC2 expression were seen in brain (Luciani et al . , supra . 1994; Luciani et al . , supra . 1996) . In contrast, hABC3 is preferentially expressed in lung with significantly lower levels of expression being seen in brain, heart, and pancreas.

Apart from the structural differences between ABCl, ABC2 and hABC3, it is always possible that the three proteins play similar functional roles in different cell populations. To date, no function has been proposed for murine ABC2. However, recent data indicate that ABCl is required for the engulfment of cells undergoing apoptosis, though the molecular mechanism underlying ABCl function is unknown (Luciani et al . , supra . 1996) . If hABC3 functions in a manner similar to ABCl, it could be expressed by pulmonary macrophages involved in host defense.

ABC transporters have been described for substrates ranging from small ions to large polysaccharides and proteins. Based on the high level of expression in lung, the substrate for hABC3 may play an integral role in the lung function, including ion or polysaccharide transport. Further clues may be provided by a closer examination of hABC3 expression in the lung. These studies would include the identification of the lung cells responsible for hABC3 expression as well as determining the subcellular localization of hABC3. The identification and cloning of the hABC3 cDNA may have implications for cystic fibrosis, since it contains a potential R-domain and is expressed at highest levels in the lung. If hABC3 does play an integral role in lung function, then modulation or alteration of hABC3 substrate specificity could have significant therapeutic implications for CF.

Several cDNAs were cloned using the GeneTrapper direct selection system and oligos designed from the 5 ' most trapped exon encoding sequences with homology to ABCl (trapped exon L48747) . The longest clone isolated with the GeneTrapper system from a normal human lung cDNA library using custom oligonucleotides designed from the 5' most exon trap was 5719 bp in length (ABCgt.l) . An additional cDNA clone (ABC.5) was isolated using a radiolabeled 1.1 kb RT-PCR product (ABC3-12) as a probe (Figure 15) . The 5' end of the ABC3 cDNA was further characterized using 5 ' RACE, with several RACE products containing multiple in-frame stop codons upstream of the start methionine.

Accordingly, the present invention provides a novel human ABC gene which has homology to the murine ABCl and ABC2 genes, as well as sequences predicted to be encoded by cosmid C48B4.4 from C. elegans (Wilson et al . , supra . ) . A 6.4 kb cDNA has been assembled for the hABC3 transporter. The assembled cDNA contains a 5116 nucleotide long open reading frame encoding 1705 amino acids, with the predicted protein having a molecular weight of 191 kDa. The proposed start methionine is 50 bp upstream of the 5 ' end of clone ABCgt.l.

Five trapped exons from PI clones 109.8C and 47.2H were shown to contain sequences with homology to the human ribosomal protein L3 cDNA, with hybridization studies indicating that the L3-like gene is oriented centromeric to telomeric (transcript L in Figure 1) . The ribosomal L3 gene product is one of five essential proteins for peptidyltransferase activity in the large ribosomal subunit (Schulze and Nierhaus, EMBO J. 1:609-613, 1982) . Not surprisingly, the L3 amino acid sequence is highly conserved across species. Mammalian L3 genes showing -98% protein sequence identity have been characterized from man (Genbank Accession No. X73460), mouse (Peckham et al . , Genes Dev. 3:2062-2071, 1989), rat (Kuwano and Wool, Biochem . Biophys . Res . Comm . 187:58-64, 1992) and cow (Simonic et al . , Biochim . Biophys . Acta 1219:706-710, 1994) . The cumulative percent identity between the trapped exons and the reported human ribosomal protein L3 cDNA was 74% (537/724) at the nucleotide level.

A full-length cDNA encoding a novel ribosomal L3 protein subtype, SEM L3 , was isolated and sequenced (Figure 11) . This gene is now designated RPL3L and has been assigned GenBank Accession No. U65581. The deduced protein sequence is 407 amino acids long and shows 77% identity to other known mammalian L3 proteins, which are themselves highly conserved. Hybridization analysis of human genomic DNA suggests this novel gene is single copy and has a tissue specific pattern of expression.

The expression pattern of the previously identified human L3 gene and the novel human RPL3L was determined using multiple tissue Northern blots. The human L3 gene showed a ubiquitous pattern of expression in all tissues with the highest expression in the pancreas. In contrast, the novel gene described herein is strongly expressed in skeletal muscle and heart tissue, with low levels of expression in the pancreas. This novel gene, RPL3L (Ribosomal Protein L3-Like) , is located in a gene-rich region near the PKDl and TSC2 genes on chromosome 16pl3.3.

The RPL3L protein is more closely related to the above mentioned cytoplasmic ribosomal proteins than to previously described nucleus-encoded mitochondrial proteins (Graack et al . , Eur. J. Biochem. 206:373-380, 1992) . The presence of a highly conserved nuclear localization sequence in the RPL3L further supports the hypothesis that it represents a novel cytoplasmic L3 ribosomal protein subtype and not a nucleus-encoded mitochondrial protein. In addition, an exon trap (Genbank Accession No. L48792) from a gene which is located telomeric of the L3-like gene was obtained (transcript M in Figure 1) . Sequences encoded by transcript M were shown to have homology to pilB from Neisseria gonorrhoeae (Taha et al . , EMBO J. 7:4367-4378, 1988) as well as to a computer predicted 17.2 kDa protein encoded by cosmid F44E2.6 from C. elegans (Wilson et al . , supra . ) .

Using sequences from exon trap L48792, a 600 bp partial cDNA was isolated and it was determined that the corresponding gene is oriented centromeric to telomeric. A 1.3 kb message was detected by the cDNA on Northern blots. Sequences conserved between the partial cDNA and the hypothetical 17.2 kDa protein were also conserved in the pilB protein from Neisseria gonorrhoeae (Taha et al . , supra . 1988), a hypothetical 19.3 kDa protein from yeast (Genbank Accession No. P25566) , and a fimbrial transcription regulation repressor from Haemophilus (Fleischmann et al . , Science 269:496-512 1995) (Figure 2) . The pilB protein has homology to histidine kinase sensors and has been shown to play a role in the repression of pilin production in Neisseria gonorrhoeae (Taha et al . , supra . 1988; Taha et al . , Mol . Microbiol . 5:137-148, 1991) . However, residues conserved between pilB, transcript M and the C. elegans, yeast, and Haemophilus sequences do not include the conserved histidine kinase domains from piIB (Taha et al . , supra . 1991) . These findings suggest that the conserved region in transcript M has a function which is independent of the proposed histidine kinase sensor activity of pilB.

An additional exon trap from region of overlap between the 109.8C and 47.2H Pi clones was shown to contain human LLRep3 sequences (Slynn et al . , Nuc . Acids Res . 18:681, 1990) . Hybridization studies indicated that the LLRep3 sequences (transcript K in Figure 1) were located between the sazD and L3-like genes. The region of highest gene density appears to be at the telomeric end of this cloned interval, particularly the region between TSC2 and D16S84, with a minimum of five genes mapping to this region (transcription units K, L and M, sazD and hERVl) .

Also mapped to this region, was an exon trap which is 86% identical (170/197) at the nucleotide level to the previously described rat augmenter of liver regeneration (Hagiya et al . , Proc . Natl . Acad. Sci . , USA 91:8142-8146, 1994) . ALR is a growth factor which augments the growth of damaged liver tissue while having no effect on the resting liver. Studies have demonstrated that rat ALR is capable of augmenting hepatocytic regeneration following hepatectomy.

This ALR-like exon trap was also shown to contain sequences from the recently described hERVl gene, which encodes a functional homologue to yeast ERV1 (Lisowsky et al . , supra . ) .

A 468 bp cDNA, hALR, has been obtained from the human ALR gene (Figure 13) . The ALR sequences encode a 119 amino acid protein which is 84.8% identical and 94.1% similar to the rat ALR protein (Figure 14) .

The cloning of human ALR has significant implications in the treatment of degenerative liver diseases. For example, biologically active rat ALR has been produced from COS-7 cells expressing rat ALR cDNA (Hagiya et al. , supra . ) . Accordingly, recombinant hALR could be used in the treatment of damaged liver. In addition, a construct expressing hALR could be used in gene therapy to treat chronic liver diseases.

Forty three of the trapped exons did not have significant homology to sequences in the protein or DNA databases, nor were ESTs (expressed sequence tags) containing sequences from the exon traps observed in dbEST. The absence of ESTs containing sequences from these novel exon traps is not surprising since one of the criterion for selecting exon traps for further analysis was the presence of an EST in the database. These trapped exons are likely to represent bona fide products, since in many cases they were trapped multiple times from different PI clones and in combination with flanking exons.

The present invention encompasses novel human genes an isolated nucleic acids comprising unique exon sequences from chromosome 16. The sequences described herein provide a valuable resource for transcriptional mapping and create a set of sequence-ready templates for a gene-rich interval responsible for at least two inheritable diseases.

Accordingly, the present invention provides isolated nucleic acids encoding human netrin (hNET) , human ATP Binding Cassette transporter (hABC3) , human ribosomal L3 (RPL3L) and human augmenter of liver regeneration (hALR) polypeptides. The present invention further provides isolated nucleic acids comprising unique exon sequences from chromosome 16. The term "nucleic acids" (also referred to as polynucleotides) encompasses RNA as well as single and double-stranded DNA, cDNA and oligonucleotides. As used herein, the phrase "isolated" means a polynucleotide that is in a form that does not occur in nature.

One means of isolating polynucleotides encoding invention polypeptides is to probe a human tissue-specific library with a natural or artificially designed DNA probe using methods well known in the art. DNA probes derived from the human netrin gene, hNET, the human ABC transporter gene, hABC3, the human ribosomal protein L3 gene, RPL3L, or the human augmenter of liver regeneration gene, hALR, are particularly useful for this purpose. DNA and cDNA molecules that encode invention polypeptides can be used to obtain complementary genomic DNA, cDNA or RNA from human, mammalian, or other animal sources, or to isolate related cDNA or genomic clones by the screening of cDNA or genomic libraries, by methods described in more detail below.

The present invention encompasses isolated nucleic acid sequences, including sense and antisense oligonucleotide sequences, derived from the sequences shown in Figures 3, 4, 8, 11 and 15. hNET-, hABC3-, RPL3L- (SEM L3-) , and hALR-derived sequences may also be associated with heterologous sequences, including promoters, enhancers, response elements, signal sequences, polyadenylation sequences, and the like. Furthermore, the nucleic acids can be modified to alter stability, solubility, binding affinity, and specificity. For example, invention-derived sequences can further include nuclease-resistant phosphorothioate, phosphoroamidate, and methylphosphonate derivatives, as well as "protein nucleic acid" (PNA) formed by conjugating bases to an amino acid backbone as described in Nielsen et al . , Science, 254:1497, 1991. The nucleic acid may be derivatized by linkage of the α-anomer nucleotide, or by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage. Furthermore, the nucleic acid sequences of the present invention may also be modified with a label capable of providing a detectable signal, either directly or indirectly. Exemplary labels include radioisotopes, fluorescent molecules, biotin, and the like.

In general, nucleic acid manipulations according to the present invention use methods that are well known in the art, as disclosed in, for example, Sambrook et al . , Molecular Cloning, A Laboratory Manual 2d Ed. (Cold Spring Harbor, NY, 1989), or Ausubel et al . , Current Protocols in Molecular Biology (Greene Assoc, Wiley Interscience, NY, NY, 1992) .

Examples of nucleic acids are RNA, cDNA, or genomic DNA encoding a human netrin, a human ABC transporter, a human ribosomal L3 subtype, or a human augmenter of liver regeneration polypeptide. Such nucleic acids may have coding sequences substantially the same as the coding sequence shown in Figures 3, 4, 8, 11 and 15, respectively.

The present invention further provides isolated oligonucleotides corresponding to sequences within the hNET, hABC3, RPL3L (formerly SEM L3) , hALR genes, or within the respective cDNAs, which, alone or together, can be used to discriminate between the authentic expressed gene and homologues or other repeated sequences . These oligonucleotides may be from about 12 to about 60 nucleotides in length, preferably about 18 nucleotides, may be single- or double-stranded, and may be labeled or modified as described below.

This invention also encompasses nucleic acids which differ from the nucleic acids shown in Figures 3, 4, 8, 11 and 15, but which have the same phenotype, i.e., encode substantially the same amino acid sequence set forth in Figures 3, 4, 8, 11 and 15, respectively. Phenotypically similar nucleic acids are also referred to as "functionally equivalent nucleic acids". As used herein, the phrase "functionally equivalent nucleic acids" encompasses nucleic acids characterized by slight and non- consequential sequence variations that will function in substantially the same manner to produce the same protein product(s) as the nucleic acids disclosed herein. In particular, functionally equivalent nucleic acids encode proteins that are the same as those disclosed herein or that have conservative amino acid variations. For example, conservative variations include substitution of a non-polar residue with another non-polar residue, or substitution of a charged residue with a similarly charged residue. These variations include those recognized by skilled artisans as those that do not substantially alter the tertiary structure of the protein.- Further provided are nucleic acids encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, and human augmenter of liver regeneration polypeptides that, by virtue of the degeneracy of the genetic code, do not necessarily hybridize to the invention nucleic acids under specified hybridization conditions. Preferred nucleic acids encoding the invention polypeptide are comprised of nucleotides that encode substantially the same amino acid sequence set forth in Figures 4, 8, 11 and 15. Alternatively, preferred nucleic acids encoding the invention polypeptide(s) hybridize under high stringency conditions to substantially the entire sequence, or substantial portions (i.e., typically at least 12 to 60 nucleotides) of the nucleic acid sequence set forth in Figures 3, 4, 8, 11 and 15, respectively.

Stringency of hybridization, as used herein, refers to conditions under which polynucleotide hybrids are stable. As known to those of skill in the art, the stability of hybrids is a function of sodium ion concentration and temperature. (See, for example, Sambrook et al . , supra . ) .

The present invention provides isolated polynucleotides operatively linked to a promoter of RNA transcription, as well as other regulatory sequences. As used herein, the phrase "operatively linked" refers to the functional relationship of the polynucleotide with regulatory and effector sequences of nucleotides, such as promoters, enhancers, transcriptional and translational stop sites, and other signal sequences. For example, operative linkage of a polynucleotide to a promoter refers to the physical and functional relationship between the polynucleotide and the promoter such that transcription of DNA is initiated from the promoter by an RNA polymerase that specifically recognizes and binds to the promoter, and wherein the promoter directs the transcription of RNA from the polynucleotide. Promoter regions include specific sequences that are sufficient for RNA polymerase recognition, binding and transcription initiation. Additionally, promoter regions include sequences that modulate the recognition, binding and transcription initiation activity of RNA polymerase. Such sequences may be cis acting or may be responsive to trans acting factors . Depending upon the nature of the regulation, promoters may be constitutive or regulated. Examples of promoters are SP6, T4, T7, SV40 early promoter, cytomegalovirus (CMV) promoter, mouse mammary tumor virus (MMTV) steroid-inducible promoter, Moloney murine leukemia virus (MMLV) promoter, and the like.

Vectors that contain both a promoter and a cloning site into which a polynucleotide can be operatively linked are well known in the art. Such vectors are capable of transcribing RNA in vi tro or in vivo, and are commercially available from sources such as Stratagene (La Jo11a, CA) and Promega Biotech (Madison, WI) . In order to optimize expression and/or in vi tro transcription, it may be necessary to remove, add or alter 5' and/or 3' untranslated portions of the clones to eliminate extra, potential inappropriate alternative translation initiation codons or other sequences that may interfere with or reduce expression, either at the level of transcription or translation. Alternatively, consensus ribosome binding sites can be inserted immediately 5' of the start codon to enhance expression. Similarly, alternative codons, encoding the same amino acid, can be substituted for coding sequences of the human netrin, human ABC3 transporter, the human ribosomal L3 subtype, or the human augmenter of liver regeneration polypeptide in order to enhance transcription (e.g., the codon preference of the host cell can be adopted, the presence of G-C rich domains can be reduced, and the like) .

Examples of vectors are viruses, such as baculoviruses and retroviruses, bacteriophages, cosmids, plasmids, fungal vectors and other recombination vehicles typically used in the art which have been described for expression in a variety of eukaryotic and prokaryotic hosts, and may be used for gene therapy as well as for simple protein expression.

Polynucleotides are inserted into vector genomes using methods well known in the art. For example, insert and vector DNA can be contacted, under suitable conditions, with a restriction enzyme to create complementary ends on each molecule that can pair with each other and be joined together with a ligase. Alternatively, synthetic nucleic acid linkers can be ligated to the termini of restricted polynucleotide. These synthetic linkers contain nucleic acid sequences that correspond to a particular restriction site in the vector DNA. Additionally, an oligonucleotide containing a termination codon and an appropriate restriction site can be ligated for insertion into a vector containing, for example, some or all of the following:a selectable marker gene, such as the neomycin gene for selection of stable or transient transfectants in mammalian cells; enhancer/promoter sequences from the immediate early gene of human CMV for high levels of transcription; transcription termination and RNA processing signals from SV40 for mRNA stability; SV40 polyoma origins of replication and ColEl for proper episomal replication; versatile multiple cloning sites; and T7 and SP6 RNA promoters for in vi tro transcription of sense and antisense RNA. Other means are well known and available in the art.

Also provided are vectors comprising a polynucleotide encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, and human augmenter of liver regeneration polypeptides, adapted for expression in a bacterial cell, a yeast cell, an amphibian cell, an insect cell, a mammalian cell and other animal cells . The vectors additionally comprise the regulatory elements necessary for expression of the polynucleotide in the bacterial, yeast, amphibian, mammalian or animal cells so located relative to the polynucleotide encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptides as to permit expression thereof. As used herein, "expression" refers to the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins. If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA, if an appropriate eukaryotic host is selected. Regulatory elements required for expression include promoter sequences to bind RNA polymerase and transcription initiation sequences for ribosome binding. For example, a bacterial expression vector includes a promoter such as the lac promoter and for transcription initiation the Shine- Dalgarno sequence and the start codon AUG (Sambrook et al . , supra . ) . Similarly, a eukaryotic expression vector includes a heterologous or homologous promoter for RNA polymerase II, a downstream polyadenylation signal, the start codon AUG, and a termination codon for detachment of the ribosome. Such vectors can be obtained commercially or assembled by the sequences described in methods well known in the art, for example, the methods described above for constructing vectors in general . Expression vectors are useful to produce cells that express the invention receptor.

This invention provides a transformed host cell that recombinantly expresses the human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptides. Invention host cells have been transformed with a polynucleotide encoding a human netrin, a human ABC3 transporter, a human ribosomal L3 subtype, or a human augmenter of liver regeneration polypeptide. An example is a mammalian cell comprising a plasmid adapted for expression in a mammalian cell. The plasmid contains a polynucleotide encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide and the regulatory elements necessary for expression of the invention protein. Appropriate host cells include bacteria, archebacteria, fungi, especially yeast, plant cells, insect cells' and animal cells, especially mammalian cells. Of particular interest are E. coli , B. Subtilis, Saccharomyces cerevisiae, SF9 cells, C129 cells, 293 cells, Neurospora , and CHO cells, COS cells, HeLa cells, and immortalized mammalian myeloid and lymphoid cell lines. Preferred replication systems include M13, ColEl, SV40, baculovirus, lambda, adenovirus, artificial chromosomes, and the like. A large number of transcription initiation and termination regulatory regions have been isolated and shown to be effective in the transcription and translation of heterologous proteins in the various hosts. Examples of these regions, methods of isolation, manner of manipulation, and the like, are known in the art. Under appropriate expression conditions, host cells can be used as a source of recombinantly produced hNET, hABC3, RPL3L (formerly SEM L3) and/or hALR.

Nucleic acids (polynucleotides) encoding invention polypeptides may also be incorporated into the genome of recipient cells by recombination events. For example, such a sequence can be microinjected into a cell, and thereby effect homologous recombination at the site of an endogenous gene encoding hNET, hABC3, RPL3L (formerly SEM L3), and/or hALR an analog or pseudogene thereof, or a sequence with substantial identity to a hNET-, hABC3-, RPL3L (SEM L3-), or hALR- encoding gene. Other recombination-based methods such as nonhomologous recombinations or deletion of endogenous gene by homologous recombination, especially in pluripotent cells, may also be used.

The present invention provides isolated peptides, polypeptides (s) and/or protein(s) encoded by the invention nucleic acids. The present invention also encompasses isolated polypeptides having a sequence encoded by hNET, hABC3, RPL3L (SEM L3) , and hALR genes, as well as peptides of six or more amino acids derived therefrom. The polypeptide(s) may be isolated from human tissues obtained by biopsy or autopsy, or may be produced in a heterologous cell by recombinant DNA methods as described herein.

As used herein, the term "isolated" means a protein molecule free of cellular components and/or contaminants normally associated with a native in vivo environment. Invention polypeptides and/or proteins include any natural occurring allelic variant, as well as recombinant forms thereof. Invention polypeptides can be isolated using various methods well known to a person of skill in the art.

The methods available for the isolation and purification of invention proteins include, precipitation, gel filtration, and chromatographic methods including molecular sieve, ion-exchange, and affinity chromatography using e.g. hNET-, hABC3-, RPL3L- (SEM L3-) , and/or hALR- specific antibodies or ligands. Other well-known methods are described in Deutscher et al . , Guide to Protein Purification : Methods in Enzymology Vol . 182, (Academic Press, 1990) . When the invention polypeptide to be purified is produced in a recombinant system, the recombinant expression vector may comprise additional sequences that encode additional amino-terminal or carboxy- terminal amino acids; these extra amino acids act as "tags" for immunoaffinity purification using immobilized antibodies or for affinity purification using immobilized ligands.

Peptides comprising hNET-, hABC3-, RPL3L- (SEM L3-) or hALR-specific sequences may be derived from isolated larger hNET, hABC3, RPL3L (SEM L3) , or hALR polypeptides described above, using proteolytic cleavages by e.g. proteases such as trypsin and chemical treatments such as cyanogen bromide that are well-known in the art. Alternatively, peptides up to 60 residues in length can be routinely synthesized in milligram quantities using commercially available peptide synthesizers.

An example of the means for preparing the invention polypeptide(s) is to express polynucleotides encoding hNET, hABC3, RPL3L (SEM L3) , and/or hALR in a suitable host cell, such as a bacterial cell, a yeast cell, an amphibian cell (i.e., oocyte) , an insect cell (i.e., drosophila) or a mammalian cell, using methods well known in the art, and recovering the expressed polypeptide, again using well-known methods. Invention polypeptides can be isolated directly from cells that have been transformed with expression vectors, described below in more detail. The invention polypeptide, biologically active fragments, and functional equivalents thereof can also be produced by chemical synthesis. As used herein, "biologically active fragment" refers to any portion of the polypeptide represented by the amino acid sequence in Figures 4, 8, 11 and 15 that can assemble into an active protein. Synthetic polypeptides can be produced using Applied Biosystems, Inc. Model 43OA or 431A automatic peptide synthesizer (Foster City, CA) employing the chemistry provided by the manufacturer.

Modification of the invention nucleic acids, polynucleotides, polypeptides, peptides or proteins with the following phrases: "recombinantly expressed/produced", "isolated", or "substantially pure", encompasses nucleic acids, polynucleotides, polypeptides, peptides or proteins that have been produced in such form by the hand of man, and are thus separated from their native in vivo cellular environment. As a result of this human intervention, the recombinant nucleic acids, polynucleotides, polypeptides, peptides and proteins of the invention are useful in ways that the corresponding naturally occurring molecules are not, such as identification of selective drugs or compounds. Sequences having "substantial sequence homology" are intended to refer to nucleotide sequences that share at least about 90% identity with invention nucleic acids; and amino acid sequences that typically share at least about 95% amino acid identity with invention polypeptides. It is recognized, however, that polypeptides or nucleic acids containing less than the above-described levels of homology arising as splice variants or that are modified by conservative amino acid substitutions, or by substitution of degenerate codons are also encompassed within the scope of the present invention.

The present invention provides a nucleic acid probe comprising a polynucleotide capable of specifically hybridizing with a sequence included within the nucleic acid sequence encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide, for example, a coding sequence included within the nucleotide sequence shown in Figures 3, 4, 8, 11 and 15, respectively.

As used herein, a "nucleic acid probe" may be a sequence of nucleotides that includes from about 12 to about 60 contiguous bases set forth in Figures 3, 4, 8, 11 and 15, preferably about 18 nucleotides, may be single- or double-stranded, and may be labeled or modified as described herein. Preferred regions from which to construct probes include 5' and/or 3' coding sequences, sequences predicted to encode transmembrane domains, sequences predicted to encode cytoplasmic loops, signal sequences, ligand binding sites, and the like.

Full-length or fragments of cDNA clones can also be used as probes for the detection and isolation of related genes. When fragments are used as probes, preferably the cDNA sequences will be from the carboxyl end-encoding portion of the cDNA, and most preferably will include predicted transmembrane domain-encoding portions of the cDNA sequence. Transmembrane domain regions can be predicted based on hydropathy analysis of the deduced amino acid sequence using, for example, the method of Kyte and Doolittle {J. Mol . Biol . 157:105, 1982) .

As used herein, the phrase "specifically hybridizing" encompasses the ability of a polynucleotide to recognize a sequence of nucleic acids that are complementary thereto and to form double-helical segments via hydrogen bonding between complementary base pairs. Nucleic acid probe technology is well known to those skilled in the art who will readily appreciate that such probes may vary greatly in length and may be labeled with a detectable agent, such as a radioisotope, a fluorescent dye, and the like, to facilitate detection of the probe. Invention probes are useful to detect the presence of nucleic acids encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptides. For example, the probes can be used for in si tu hybridizations in order to locate biological tissues in which the invention gene is expressed. Additionally, synthesized oligonucleotides complementary to the nucleic acids of a polynucleotide encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptides are useful as probes for detecting the invention genes, their associated mRNA, or for the isolation of related genes using homology screening of genomic or cDNA libraries, or by using amplification techniques well known to one of skill in the art.

Also provided are antisense oligonucleotides having a sequence capable of binding specifically with any portion of an mRNA that encodes human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide so as to prevent translation of the mRNA. The antisense oligonucleotide may have a sequence capable of binding specifically with any portion of the sequence of the cDNA encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide. As used herein, the phrase "binding specifically" encompasses the ability of a nucleic acid sequence to recognize a complementary nucleic acid sequence and to form double- helical segments therewith via the formation of hydrogen bonds between the complementary base pairs. An example of an antisense oligonucleotide is an antisense oligonucleotide comprising chemical analogs of nucleotides (i.e., synthetic antisense oligonucleotide, SAO) .

Compositions comprising an amount of the antisense oligonucleotide, (SAOC) , effective to reduce expression of the human netrin, the human ABC3 transporter, the human ribosomal L3 subtype, or the human augmenter of liver regeneration polypeptide by passing through a cell membrane and binding specifically with mRNA encoding the human netrin, the human ABC3 transporter, the human ribosomal L3 subtype, or the human augmenter of liver regeneration polypeptide so as to prevent its translation and an acceptable hydrophobic carrier capable of passing through a cell membrane are also provided herein. The acceptable hydrophobic carrier capable of passing through cell membranes may also comprise a structure which binds to a receptor specific for a selected cell type and is thereby taken up by cells of the selected cell type. The structure may be part of a protein known to bind to a cell-type specific receptor.

This invention provides a means to modulate levels of expression of invention polypeptides by the use of a synthetic antisense oligonucleotide composition (SAOC) which inhibits translation of mRNA encoding these polypeptides. Synthetic oligonucleotides, or other antisense chemical structures designed to recognize and selectively bind to mRNA, are constructed to be complementary to portions of the nucleotide sequences shown in Figures 3, 4, 8, 11 and 15, of DNA, RNA or chemically modified, artificial nucleic acids. The SAOC is designed to be stable in the blood stream for administration to a subject by injection, or in laboratory cell culture conditions. The SAOC is designed to be capable of passing through the cell membrane in order to enter the cytoplasm of the cell by virtue of physical and chemical properties of the SAOC which render it capable of passing through cell membranes, for example, by designing small, hydrophobic SAOC chemical structures, or by virtue of specific transport systems in the cell which recognize and transport the SAOC into the cell.

In addition, the SAOC can be designed for administration only to certain selected cell populations by targeting the SAOC to be recognized by specific cellular uptake mechanisms which bind and take up the SAOC only within select cell populations. For example, the SAOC may be designed to bind to a receptor found only in a certain cell type, as discussed supra . The SAOC is also designed to recognize and selectively bind to the target mRNA sequence, which may correspond to a sequence contained within the sequence shown in Figures 3, 4, 8, 11 and 15. The SAOC is designed to inactivate the target mRNA sequence by either binding to the target mRNA and inducing degradation of the mRNA by, for example, RNase I digestion, or inhibiting translation of the mRNA target by interfering with the binding of translation-regulating factors or ribosomes, or inclusion of other chemical structures, such as ribozyme sequences or reactive chemical groups which either degrade or chemically modify the target mRNA. SAOCs have been shown to be capable of such properties when directed against mRNA targets (see Cohen et al . , TIPS, 10:435, 1989 and Weintraub, Sci . American, January pp.40, 1990) .

This invention further provides a composition containing an acceptable carrier and any of an isolated, purified human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide, an active fragment thereof, or a purified, mature protein and active fragments thereof, alone or in combination with each other. These polypeptides or proteins can be recombinantly derived, chemically synthesized or purified from native sources. As used herein, the term "acceptable carrier" encompasses any of the standard pharmaceutical carriers, such as phosphate buffered saline solution, water and emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.

Also provided are antibodies having specific reactivity with the human netrin, the human ABC3 transporter, the human ribosomal L3 subtype, or the human augmenter of liver regeneration polypeptides of the subject invention. Active fragments of antibodies are encompassed within the definition of "antibody" . Invention antibodies can be produced by methods known in the art using the invention proteins or portions thereof as antigens. For example, polyclonal and monoclonal antibodies can be produced by methods well known in the art, as described, for example, in Harlow and Lane, Antibodies : A Laboratory Manual (Cold Spring Harbor Laboratory 1988) .

The polypeptides of the present invention can be used as the immunogen in generating such antibodies. Alternatively, synthetic peptides can be prepared (using commercially available synthesizers) and used as immunogens. Where natural or synthetic hNET-, hABC3-, RPL3L- (SEM L3-), and/or hALR-derived peptides are used to induce a hNET-, hABC3-, RPL3L- (SEM L3-) , and/or hALR- specific immune response, the peptides may be conveniently coupled to an suitable carrier such as KLH and administered in a suitable adjuvant such as Freund's. Preferably, selected peptides are coupled to a lysine core carrier substantially according to the methods of Tarn, Proc . Natl . Acad. Sci , USA 85:5409-5413, 1988. The resulting antibodies may be modified to a monovalent form, such as, for example, Fab, Fab₂, FAB', or FV. Anti-idiotypic antibodies may also be prepared using known methods. In one embodiment, normal or mutated hNET, hABC3, RPL3L (SEM L3) , or hALR polypeptides are used to immunize mice, after which their spleens are removed, and splenocytes used to form cell hybrids with myeloma cells and obtain clones of antibody-secreted cells according to techniques that are standard in the art. The resulting monoclonal antibodies are screened for specific binding to hNET, hABC3, RPL3L (SEM L3) , and/or hALR proteins or hNET-, hABC3-, RPL3L- (SEM L3-) , and/or hALR-related peptides.

In another embodiment, antibodies are screened for selective binding to normal or mutated hNET, hABC3, RPL3L (SEM L3) , or hALR sequences. Antibodies that distinguish between normal and mutant forms of hNET, hABC3, RPL3L (SEM L3) , or hALR may be used in diagnostic tests (see below) employing ELISA, EMIT, CEDIA, SLIFA, and the like. Anti- hNET, hABC3 , RPL3L (SEM L3) , or hALR antibodies may also be used to perform subcellular and histochemical localization studies. Finally, antibodies may be used to block the function of the hNET, hABC3, RPL3L (SEM L3) , and/or hALR polypeptide, whether normal or mutant, or to perform rational drug design studies to identify and test inhibitors of the function (e.g., using an anti-idiotypic antibody approach) .

Amino acid sequences can be analyzed by methods well known in the art to determine whether they encode hydrophobic or hydrophilic domains of the corresponding polypeptide. Altered antibodies such as chimeric, humanized, CDR-grafted or bifunctional antibodies can also be produced by methods well known in the art. Such antibodies can also be produced by hybridoma, chemical synthesis or recombinant methods described, for example, in Sambrook et al . , supra . , and Harlow and Lane, supra . Both anti-peptide and anti-fusion protein antibodies can be used, (see, for example, Bahouth et al . , Trends Pharmacol . Sci . 12:338, 1991; Ausubel et al . , supra . ) . Invention antibodies can be used to isolate invention polypeptides. Additionally, the antibodies are useful for detecting the presence of the invention polypeptides, as well as analysis of polypeptide localization, composition, and structure of functional domains. Methods for detecting the presence of a human netrin, a human ABC3 transporter, a human ribosomal L3 subtype, or a human augmenter of liver regeneration polypeptide comprise contacting the cell with an antibody that specifically binds to the polypeptide, under conditions permitting binding of the antibody to the polypeptide, detecting the presence of the antibody bound to the cell, and thereby detecting the presence of the invention polypeptide on the cell. With respect to the detection of such polypeptides, the antibodies can be used for in vi tro diagnostic or in vivo imaging methods.

Immunological procedures useful for in vi tro detection of the target human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide in a sample include immunoassays that employ a detectable antibody. Such immunoassays include, for example, ELISA, Pandex microfluorimetric assay, agglutination assays, flow cytometry, serum diagnostic assays and immunohistochemical staining procedures which are well known in the art. An antibody can be made detectable by various means well known in the art. For example, a detectable marker can be directly or indirectly attached to the antibody. Useful markers include, for example, radionuclides, enzymes, fluorogens, chromogens and chemiluminescent labels.

For in vivo imaging methods, a detectable antibody can be administered to a subject and the binding of the antibody to the invention polypeptide can be detected by imaging techniques well known in the art. Suitable imaging agents are known and include, for example, gamma-emitting radionuclides such as ^1:L1In, ^99mTc, ⁵¹Cr and the like, as well as paramagnetic metal ions, which are described in U.S. Patent No. 4,647,447. The radionuclides permit the imaging of tissues by gamma scintillation photometry, positron emission tomography, single photon emission computed tomography and gamma camera whole body imaging, while paramagnetic metal ions permit visualization by magnetic resonance imaging.

The invention provides a transgenic non-human mammal that is capable of expressing nucleic acids encoding a human netrin, a human ABC3 transporter, a human ribosomal L3 subtype, or a human augmenter of liver regeneration polypeptide. Also provided is a transgenic non-human mammal capable of expressing nucleic acids encoding a human netrin, a human ABC3 transporter, a human ribosomal L3 subtype, or a human augmenter of liver regeneration polypeptide so mutated as to be incapable of normal activity, i.e., does not express native protein.

The present invention also provides a transgenic non-human mammal having a genome comprising antisense nucleic acids complementary to nucleic acids encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide so placed as to be transcribed into antisense mRNA complementary to mRNA encoding a human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide, which hybridizes thereto and, thereby, reduces the translation thereof. The polynucleotide may additionally comprise an inducible promoter and/or tissue specific regulatory elements, so that expression can be induced, or restricted to specific cell types. Examples of polynucleotides are DNA or cDNA having a coding sequence substantially the same as the coding sequence shown in Figures 3, 4, 8, 11 and 15. Examples of non-human transgenic mammals are transgenic cows, sheep, goats, pigs, rabbits, rats and mice. Examples of tissue specificity-determining elements are the metallothionein promoter and the T7 promoter. Animal model systems which elucidate the physiological and behavioral roles of invention polypeptides are produced by creating transgenic animals in which the expression of the polypeptide is altered using a variety of techniques. Examples of such techniques include the insertion of normal or mutant versions of nucleic acids encoding human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide by microinjection, retroviral infection or other means well known to those skilled in the art, into appropriate fertilized embryos to produce a transgenic animal. See, for example, Carver et al . , Bio /Techno logy 11:1263-1270, 1993; Carver et al., Cytotechnology 9:77-84, 1992; Clark et al., Bio /Technology 7:487-492, 1989; Simons et al . , Bio /Technology 6:179-183, 1988; Swanson et al., Bio /Techno logy 10 : 557-559, 1992; Velander et al . , Proc. Natl. Acad. Sci., USA 89:12003- 12007, 1992; Hammer et al., Nature 315:680-683, 1985; Krimpenfort et al., Bio /Technology 9: 844-847, 1991; Ebert et al., Bio /Technology 9:835-838, 1991; Simons et al., Nature 328:530-532, 1987; Pittius et al . , Proc. Natl. Acad. Sci., USA 85:5874-5878, 1988; Greenberg et al . , Proc. Natl. Acad. Sci., USA 88:8327-8331, 1991; Whitelaw et al . , Transg. Res. 1:3-13, 1991; Gordon et al . , Bio /Techno logy 5:1183-1187, 1987; Grosveld et al . , Cell 51:975-985, 1987; Brinster et al . , Proc. Natl. Acad. Sci., USA 88:478-482, 1991; Brinster et al., Proc. Natl. Acad. Sci., USA 85:836- 840, 1988; Brinster et al . , Proc. Natl. Acad. Sci., USA 82:4438-4442, 1985; Al-Shawi et al., Mol. Cell. Biol. 10(3) .-1192-1198, 1990; Van Der Putten et al., Proc. Natl. Acad. Sci., USA 82:6148-6152, 1985; Thompson et al., Cell 56:313-321, 1989; Gordon et al., Science 214:1244-1246, 1981; and Hogan et al . , Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratory, 1986) .

Another technique, homologous recombination of mutant or normal versions of these genes with the native gene locus in transgenic animals, may be used to alter the regulation of expression or the structure of the invention polypeptides (see, Capecchi et al . , Science 244:1288, 1989; Zimmer et al . , Nature 338:150, 1989) . Homologous recombination techniques are well known in the art. Homologous recombination replaces the native (endogenous) gene with a recombinant or mutated gene to produce an animal that cannot express native (endogenous) protein but can express, for example, a mutated protein which results in altered expression of the human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide.

In contrast to homologous recombination, microinjection adds genes to the host genome, without removing host genes. Microinjection can produce a transgenic animal that is capable of expressing both endogenous and exogenous human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptides. Inducible promoters can be linked to the coding region of the nucleic acids to provide a means to regulate expression of the transgene. Tissue-specific regulatory elements can be linked to the coding region to permit tissue-specific expression of the transgene. Transgenic animal model systems are useful for in vivo screening of compounds for identification of ligands, i.e., agonists and antagonists, which activate or inhibit polypeptide responses.

The nucleic acids, oligonucleotides (including antisense) , vectors containing same, transformed host cells, polypeptides, as well as antibodies of the present invention, can be used to screen compounds in vi tro to determine whether a compound functions as a potential agonist or antagonist to the invention protein. These in vi tro screening assays provide information regarding the function and activity of the invention protein, which can lead to the identification and design of compounds that are capable of specific interaction with invention proteins. In accordance with still another embodiment of the present invention, there is provided a method for identifying compounds which bind to human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptides. The invention proteins may be employed in a competitive binding assay. Such an assay can accommodate the rapid screening of a large number of compounds to determine which compounds, if any, are capable of binding to invention polypeptides. Subsequently, more detailed assays can be carried out with those compounds found to bind, to further determine whether such compounds act as modulators, agonists or antagonists of invention polypeptides.

In accordance with another embodiment of the present invention, transformed host cells that recombinantly express invention polypeptides can be contacted with a test compound, and the modulating effect (s) thereof can then be evaluated by comparing the human netrin, human ABC3 transporter, human ribosomal L3 subtype, or human augmenter of liver regeneration polypeptide-mediated response in the presence and absence of test compound, or by comparing the response of test cells or control cells (i.e., cells that do not express invention polypeptides) , to the presence of the compound.

As used herein, a compound or a signal that "modulates the activity" of an invention polypeptide refers to a compound or a signal that alters the activity of the human netrin, the human ABC3 transporter, the human ribosomal L3 subtype, or the human augmenter of liver regeneration polypeptide so that the activity of the invention polypeptide is different in the presence of the compound or signal than in the absence of the compound or signal. In particular, such compounds or signals include agonists and antagonists. An agonist encompasses a compound or a signal that activates polypeptide function. Alternatively, an antagonist includes a compound or signal that interferes with polypeptide function. Typically, the effect of an antagonist is observed as a blocking of agonist-induced protein activation. Antagonists include competitive and non-competitive antagonists. A competitive antagonist (or competitive blocker) interacts with or near the site specific for agonist binding. A non-competitive antagonist or blocker inactivates the function of the polypeptide by interacting with a site other than the agonist interaction site.

The following examples are intended to illustrate the invention without limiting the scope thereof.

Example I: Contig Assembly

A. Cosmids

Multiple cosmids were used as reagents to initiate walks in YAC and PI libraries. Clones 16-166N (D16S277), 16-191N (D16S279), 16-198N (D16S280) and l6-140N (D16S276) were previously isolated from a cosmid library (Lerner et al . , Mamm. Genome 3:92-100, 1992) . Cosmids CCMM65 (D16S84), c291 (D16S291) , CAJ42 (ATP6C) and cKG8 were recovered from total human cosmid libraries (made in-house or by Stratagene, La Jolla, CA) using either a cloned insert (CMM65) or sequence-specific oligonucleotides as probe. The c326 cosmid contig and clone 413C12 originated from a flow-sorted chromosome 16 library (Stallings et al . , Genomics 13 (4) : 1031-1039, 1992) . The c326 contig was comprised of clones 2H2, 77E8, 325A11 and 325B10.

B. YACs

Screening of gridded interspersed-repetitive sequence (IRS pools from Mark I, Mark II and Mega-YAC libraries) with cosmid-specific IRS probes was as previously described (Liu et al . , Genomics 26:178-191, 1995) . IRS probes were made from cosmids 16-166N, 16-191N, CAJ42, 16-198N, 325A11, cCMM65, and 16-140N. Biotinylated YAC probes were generated by nick-translating complex mixtures of IRS products from each YAC. Mixtures of sufficient complexity were achieved by performing independent DNA amplifications of total yeast DNA using various Alu primers (Lichter et al . , Proc . Natl . Acad. Sci . , USA 87:6634-6638, 1990) and then combining the appropriate reactions containing the most diverse products.

C. Pis

Chromosome walking experiments were done using a single set of membranes which contained the gridded PI library pools (Shepherd et al . , supra . 1994) . The gridded filters were kindly provided by Dr. Mark Leppert and the Technology Access Section of the Utah Center for Human Genome Research at the University of Utah. PI gridded membranes were screened using end probes derived from a set of chromosome 16 cosmids (see above) and PI clones as they were identified. Both RNA transcripts and bubble-PCR products were utilized as end probes.

D. Probes

Radiolabeled transcripts were generated using restriction enzyme digested cosmids or Pis {Alul, Haelll, Rsal, TaqI) as template for phage RNA polymerases T3, T7 and SP6. The T3 and T7 promoter elements were present on the cosmid-derived templates while T7 and SP6 promoter sequences were contained on the Pl-based templates. Transcription reactions were performed as recommended by the manufacturer (Stratagene, La Jolla, CA) in the presence of [αP³²]-ATP (Amersham, Arlington Heights, IL) .

Bubble-PCR products were synthesized from restriction enzyme digested Pis (Alul, Haelll, Rsal, TaqI) . Bubble adaptors with appropriate overhangs and phosphorylated 5 ' ends were ligated to digested PI DNA basically as described for YACs (Riley et al . , Nuc . Acids Res . 18:2887-2890, 1990) . The sequence of the universal vectorette primer derived from the bubble adaptor sequence was 5 ' -GTTCGTACGAGAATCGCT-3 ' (SEQ ID NO:67), and differed from that of Riley and co-workers with 12 fewer 5' nucleotides . The T_m of the truncated vectorette primer more closely matched that of the paired amplimer from the vector-derived promoter sequence (SP6, T7) . The desired bubble-PCR product was gel purified prior to radiolabeling (Feinberg et al . , Anal . Biochem . 132:6-13, 1983; Feinberg and Vogelstein, Anal . Biochem. 137:266-267, 1984) .

The specificity of all end probes was determined prior to their use on the single set of gridded PI filter arrays. Radiolabeled probes were pre-annealed to Cotl DNA as recommended (Life Technologies Inc., Gaithersburg, MD) and then hybridized to strips of nylon membrane to which were bound 10-20 ng each of the following DNAs: the cloned genomic template used to create the probe; one or more unrelated cloned genomic DNAs; cloned vector (no insert) ; and human genomic DNA.

Hybridizations were performed in CAK solution (5x SSPE, 1% SDS, 5x Denhardt's Solution, 100 mg/mL torula RNA) at 65°C overnight. Individual end probes were present at a concentration of 5xl0⁵ cpm/mL. Hybridized membranes were washed to a final stringency of 0.lx SSC/0.1% SDS at 65° C. The hybridization results were visualized by autoradiography. Probes which hybridized robustly to their respective cloned template while not hybridizing to unrelated cloned DNAs, vector DNA or genomic DNA were identified and used to screen the gridded PI filters.

Hybridization to the arrayed PI pools was performed as described for the nylon membrane strips (above) except that multiple probes were used simultaneously. Positive clones were identified, plated at a density of 200-500 cfu per 100 mm plate (LB plus 25 mg/mL kanamycin) , lifted onto 82 mm HATF membranes (Millipore, Bedford, MA), processed for hybridization (Sambrook et al . , supra . ) and then rescreened with the complex probe mixture. A single positive clone from each pool was selected and replated onto a master plate. To identify the colony purified genomic PI clone and its corresponding probe, multiple PI DNA dot blots were prepared and each hybridized to individual radiolabeled probes. All hybridizations contained a chromosome 16pl3.3 reference probe, e.g. cAJ42, as well as a uniquely labeled PI DNA probe.

Example II: Exon Trapping

Genomic Pi clones were prepared for exon trapping experiments by digestion with PstI, double digestion with BamHI/Bglll, or by partial digestion with limiting amounts of Sau3AI . Digested PI DNAs were ligated to BamHI-cut and dephosphorylated vector, pSPL3B, while Pstl-digested PI DNA was subcloned into PstT-cut dephosphorylated vector, pSPL3B.

Ligations were performed in triplicate using 50 ng of vector DNA and 1, 3 or 6 mass equivalents of digested Pi DNA. Transformations were performed following an overnight 16°C incubation, with 1/10 and 1/2 of the transformation being plated on LB (ampicillin) plates. After overnight growth at 37°C, colonies were scraped off those plates having the highest transformation efficiency (based on a comparison to "no insert" ligation controls) and miniprepped using the alkaline lysis method. To examine the proportion of the pSPL3B containing insert, a small portion of the miniprep was digested with Hindlll, which cuts pSPL3B on each side of the multiple cloning site.

Example III: RNA Preparation

Approximately 10 μg of the remaining miniprep DNA was ethanol precipitated, resuspended in 100 μl of sterile PBS and electroporated into approximately 2 x 10⁶ COS-7 cells (in 0.7 ml of ice cold PBS) using a BioRad GenePulser electroporator (1.2 kV, 25 μF and 200 Ω) . The electroporated cells were incubated for 10 min. on ice prior to their addition to a 100 mm tissue culture dish containing 10 ml of prewarmed complete DMEM.

Cytoplasmic RNA was isolated 48 hours post-transfection. The transfected COS-7 cells were removed from tissue culture dishes using 0.25% trypsin/1 mM EDTA (Life Technologies Inc., Gaithersburg, MD) . Trypsinized cells were washed in DMEM/10% FCS and resuspended in 400 μl of ice cold TKM (10 mM Tris-HCl pH 7.5, 10 mM KC1, 1 mM MgCl₂) supplemented with 1 μl of

RNAsin (Promega, Madison, WI) . After adding 20 μl of 10% Triton X-100, the cells were incubated for 5 min. on ice. The nuclei were removed by centrifugation at 1200 rpm for 5 min. at 4°C. Thirty microliters of 5% SDS was added to the supernatant, with the cytoplasmic RNA being further purified by three rounds of extraction using phenol/chloroform/isoamyl alcohol (24:24:1) . The cytoplasmic RNA was ethanol precipitated and resuspended in 50 μl of H₂0.

Reverse transcription and PCR were performed on the cytoplasmic RNA prepared above as described (Church et al . , supra . 1994) using commercially available exon trapping oligonucleotides (Life Technologies Inc., Gaithersburg, MD) . The resulting CUA-tailed products were shotgun subcloned into pAMPlO as recommended by the manufacturer (Life Technologies Inc.) . Random clones from each ligation were analyzed by colony PCR using secondary PCR primers (Life Technologies Inc.) .

Miniprep DNA containing the pAMPlO/exon traps was prepared from overnight cultures by alkaline lysis using the EasyPrep manifold or a QIAwell 8 system according to the manufacturers' instructions (Pharmacia, Pistcataway, NJ and Qiagen Inc., Chatsworth, CA, respectively) . DNA products containing trapped exons, based on comparison to the 177 bp "vector only" DNA product, were selected for sequencing.

Example IV: Sequencing

DNA sequencing was performed using Pharmacia ALF and Applied Biosystems 377 PRISM automated DNA sequencers (Piscataway, NJ, and Foster City, CA) . DNA sequences were aligned using Sequencher DNA analysis software (Genecodes, Ann Arbor, MI) . DNA and protein database searches were performed using the BLASTN (Altschul et al . , J. Mol . Biol . 215:403-410, 1990) and BLASTX (Altschul et al . , supra . 1990; Gish et al . , Nat . Genet. 3:266-272, 1993) programs. SASE sequences were analyzed by processing BLAST (Altschul et al . , supra . 1990; Gish et al . , supra . 1993) and FASTA (Lipman et al . , Science 227:1435-1441, 1985) searches. Protein sequences were analyzed using MacVector (Oxford Molecular Group, Cambell, CA) , BCM Launcher (Smith et al . , Genome Research 6:454-462, 1996), ClustalW (Thompson et al . , Nucleic Acids Res . 22:4673-4680, 1994), and PSORT (Νakai et al . , Genomics 14:897-911 1992) .

Example V: RT-PCR, RACE, SASE and cDΝA Isolation

Based upon the sequence determined (above) two oligonucleotide primers (Table II) were designed for each exon trap using Oligo 4.0 (National Biosciences Inc., Plymouth, MN) .

To determine which tissue-specific library to screen for transcript or cDNA, RT-PCR reactions and/or PCR reactions were performed using different tissue-derived RNAs and/or cDNA libraries, respectively, as template with the oligonucleotide primers designed for each exon trap (above) .

The oligonucleotides designed from the exons (Table II) , were then used in one or more of the following positive selection formats to screen the corresponding tissue-specific cDNA library.

For RT-PCR experiments, the first oligonucleotide was used as a sense primer and the second oligonucleotide was used as an antisense primer. RT-PCR was performed as described using polyA⁺ RNA from adult brain and placenta (Kawasaki, In PCR Protocols : A Guide to Methods and Applications, Eds. Innis et al . , Academic Press, San Diego, CA, pp. 21-27, 1990) . All PCR products were cloned using the pGEM-T vector as described by the manufacturer (Promega, Madison, WI) .

To clone sequences 3' to selected exon traps, rapid amplification of cDNA ends (RACE) was performed as described (Frohman, PCR Met . Appl . 4:S40-S58, 1994) . In 3' RACE experiments, the first oligonucleotide was used as the external primer and the second oligonucleotide was used as the internal primer.

For the Genetrapper cDNA Positive Selection System, the first oligonucleotide primer was biotinylated and used for direct selection, while the second oligonucleotide was used in the repair.

In addition to exon trapping, the cloned contig was also screened using cDNA selection essentially as described (Parimoo et al . , Anal . Biochem. 228:1-17 1995), using the genomic Pi clones from this interval (Dackowski et al . , Genome Res . 6:515-524, 1996) . Other coding sequence was obtained by SAmple SEquencing (SASE) .

SASE was performed as a functional genomics method for gene identification. Briefly, DNA from individual Pis were partially digested with Sau3A and 3 kb fragments were subcloned into the pBluescriptKS⁺ plasmid (Stratagene, La Jolla, CA) . Subclones were sequenced from both ends to generate sequences semi-randomly from the PI clone. Example VI: Nucleotide Sequence Analysis

hNET: A random shotgun library was prepared from the 53.8B Pi clone (Figure 18) by subcloning randomly sheared PI DNA into the pAMPlO vector (Life Technologies Inc., Gaithersburg, MD) essentially as described (Andersson et al . , (1994) Anal . Biochem . 218:300-308) . Pi DNA was randomly sheared using a nebulizer (Hudson RCI, Temecula, CA) . The library was initially screened with a 6 kb Xhol fragment, which had been shown to contain the netrin encoding exon traps (Figure 18) . The library was subsequently screened with an adjacent 3.5 kb Xhol fragment in order to obtain additional clones for sequencing. Positive clones were sequenced using forward and reverse vector primers as previously described (The American PKDl Consortium (1995) Hum. Mol . Genet . 4:575-582) .

The genomic sequence was edited and assembled using Sequencher (GeneCodeε, Ann Arbor, MI) . The coding region was predicted using the World Wide Web version of the GRAIL2 program (Uberbacher and Mural (1991) Proc . Natl . Acad. Sci . , USA 88:11261-11265; Xu et al . (1994) Genet. Eng. N. Y. 16:241-253) and a MacVector (Oxford Molecular Group, Cambell, CA) Pustell DNA/protein matrix analysis comparing the genomic sequence (translated in all reading frames) to the chicken netrins. Database searches were performed using BLASTN (Altschul et al . (1990) J. Mol . Biol . 215:403-410) and BLASTX (Altschul et al . , 1990, supra ; Gish and States (1993) Nat . Genet. 3:266-272) .

RT-PCR: Both adult (brain, heart, kidney, leukocytes, liver, lung, a lymphoblastoid cell line, placenta, spleen, and testis) and fetal (kidney and brain) cDΝA libraries were prescreened for the presence of netrin cDΝAs by PCR as described (Van Raay et al. , 1996, supra) . Nested RT-PCR was utilized to clone transcribed sequences from the netrin gene. Briefly, spinal cord polyA+ RNA (Clontech, Palo Alto, CA) was reverse transcribed using random primers as described (Kawasaki, 1990 In "PCR Protocols: A Guide to Methods and Applications" (M.A. Innis, D.H. Gelfand, J.J. Sninsky, and T.J. White. Eds.), pp. 21-27, Academic Press, Inc., San Diego) .

Primers for PCR (Table IV) were designed based on the exons predicted from the analysis of the genomic sequence and used to amplify spinal cord RNA since spinal cord has been previously shown to express low levels of chicken netrin (Serafini et al . supra . ) . Nested PCR was required to detect RT-PCR products from human spinal cord RNA. Spinal cord RNA was reverse transcribed with random primers and primary PCR was performed in the presence of 2.5 M betaine (Sigma Chemical Co., St. Louis, MO) using the primers designed from the gene model (Table IV) . The primary PCR reactions were then diluted 1:20 and secondary PCR was performed on 1 μL of the diluted primary reactions using nested primers (also designed from the gene model) , again in the presence of betaine. The inclusion of betaine at a final concentration of 2.5 M in the PCR reactions dramatically increased the purity and yield of the human netrin RT-PCR products (see, for example, International Publication No. WO 96/12041; Reeves et al . (1994) Am. J. Hum. Genet . 55:A238; Baskaran et al . (1996) Genome .Research 6:633-638) .

RT-PCR products were subcloned using pGEM-T (Promega, Madison, WI) as recommended by the manufacturer. The resulting RT-PCR clones were sequenced with vector primers and internal primers using the ABI dye terminator chemistry (Perkin Elmer, Foster City, CA) and an ABI 377 automated sequencer (Perkin Elmer, Foster City, CA) . Multiple sequence alignments were performed using ClustalW (Thompson et al . , (1994) Nucleic Acids Res . 22:4673-4680) .

Sequence analysis of the RT-PCR products indicated that hNET contains at least six exons. The RT- PCR data indicate that the fourth predicted exon is actually split by an intron in the human netrin gene and is present as two exons . Three of the RT-PCR exons were shown to be identical to the original exon traps. Aside from the extra exon, the gene model is nearly identical to the RT- PCR products. The cDNA coding sequence, predicted protein product and full length sequence are shown in Figures 4A through 4C, respectively.

Northern blot analysis: Genomic and RT-PCR probes were radiolabeled (Feinberg and Vogelstein, Anal. Biochem . 132:6-13, 1983) and used to probe Northern blots containing RNAs from a variety of adult tissues (Clontech, Palo Alto, CA) , including a panel of RNAs from different neural tissues including spinal cord. In addition, a human RNA Master Blot (Clontech, Palo Alto, CA) containing RNAs from 50 different adult and fetal tissues was screened as recommended by the manufacturer.

hABC3 : A human lung cDNA library (LTI, Gaithersburg, MD) was screened with the GeneTrapper system (LTI, Gaithersburg, MD) using capture and repair oligonucleotides (5 '-CATTGCCCGTGCTGTCGTG-3 ' (SEQ ID NO:52) and 5 ' -CATCGCCGCCTCCTTCATG-3 ' (SEQ ID NO:53), respectively) designed from trapped exon L48757, the 5" most trapped exon with homology to murine ABCl. Direct cDNA library screening was also performed using an RT-PCR clone as probe. 5' RACE (Frohman, M.A. in Methods Enzymol . (J.N. Abelson and M.I. Simon Eds.) pp. 340-356, Academic Press, San Diego, CA 1993) was used to isolate additional 5' sequences from the ABC3 transcript.

Northern blot analysis: A 679 bp fragment from the 3 ' untranslated region (UTR) of the ABC3 cDNA was radiolabeled by random priming (Feinberg et al . , supra . 1983) and used to probe a multiple tissue northern blot (Clontech, Palo Alto, CA) under conditions recommended by the manufacturer. Identification of coding sequence for the novel ABC transporter: The gene for a novel ATP binding cassette (ABC) transporter, designated ABC3 , has been mapped to the PKDl locus on chromosome 16 (Burn et al . , Genome Res . 6:525-537, 1996) . Eight exons from the hABC3 gene were obtained from the 30.IF, 64.12C and 96.4B PI clones using exon trapping. See, Figure 16 showing the genomic interval surrounding the hABC3 gene at the top, with NotI sites, DΝA markers, and distance in kilobases (in kb) also being shown. Genomic PI clones from the interval which contain sequence from the hABC3 gene are shown below the genomic map. The relative position of the hABC3 cDΝA is provided below the Pi clones, with the selected cDΝA, trapped exons, RT-PCR clones, and cDΝAs being indicated. Trapped exons and RT-PCR clones used in the isolation of additional hABC3 sequences have been labeled. The discontinuity in the line for clone ABCgt.l represents the absence of an alternatively spliced exon.

Seven of these trapped exons encoded sequences having homology to murine ABCl and ABC2 based on BLASTX analysis (Altschul et al . , supra . 1990; Gish et al . , supra . 1993), with sequences from the trapped exons L48758, L48759, and L48760 having highest homology. Sequences encoded by the trapped exon L48760 also had homology to a Caenorhabdi tis elegans ABC transporter predicted from genomic sequence (Wilson et al . , supra . ) .

cDΝA selection yielded a single 261 bp cDΝA clone which mapped near the 5' end of the ABC3 gene. Like L48760, this clone encoded sequences having homology to the hypothetical C. elegans ABC transporter. Initial analysis of the SASE results from the 30.IF PI clone indicated that 4 of the 164 reactions encoded sequences with homology to ABCl or ABC2. Subsequent comparison of the SASE data to the final hABC3 cDΝA indicated that an additional seven sequencing reactions contained coding sequences from the ABC3 gene. A total of 1.6 kb of ABC3 coding sequence aligned with the SASE data. In that only 3.5 kb of coding sequence from the 5' end of the hABC3 gene map to the 30. IF Pi clone, this represents a level of 45% coverage for the SASE analysis.

Assembly and analysis of a cDNA for the novel ABC transporter: Two complementary approaches were employed to assemble the full-length hABC3 cDNA. First, RT-PCR was utilized to link the trapped exons, selected cDNA, and SASE data. Secondly, cDNA library screening was performed using direct selection as well as radiolabeled probes.

Using primers designed from the trapped exons L48757, L48758, L48760 and L75924, three RT-PCR products, containing 3.3 kb of coding sequence were cloned (Table I and Figure 16) . An additional RT-PCR primer was designed from a region of identity between the selected cDNA and the SASE data (Table I) . A 900 bp RT-PCR clone was obtained using the latter primer in conjunction with a trapped exon derived primer. In total, 4.2 kb of coding sequence was obtained using RT-PCR.

Several cDNAs were cloned using the GeneTrapper direct selection system and oligos designed from the 5' most trapped exon encoding sequences with homology to ABCl (trapped exon L48747) . The longest clone isolated with the GeneTrapper system was 5719 bp in length (ABCgt.l) (Figure 8) . This cDNA contains a 792 bp 3' untranslated region with a consensus polyadenylation - cleavage site 20 bp upstream of the polyA tail. An additional cDNA clone (ABC.5) was isolated using a radiolabeled 1.1 kb RT-PCR product (ABC3-12) as a probe (Figure 16) . The 5' end of the ABC3 cDNA was further characterized using 5' RACE, with several RACE products containing multiple in-frame stop codons upstream of the start methionine.

Sequence analysis indicated that clone ABCgt.l lacks 147 bp of sequence found in the RT-PCR clones and the cDNA clone ABC.5. The additional 147 bp segment is likely to be the result of alternative splicing, in that it does not interrupt the open reading frame. The presence of both transcript populations has been confirmed by PCR using primers flanking the alternatively spliced exon.

A 6.4 kb cDNA has been assembled for the hABC3 transporter. The assembled cDNA contains a 5116 nucleotide long open reading frame encoding 1705 amino acids, with the predicted protein having a molecular weight of 191 kDa. The proposed start methionine is 50 bp upstream of the 5' end of clone ABCgt.l. Although the sequence surrounding the start methionine matches the Kozak sequence in only 6 of 10 positions (Kozak, J^". Cell Biol . 115:887-903, 1991), the two positions which have been shown to be critical for function (an A at -3 and a G at +4) are conserved in hABC3. The hABC3 cDNA contains a 792 bp 3 ' UTR with a consensus polyadenylation/cleavage site 20 bp upstream of the polyA tract.

A 6.8 kb transcript is detected by a 3 ' UTR cDNA probe on northern blots with highest levels of expression being observed in lung with lesser amounts in brain, heart, and pancreas. Significantly lower levels of expression were observed in placenta and skeletal muscle after longer exposure times. The ABC3 transcript was not detected in either liver or kidney.

RPL3L (SEM L3) : The longest cDNA is 1548 nucleotides in length (Figure 11) . All three cDNAs have an open reading frame (ORF) of 1224 nucleotide with the longest cDNA containing a 48 nucleotide 5' untranslated region. An inframe stop codon at position 7 is followed by the Kozak initiation sequence CCACCATGT (SEQ ID NO:68) (Kozak, supra . ) . The 3' UTR for each of the three cDNAs vary in length, and lacks a consensus polyadenylation cleavage site.

The longest cDNA was compared to the human, bovine and murine ribosomal L3 genes. At the nucleotide level there is only 74% identity between the RPL3L (SEM L3) cDNA and the consensus from these other ribosomal L3 cDNAs. This is in sharp contrast to the 98% identity shared between human, bovine, and murine L3 nucleotide sequences. There is no similarity between the 3 ' UTR of the cDNAs isolated here and the other L3 genes.

hALR: Sequences were cloned from the human ALR gene by 3' RACE using primers (e.g., external 5'- TGGCCCAGTTCATACATTTA-3 ' (SEQ ID NO:69) and internal 5'- TTACCCCTGTGAGGAGTGTG-3 ' (SEQ ID NO:70)) designed from the exon trap. A total of 468 bp have been obtained from the human ALR gene (Figure 13) .

Example VII : Amino Acid Sequence Analysis

hNET: hNET cDNA has at least 210 bp of 5' untranslated sequence, a 5' start methionine codon, a 3' stop codon (TGA) and is predicted to be 580 amino acids in length (Figure 4) , with the common domain structure of the netrin family being conserved (Figure 20A) . Overall, the human netrin was found to have higher homology to chicken netrin-2 than netrin-1, i.e., 56.3% versus 53.9%. As is the case with the other members of the netrin family, the region of greatest conservation includes the three EGF repeats, while the C-terminal domains are less well conserved (Figure 20A) . The EGF repeats are 78.7% and 82.2% identical between the human netrin and chicken netrin-1 and netrin-2, respectively, and 66.3% identical when compared to UNC-6. The C-terminal domains of the human netrin and chicken netrin -1 and -2 are 41.9% and 42.5% indentical, respectively with the same domain of UNC-6 being only 29.4% identical to human netrin. Overall, the human netrin more closely resembles the chicken netrins and UNC-6 than Drosophila NETA and NETS, since NETA contains an expansion in the C-domain while NETS contains additional sequences in the VI and V-1 domains (Harris et al . , 1996, supra ; Mitchell et al . , 1996, supra) . The Structure of the Netrin Genes is Conserved Between Drosophila and Human

The positions of the introns in the human gene were compared to the encoded protein to determine if the overall gene structure of the netrin/UNC-6 family is conserved (Figure 20B) . This analysis revealed striking similarities between the Drosophila netrin genes and the human netrin gene. In the human gene, exon 1 contains the signal peptide, domain VI and the first EGF domain (domain V-1) , while exons two and three each contain an EGF repeat, domains V-2 and V-3, respectively. Exons 4, 5, and 6 contain portions of the C-domain. With the exception of an additional intron in the C-domain, this motif/exon arrangement is conserved in the Drosophila netrin genes. The coding regions of the two Drosophila netrin genes have been shown to be highly conserved with each being disrupted by six introns that occur in homologous sites (Harris et al . , 1996, supra) . The position of five of the six Drosophila introns was found to be conserved in the human gene (Figure 20B) . The UNC-6 gene contains 12 introns in the coding region (Ishii et al . , 1992, supra) , the position of five of which correlate with the positions of the introns in the human gene. Interestingly, the sixth Drosophila intron that does not have a counterpart in the human gene and is the only intron from Drosophila that is not conserved in the UNC-6 gene.

hABC3 : Database searches revealed homology between ABC3 and murine ABCl and ABC2 (Luciani et al . , supra . 1994) . In addition to the murine ABCl and ABC2 proteins, ABC3 also shows homology to the putative C. elegans protein encoded by the cosmid sequence of C48B4.4 (Wilson et al . , supra . ) . Overall, ABC3 , ABCl, ABC2 and sequences encoded by C. elegans cosmid C48B4.4 have highest homology in the regions surrounding the ATP binding cassettes (Figure 17) . However, when one compares the sequence between the first ATP binding cassette and the second transmembrane domain, referred to as the linker domain (Luciani et al . , supra . 1994) , ABC3 shares much lower homology to these same 3 proteins listed above (amino acids 765-1044 in ABC3 in Figure 17) . The linker domain of ABC3 is approximately 200 residues shorter than the linker domain present in ABCl and ABC2. Consequently, an optimum protein alignment positions a gap in the ABC3 sequence immediately C-terminal of a conserved HHl hydrophobic domain (Luciani et al . , supra . 1994) , located at position 917 through 959 in ABC3 (Figure 17) . Additional comparisons indicate that the ABC3 linker domain is nearly identical in size to the linker domain encoded by C. elegans cosmid C48B4.4. As is the case with ABCl and ABC2, the linker domain of ABC3 contains numerous polar residues and several potential phosphorylation sites.

Further analysis of the deduced ABC3 protein sequence revealed additional similarities to the ABC1/ABC2 subfamily. Based on PSORT analysis (Nakai et al . , supra . ) , the ABC3 protein does not appear to contain an N-terminal signal sequence and is likely to be a Type III membrane protein (Singer, Annu . Rev. Cell Biol . 6:247-296 1990) , with sequences N-terminal of the first transmembrane domain being located in the cytoplasm (Figure 17) . Similar topography has been described for ABCl (Luciani et al . , supra . 1994) and all other ABC transported described to date (Higgins, supra . 1992) . As mentioned above, murine ABCl and ABC2 have been shown to contain a novel hydrophobic region, HHl, within the conserved linker domain. Although the HHl domain is not well conserved at the amino acid level in ABC3, an HHl domain does appear to be present within the linker region based on hydrophilicity analysis . A similar HHl domain is also found in sequences encoded by cosmid C48B4.4 from C. elegans . In all these cases, the HHl domain is predicted to have a β-sheet conformation.

RPL3L (SEM L3) : The RPL3L (SEM L3) cDNA open reading frame predicts a 407 amino acid polypeptide of 46.3 kD (Figure 11) . In vi tro transcription - translation of RPL3L (SEM L3) cDNA resulted in a protein product with an apparent molecular weight of 46 kD which is in close agreement with the predicted weight of 46.3 kD.

Two nuclear targeting sequences, which are 100% conserved between man, mouse and cow, diverged slightly in the RPL3L (SEM L3) amino acid sequence. The first targeting site is the 21 amino acid N-terminal oligopeptide. The serine and arginine present at positions 13 and 19 respectively, in human, bovine and murine L3 are replaced with histidines in RPL3L (SEM L3) (Figure 12) . The second potential nuclear targeting site is the bipartite motif. Here the human, bovine and murine proteins have a KKR- (aa) ₁₂-KRR ^at position 341-358 while the SEM L3 gene has KKR- (aa) ₁₀-HHSRQ at position 341-358.

The second half of this bipartite motif, while remaining basic, does not match those found in other nuclear targeting motifs (Simonic et al . , supra . 1994) . Overall, there is 77.2% amino acid identity between the RPL3L (SEM L3) and the consensus from the other mammalian L3 ribosomal genes, with 56% of the nucleotide differences between RPL3L (SEM L3) and the human L3 being silent.

hALR: hALR cDNA sequences encode a 119 amino acid protein which is 84.8% identical and 94.1% similar to the rat ALR protein (see, Figures 13 and 14) .

Although the invention has been described with reference to the disclosed embodiments, it should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the claims which follow the Sequence Listing. SEQUENCE LISTING

(1) GENERAL INFORMATION:

(l) APPLICANT: GENZYME CORPORATION

(11) TITLE OF INVENTION: NOVEL HUMAN CHROMOSOME 16 GENES, COMPOSITIONS, METHODS OF MAKING AND USING SAME

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(D) SOFTWARE: Patentin Release #1.0, Version #1.30

(vi ) CURRENT APPLICATION DATA:

(A) APPLICATION NUMBER:

(B) FILING DATE: 16-JAN-1997

(C) CLASSIFICATION:

(vil) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER: US 08/665,259

(B) FILING DATE: 17-JUN-1996

(vil) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER: US 08/720,614

(B) FILING DATE: 01-OCT-1996

(vil) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER: US 08/762,500

(B) FILING DATE: 09-DEC-1996

(vil) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER: PCT/US96/10469

(B) FILING DATE: 17-JUN-1996

(viil) ATTORNEY/AGENT INFORMATION:

(A) NAME: Dugan, Deborah A.

(B) REGISTRATION NUMBER: 37,315

(C) REFERENCE/DOCKET NUMBER: IG5-9.4

(IX) TELECOMMUNICATION INFORMATION:

(A) TELEPHONE: (508) 872-8400

(B) TELEFAX: (508} 872-5415

(2) INFORMATION FOR SEQ ID NO: 1 :

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 179 amino acids

(B) TYPE: ammo acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(n) MOLECULE TYPE: peptide (XI) SEQUENCE DESCRIPTION: SEQ ID NO^• 1 :

Leu His Leu Glu Gly Pro Phe lie Ser Arg Glu Lys Arg Gly Thr His

1 5 10 15

Pro Glu Ala His Leu Arg Ser Phe Glu Ala Asp Ala Phe Gin Asp Leu 20 25 30

Leu Ala Thr Tyr Gly Pro Leu Asp Asn Val Arg lie Val Thr Leu Asp 35 40 45

Pro Glu Leu Gly Arg Ser His Glu Val Phe Arg Thr Leu Thr Xaa Arg 50 55 60

Ser lie Cys Val Ser Leu Gly His Ser Val Ala Asp Leu Arg Ala Ala 65 70 75 80

Glu Asp Ala Val Trp Ser Gly Ala Thr Phe lie Thr His Leu Phe Asn 85 90 95

Ala Met Leu Pro Phe His His Arg Asp Pro Gly lie Val Gly Leu Leu 100 105 110

Thr Ser Asp Arg Pro Ala Gly Arg Cys lie Phe Tyr Gly Met lie Ala 115 120 125

Asp Gly Thr His Thr Asn Pro Ala Ala Leu Arg lie Ala His Arg Ala 130 135 140

His Pro Gin Gly Leu Val Leu Val Thr Asp Ala lie Pro Ala Leu Gly 145 150 155 160

Leu Gly Asn Gly Arg His Thr Leu Gly Gin Gin Glu Val Glu Val Asp 165 170 175

Gly Leu Thr

(2) INFORMATION FOR SEQ ID NO:2:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 90 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:

His Leu Glu Gly Pro Phe lie Ser Lys Arg Gly His Pro Glu Ser Tyr 1 5 10 15

Gly Asn lie Val Thr Pro Glu Leu Glu Val Ser Gly His Ser Ala Leu 20 25 30

Glu Ala Val Ser Gly Ala lie Thr His Leu Phe Asn Ala Met His His 35 40 45

Arg Asp Pro Gly Gly Leu Leu Thr Ser Leu Tyr Gly lie Asp Gly His 50 55 60 X LLL rtia Leu Arg lie Ala Gly Leu Val Leu Val Thr Asp Ala He Ala 65 70 75 80

Leu Gly Gly His Leu Gly Gin Val Gly Leu 85 90

(2) INFORMATION FOR SEQ ID NO: 3:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 64 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3 :

Leu His Leu Glu Gly Pro Lys Gly Thr His Arg Ala Ala Asp Leu Asp

1 5 10 15

Val Thr Leu Pro Glu Glu Val Leu He Val Ser Gly His Ser Ala Leu 20 25 30

Ala Gly Thr Phe Thr His Leu Asn Ala Met Pro Gly Leu Leu He Gly 35 40 45

He Ala Asp Gly His Ala Arg Ala Arg Leu Leu Val Thr Asp Ala Gly 50 55 60

(2) INFORMATION FOR SEQ ID NO:4 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 55 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:

Leu His Glu Pro Ser Glu Lys Gly His Arg Asp Leu Gly Asp Thr Glu 1 5 10 15

He Val Ser Gly His Ser Ala Ala Ala Gly Ala Thr Phe Thr His Leu 20 25 30

Asn Ala Met Pro Gly Gly He Asp Gly His Asn Arg He Leu Val Thr 35 40 45

Asp He Ala Gly Leu Gly Thr 50 55

(2) INFORMATION FOR SEQ ID NO: 5 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 49 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:

Cys Asp Cys His Pro Val Gly Ala Ala Gly Lys Thr Cys Asn Gin Thr

1 5 10 15

Thr Gly Gin Cys Pro Cys Lys Asp Gly Val Thr Gly Leu Thr Cys Asn 20 25 30

Arg Cys Ala Pro Gly Phe Gin Gin Ser Arg Ser Pro Val Ala Pro Cys 35 40 45

Val

(2) INFORMATION FOR SEQ ID NO: 6 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 48 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:

Cys Asp Cys His Pro Val Gly Ala Ala Gly Lys Thr Cys Asn Gin Thr

1 5 10 15

Thr Gly Gin Cys Pro Cys Lys Asp Gly Val Thr Gly Leu Thr Cys Asn 20 25 30

Arg Cys Ala Pro Gly Phe Gin Gin Ser Arg Ser Pro Val Ala Pro Cys

35 40 45

(2) INFORMATION FOR SEQ ID NO: 7 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 44 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7 :

Cys Asp Cys His Pro Val Gly Ala Ala Gly Thr Cys Asn Gin Thr Thr 1 5 10 15

Gly Gin Cys Pro Cys Lys Asp Gly Val Thr Gly Thr Cys Asn Arg Cys 20 25 30

Ala Lys Gly Gin Gin Ser Arg Ser Pro Ala Pro Cys 35 40

(2) INFORMATION FOR SEQ ID NO: 8:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 35 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:

Cys Cys His Pro Val Gly Gly Cys Asn Gin Gly Gin Cys Cys Lys Gly

1 5 10 15

Val Thr Gly Thr Cys Asn Arg Cys Ala Lys Gly Gin Gin Ser Arg Ser 20 25 30

Val Pro Cys 35

(2) INFORMATION FOR SEQ ID NO: 9 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 49 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:

His Ser Pro Ser Leu Ser Ala Glu Thr Pro He Pro Gly Pro Thr Glu 1 5 10 15

Asp Ser Ser Pro Val Gin Pro Gin Asp Cys Asp Ser His Cys Lys Pro 20 25 30

Ala Arg Gly Ser Tyr Arg He Ser Leu Lys Lys Phe Cys Lys Lys Asp 35 40 45

Tyr (2) INFORMATION FOR SEQ ID NO: 10:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 ammo acids

(B) TYPE: ammo acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(n) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:

He Ser Pro Asp Cys Asp Ser Cys Lys Pro Ala Gly Tyr He Lys Lys 1 5 10 15

Cys Lys Lys Asp Tyr 20

(2) INFORMATION FOR SEQ ID NO:11:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 ammo acids

(B) TYPE: ammo acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(n) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11:

Pro Pro Thr Ser Ser Pro Asp Cys Asp Ser Cys Lys Gly He Lys Lys 1 5 10 15

Cys Lys Lys Asp Tyr 20

(2) INFORMATION FOR SEQ ID NO:12:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 88 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(n) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12:

Met Leu Val Gly Asp Ser Gly Val Gly Lys Thr Cys Leu Leu Val Arg

1 5 10 15

Phe Lys Asp Gly Ala Phe Leu Ala Gly Thr Phe He Ser Thr Val Gly 20 25 30

He Asp Phe Arg Asn Lys Val Leu Asp Val Asp Gly Val Lys Ala Lys 35 40 45 Ltd ώln Met Trp Asp Thr Ala Gly Gin Glu Arg Phe Arg Ser Val Thr 50 55 60

His Ala Tyr Tyr Arg Asp Ala His Ala Leu Leu Leu Leu Tyr Asp Val 65 70 75 80

Thr Asn Lys Ala Ser Phe Asp Asn 85

(2) INFORMATION FOR SEQ ID NO:13:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 83 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:

Met Leu Val Gly Asp Ser Gly Val Gly Lys Thr Cys Leu Leu Val Arg

1 5 10 15

Phe Lys Asp Gly Ala Phe Leu Ala Gly Thr Phe He Ser Thr Val Gly 20 25 30

He Asp Phe Arg Asn Lys Val Leu Asp Val Asp Gly Lys Lys Leu Gin 35 40 45

Trp Asp Thr Ala Gly Gin Glu Arg Phe Arg Ser Val Thr His Ala Tyr 50 55 60

Tyr Arg Asp Ala His Ala Leu Leu Leu Leu Tyr Asp Thr Asn Lys Ser 65 70 75 80

Phe Asp Asn

(2) INFORMATION FOR SEQ ID NO:14:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 83 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:

Phe Gin Asn His Phe Glu Pro Gly Val Tyr Val Cys Ala Lys Cys Gly 1 5 10 15

Tyr Glu Leu Phe Ser Ser Arg Ser Lys Tyr Ala His Ser Ser Pro Trp 20 25 30

Pro Ala Phe Thr Glu Thr He His Ala Asp Ser Val Ala Lys Arg Pro 35 40 45 old nis Asn Arg Ser Glu Ala Leu Lys Val Ser Cys Gly Lys Cys Gly 50 55 60

Asn Gly Leu Gly His Glu Phe Leu Asn Asp Gly Pro Lys Pro Gly Gin 65 70 75 80

Ser Arg Phe

(2) INFORMATION FOR SEQ ID NO: 15:

(1) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 28 amino acids

(B) TYPE: ammo acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ll) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15:

Phe Pro Gly Tyr Val Gly Leu Phe Ser Ser Lys Tyr Trp Pro Phe Thr

1 5 10 15

He Ala Ser Val Val Leu Gly His Phe Asp Gly Pro 20 25

(2) INFORMATION FOR SEQ ID NO: 16:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 26 ammo acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16:

Glu Gly Val Tyr Cys Ala Cys Asp Leu Ser Ser Lys Trp Pro Ala Phe 1 5 10 15

Glu Ala Cys Cys Leu Gly His Phe Gly Lys 20 25

(2) INFORMATION FOR SEQ ID NO: 17:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 32 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO.17.

Phe His Phe Glu Gly Tyr Val Cys Cys Gly Glu Leu Phe Ser Lys Trp

1 5 10 15

Pro Ala Phe Glu Val Cys Cys Leu Gly His Phe Asn Asp Gly Pro Lys 20 25 30

(2) INFORMATION FOR SEQ ID NO: 18.

(l) SEQUENCE CHARACTERISTICS.

(A) LENGTH: 28 ammo acids

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(n) MOLECULE TYPE, peptide

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO: 18:

Phe Gly Tyr Val Gly Phe Ser Ser Lys Trp Pro Phe Thr He Asp Val

1 5 10 15

Gly Asn Leu Gly His Phe Asp Gly Pro Lys Gly Arg 20 25

(2) INFORMATION FOR SEQ ID NO: 19:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6803 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: DNA (genomic)

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO:19:

GGAGCTCGGT TGGAAACCCC CCGAGGCATA ATAGGCGCTC GATAAATGTG CAATAGGTGA 60

ACATGTGGTG GCTTGCAGGC GTCTGGGGGG AGACAGCAGG TTCTGGGCTG GGCAGGGAAT 120

TATTGGATCA ACGGGCATCT TACAGGAAAG ACTCTCAGCT CCCTGCCGCC TAGGACTGTC 180

CAGCCCATCT ATGCCCTCTC CCCAGCCTGT GCCCCAAAGC TGGAGCTGCC ACTCTAGGGG 240

TGAGGGGTGG GGTGGGGAGG GGGAGGCGAA GCACTGCGGC CTGAGTTGCA GGTGGGGGGA 300

GGGGAGGCGG AGCTTCTTTG TTGCAGAAGG TGCCAGGAGG GGGCAGGGCC AGTGGAGAGG 360

TGGGAGGTGG GAGAGGCCCC AGCCAGGGGC TGGGACAGGT GGCTGGGTCC CTGGGGAGCA 420

ATAAGTCCCG CTTGGGCGCT GTGGGGAGGC CCTTCCTAAC TCCCAAACAC CATCTGTGAG 480

GGCTGGGGGT GGGGGCAGAG TAGCGTGTGC AGAGGACTGT TCCTGGGGAG AGGCCCTGTG 540

ACCAGCGGCC TCCTCCCTGG GGAGCTGGCG GTACAATGGC CCTCTGGGCC CACGGCCTCC 600 CGCCGCTGCT GCTGACCCAG ATGAACAATT GGGGCAGGGC TGAGCCCCAG GCACCTACTT 660

TCCCCCACCC CAGAAGCCAC CAGACGTTCT GCAGACCCCA GTCCTGGCTC ACAGGGAAGC 720

TGAGCTGGAG ACAAAGCCAG CCCCTCTGAT GAGGGTGGAA GAGGCTGCTG GCCACTGTCC 780

CTCTTGCAGC CTGGCTGGCA GCCAGTCTGG CAGTGGCCCT GACGTCCAGA GACAGCTTGG 840

GTTTCCCCAG AGGCTTGTCT CTGGCCAGTG GGACCCCTCT GTCAGGCCTG GGCTTTTCTC 900

TCCACTGTCC CAGAATGATG ATCTCAGCCC CCATAGTCCC CCCAGGGTTC CTCCCACCCT 960

TAGGGTGGGG TGTCGGGGGG TGGGGGTTGG GAGCCAGAAG GACCTTGAAG AGGGTGGTTG 1020

GGACGTTTCA GGTTCTAAGC TTGACCCACA GAGCGGAGCG TGAGCCCCGT CAGGTTGAGG 1080

TCCCTCAACT TGTAAAGGAC ACAATTCCAT TCTCTTTATC AGGAAGCTGA GGGGCAGGGG 1140

CCCTGTGGCA GAGAGAGAGC CCCTTAGCCC TCTCTGTTCA GTCCTCCGGT GCCCCCATCC 1200

CTGTGCATCT GTGGCTGTCA CATGCAGATG TGTGGCAAGG AGAAGGTGCC CACCAGCCAG 1260

TGTCAGTTGC TCCAGGAGCC AAGCCAGGTG CCCTATCACC CTGTCTTCCC GTTCCTCCCC 1320

TCCATGGTCA GGCCCTCCTG CTCCCTCCTC TGGTCCTTCA GTTTCCCCTA GGAGGCTTCC 1380

GTGTCCTCCT GCCCCTCCTC TCCCCAACAG CGGGATGCGT CTACCTCTCC ATTCTCTTCC 1440

TCCTGGTCCT TGCTCATCTC TGGTCGTGTC CAGGGTAGCA CCCACGTGGC CTCCTCCACC 1500

AGCTGCAGGC CTGGCCTCCC ATCTGAAACG GGGCATTCAG GCCTCGATGC TGGCCCTGCA 1560

CGGAACTTGT TCCCTGCCCC TCCCTGGGAT GCTTGGCCTC CTCTGTCAAG GACCTGAAAG 1620

TCGGAGGGGA GGAGGTTTCT CTGACCAGAG CTGTTCCTGG ACCCTCTTTG GTGGTGTCGC 1680

TCCCAGGCAC AGCTACCCCA TCCCCAGCTA GTCCCCAGGC CACCCAGCTG GGCTTCTGCC 1740

TCAGTTTCCC TGCCCAAACG TGCTGTGACG TAGGGCAGTG GGCTCCGGGT TGCGACCAGC 1800

CCCTTCCCAT GATTAAACCC TACTCCCTGC CCCTGCAGAG GGGTCCTCAA CAGCTAACCA 1860

AGCCCCCGAA CCCCAAGAAG CCACCCCATC CCACCCTCCA GCTTCCATGT CCTCCCTGCC 1920

AGCTGGGCCC GTGGCAGAGG TGCCCCTAGA AACTTGCAGA CCCAGGGAGC TTTGGGATCA 1980

GAATCTGGCC TGGTGCAGGG GATGCTGGCC TCATGTCTTA GCCCAGCTCA GGCCCATGGG 2040

GGTGCCCCCC TTCCTCAACA TGGGCAGGAG ACACTCCAAT TTGTGCAGCT CTCGACTTGG 2100

GCCTGATGCC ACTTGAGACT CATCAAATCC AACAGCTTCA GAGCGCGTGC TGAGTAACAG 2160

GCATCTGGCA GGTGAGGAAA CAGGAGCCCA AGACATGCAG CCAGAAATGG GGCAGTTGGA 2220

TTCAAAATTA GACCTGACCG AATCCTGGGT TCCTTCTACT CGAGTAGATG CTGCTTTGGG 2280

GATGACCCTT CAACTGGTGG TTACTTGGCT TCCCTACCTG GGGAACATCC AGGGCCTCTG 2340

CTGTCAGACC CGGGGCCTTG CCTGCCTGAT GGTCTTCAGG GAGGAGGCGA CCCAGACCCC 2400

CGTCCAGCAC GTGGCACAGC CCCAGGAGCA GTAAAGACCT GGCTGTGGGC CCAGGACCCT 2460

GCTGGGTGGT CCCCCACGGG CTGCGAAGGC TGAGCTGCCC CCCTCCAGAC CCCTCCCGCC 2520

AGCGCATTCC TGGCTCCCCG GCCCCTCCCC TGGCTCCCGG GCCTCCCAGC CCCCTTCCCC 2580 GCTGGCCCAG CCCGCGTCTG AATCTGCTTC TGATTCCAGC TCTGCGATGA GGCCCCCTCC 2640

CCTCCCCTGC CTCCTTCCCG ACCCGAGCAG CCCCGCCCCC GGCTGGGCCC GGGCTTGCGC 2700

CTGCTGCGCC CCCCACCCCC TCCTGGCACA GCTCGTCCGC CCTCGCTGCA GCCGGGAGGA 2760

GGCGGCGGCC CGTGCACCGC AGGCCCCGCC CGCCCACGGC CCTTCCCGGG AGGCCGGGAG 2820

ACCTGCTCCG CCCGGCCCTC GGTGGGTGAG TGCGAGCGGC GGGTGGGGCC TCCGCGGGCG 2880

GAGGCACCGG GAGCGGGGGC GACGCCTGTC ATCGCTCTAG GCCCAGCGGG AGGACGCGCC 2940

AACATCCCCG CTGCTGTGCT GGGCCCGGGG CGTGCCCGCC GCTGCTCCCA CCTCTGGGCC 3000

GGGCTGGGGC CGCCCGGGGG CCCTGTTCCT CGGCATTGCG GGCCTGGTGG GCAGAGCCGC 3060

GGAGAGGGCT TCTTTTCCCC AAGGGCAGCG TCTTGGGGCC CGGCCACTGG CTGACCCGCA 3120

GCGGCTCCGG CCATGCCTGG CTGGCCCTGG GGGCTGCTGC TGACGGCAGG CACGCTCTTC 3180

GCCGCCCTGA GTCCTGGGCC GCCGGCGCCC GCCGACCCCT GCCACGATGA GGGGGGTGCG 3240

CCCCGCGGCT GCGTGCCAGG ACTGGTGAAC GCCGCCCTGG GCCGCGAGGT GCTGGCTTCC 3300

AGCACGTGCG GGCGGCCGGC CACTCGGGCC TGCGACGCCT CCGACCCGCG ACGGGCACAC 3360

TCCCCCGCCC TCCTTACTTC CCCAGGGGGC ACGGCCAGCC CTCTGTGCTG GCGCTCGGAG 3420

TCCCTGCCTC GGGCGCCCCT CAACGTGACT CTCACGGTGC CCCTGGGCAA GGCTTTTGAG 3480

CTGGTCTTCG TGAGCCTGCG CTTCTGCTCA GCTCCCCCAG CCTCCGTGGC CCTGCTCAAG 3540

TCTCAGGACC ATGGCCGCAG CTGGGCCCCG CTGGGCTTCT TCTCCTCCCA CTGTGACCTG 3600

GACTATGGCC GTCTGCCTGC CCCTGCCAAT GGCCCAGCTG GCCCAGGGCC TGAGGCCCTG 3660

TGCTTCCCCG CACCCCTGGC CCAGCCTGAT GGCAGCGGCC TTCTGGCCTT CAGCATGCAG 3720

GACAGCAGCC CCCCAGGCCT GGACCTGGAC AGCAGCCCAG TGCTCCAAGA CTGGGTGACC 3780

GCCACCGACG TCCGTGTAGT GCTCACAAGG CCTAGCACGG CAGGTGACCC CAGGGACATG 3840

GAGGCCGTCG TCCCTTACTC CTACGCAGCC ACCGACCTCC AGGTGGGCGG GCGCTGCAAG 3900

TGCAATGGAC ATGCCTCACG GTGCCTGCTG GACACACAGG GCCACCTGAT CTGCGACTGT 3960

CGGCATGGCA CCGAGGGCCC TGACTGCGGC CGCTGCAAGC CCTTCTACTG CGACAGGCCA 4020

TGGCAGCGGG CCACTGCCCG GGAATCCCAC GCCTGCCTCG GTGAGGCCTT GGAGGGTGGC 4080

CTGGGGACCT TGGACACAAC CAGCCTGCCC CTGACCCATC CCTCCCTGCA GCTTGCTCCT 4140

GCAACGGCCA TGCCCGCCGC TGCCGCTTCA ACATGGAGCT GTACCGACTG TCCGGCCGCC 4200

GCAGCGGGGG TGTCTGTCTC AACTGCCGGC ACAACACCGC CGGCCGCCAC TGCCACTACT 4260

GCCGGGAGGG CTTCTATCGA GACCCTGGCC GTGCCCTGAG TGACCGTCGG GCTTGCAGGG 4320

GTGAGCCACC ACCGGCCACC TGCAGGCCCT CACCCTCTGA CTTCCCAGAT CCCCAGACAG 4380

GCTTCTGACC AGGCCCTTCC CACCTCTGTC CTCAGCCTGC GACTGTCACC CGGTTGGTGC 4440

TGCTGGCAAG ACCTGCAACC AGACCACAGG CCAGTGTCCC TGCAAGGATG GCGTCACTGG 4500

CCTCACCTGC AACCGCTGCG CGCCTGGCTT CCAGCAAAGC CGCTCCCCAG TGGCGCCCTG 4560

83

SBBSmUIESHEET(RfliE₂6) TGTTAGTGAG TGACCCTGCC CCGCCTCAGC CACCAAGCCA AGGCCACCCC AGCTCCCTGC 4620

TGTTGTCCCG TCTATTCCCC GAGCCCTGCA GATCTCTCTG CCCCTCCATC GCAGGCCATT 4680

CTCCCTCCCT CTCTGCAGAG ACCCCTATCC CTGGACCCAC TGAGGACAGC AGCCCTGTGC 4740

AGCCCCAGGG TGAGTGGACA CAGGACAGGG CCCCAGACTG GCATGACTTT GGGGGAGGGG 4800

GCTCTGGGAG GAGAGGGTGG GGAAAGGGAG TCTGTGCCAG CCTCCCACCT TCTACCCAGA 4860

CTGTGACTCG CACTGCAAAC CTGCCCGTGG CAGCTACCGC ATCAGCCTAA AGAAGTTCTG 4920

CAAGAAGGAC TATGGTAGGT GCCCTCAGGC CTCCCGCGGA CCTTCCCACC TTCCTCCTCT 4980

CCCTACCTTC CCTCCTCCGC CAGCTTCCCC TTGGAACGCC TTGACCCTTG CTGGGCCCCA 5040

AGGCCCATCC TCATCCCTCA GGTCCTCCAC GGGCAGCGAC CCCGCCCCTT CAGCCCCCAC 5100

TGCCCTCCTG GTGTCCTCCC CGTGCCTCCC CCTACCGCGG GCAGGCCGCC CCTTCCTGAC 5160

CCCGCCCCCT CTCGCTCTCC CCGCAGCGGT GCAGGTGGCG GTGGGTGCGC GCGGCGAGGC 5220

GCGCGGCGCG TGGACACGCT TCCCGGTGGC GGTGCTCGCC GTGTTCCGGA GCGGAGAGGA 5280

GCGCGCGCGG CGCGGGAGTA GCGCGCTGTG GGTGCCCGCC GGGGATGCGG CCTGCGGCTG 5340

CCCGCGCCTG CTCCCCGGCC GCCGCTACCT CCTGCTGGGG GGCGGGCCTG GAGCCGCGGC 5400

TGGGGGCGCG GGGGGCCGGG GGCCCGGGCT CATCGCCGCC CGCGGAAGCC TCGTGCTACC 5460

CTGGAGGGAC GCGTGGACGC GGCGCCTGCG GAGGCTGCAG CGACGCGAAC GGCGGGGGCG 5520

CTGCAGCGCC GCCTGAGCCC GCCGGCTGGG CAGGGCGGCC GCTGCTCCCA CATCTAGGCG 5580

CACGTTCACC CTGTGCCTTC GCCTGCCAAG GAGTCCTTGC TCGCGTCGCG CGTGTCGCCA 5640

CCTGGGCCGC CGCCCCGTCC CCGCCGGCAG CTCCCTCGGT ACCTCCCGTC TGGCCCTGGG 5700

GGGATGTGAC CGGCGCACGG ACAGCCCGCC CCGCACAGAG GCAGATGATA TGGCACACCC 5760

GGAGGACCCC ATGGTCTCCC GCCCTCTGGC TGTCGGCCCT GTCCCAGGGG CACTGGGATA 5820

CCCGGAAGGC TGTGAATCCT TCGTGATGCC GGGCCCTCTC GGGGATCTCA GATCATCCCC 5880

GGGGCCGCTG TGATGCACCC CCACCTGTGC GGCGACCCGC CAGGAGCGCA CTGACCTCCC 5940

CAAAGACTGT GGCCACCGCA GGCGCCTTGG ACCCCCATGG GGGACAGGGC GTCCCCTGCC 6000

TCCTGCAGCC CCACGAGGGC GGCGGCCTTG GCCCTGCGGC TGGGCGTCCG CGTCCGGGCG 6060

CCCCGCGGCG TCTGCTGCCG GGTCCCGTAA CTTTCTTGGC CGCCTGTGTC CCCGTCTGCC 6120

GGCTCCGTCC GGCCGTCCCT CTCTCTGCCG CGTCTCTGAC CCTCGGCGCC ACAGCTCCTC 6180

AGCTCAGGGC CCGTCCCAGA ACCTCCTTCC AGCCCTTCTC CCCCGACTCG GGAAGGGACG 6240

TCGTGCCCAC GCGGTTCCGG ATCCACGCGT GACCCGGCCG GACCGCGACT CCGACAGGCG 6300

GCTGTCCGGG CCCCCGATGC CCTCGGCAGG GCCGTGCCAC CCCCCGCCCC TTGTTGTCCC 6360

CCCGGGACCG GCACTGCCGT TTGCCTCCTC TCCGCACGGG ACCGGTTCCC GGCCGGCCCC 6420

AGCTTCCGCC GCTGCGGCCG CCGACCGTCA GCGCGCATGC CCAGAGCCGG GCAGGCCGGA 6480

GCCCCGCCGG CTCTCCGGGG TGGGCACAGG GCGACAGCTC GGCGGGGGCG GGGCCGAGCA 6540

84

«»SmBϊlSHEET R CGCGCGTGCG CAGAAAGGCC GGCGCGGCAG GCTGAGGAGA AAGCGGCGCG CGGAGGTGGG 6600

TGCGCTCGGG GCGTGCGGGG GGCGCGCGGC GGGGTGGCGG GTGGCGGGGC CGGGTCCCCG 6660

CTGTCACCGC GGTCGGCGCG TGCTGGGGGC GGGAGCGTGG GGGCCGGGCT GCGTGCCCCA 6720

TTCGAGGCGG GGATCCCCGG CCACGCGCGG GTTGGGGGCT CCAGAGCCCG GCACCGCCCG 6780

GCGCTGCAGC TGCGGCTTGG CCT 6803 (2) INFORMATION FOR SEQ ID NO:20:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1743 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ll) MOLECULE TYPE: cDNA

(IX) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 1..1740

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20:

ATG CCT GGC TGG CCC TGG GGG CTG CTG CTG ACG GCA GGC ACG CTC TTC 48 Met Pro Gly Trp Pro Trp Gly Leu Leu Leu Thr Ala Gly Thr Leu Phe 1 5 10 15

GCC GCC CTG AGT CCT GGG CCG CCG GCG CCC GCC GAC CCC TGC CAC GAT 96 Ala Ala Leu Ser Pro Gly Pro Pro Ala Pro Ala Asp Pro Cys His Asp 20 25 30

GAG GGG GGT GCG CCC CGC GGC TGC GTG CCA GGA CTG GTG AAC GCC GCC 144 Glu Gly Gly Ala Pro Arg Gly Cys Val Pro Gly Leu Val Asn Ala Ala 35 40 45

CTG GGC CGC GAG GTG CTG GCT TCC AGC ACG TGC GGG CGG CCG GCC ACT 192 Leu Gly Arg Glu Val Leu Ala Ser Ser Thr Cys Gly Arg Pro Ala Thr 50 55 60

CGG GCC TGC GAC GCC TCC GAC CCG CGA CGG GCA CAC TCC CCC GCC CTC 240 Arg Ala Cys Asp Ala Ser Asp Pro Arg Arg Ala His Ser Pro Ala Leu 65 70 75 80

CTT ACT TCC CCA GGG GGC ACG GCC AGC CCT CTG TGC TGG CGC TCG GAG 288 Leu Thr Ser Pro Gly Gly Thr Ala Ser Pro Leu Cys Trp Arg Ser Glu 85 90 95

TCC CTG CCT CGG GCG CCC CTC AAC GTG ACT CTC ACG GTG CCC CTG GGC 336 Ser Leu Pro Arg Ala Pro Leu Asn Val Thr Leu Thr Val Pro Leu G]y 100 105 110

AAG GCT TTT GAG CTG GTC TTC GTG AGC CTG CGC TTC TGC TCA GCT CCC 384 Lys Ala Phe Glu Leu Val Phe Val Ser Leu Arg Phe Cys Ser Ala Pro 115 120 125

CCA GCC TCC GTG GCC CTG CTC AAG TCT CAG GAC CAT GGC CGC AGC TGG 432 Pro Ala Ser Val Ala Leu Leu Lys Ser Gin Asp His Gly Arg Ser Trp 130 135 140 GCC CCG CTG GGC TTC TTC TCC TCC CAC TGT GAC CTG GAC TAT GGC CGT 480

Ala Pro Leu Gly Phe Phe Ser Ser His Cys Asp Leu ASD Tyr Gly Arg 145 150 155 160

CTG CCT GCC CCT GCC AAT GGC CCA GCT GGC CCA GGG CCT GAG GCC CTG 528

Leu Pro Ala Pro Ala Asn Gly Pro Ala Gly Pro Gly Pro Glu Ala Leu 165 170 175

TGC TTC CCC GCA CCC CTG GCC CAG CCT GAT GGC AGC GGC CTT CTG GCC 576

Cys Phe Pro Ala Pro Leu Ala Gin Pro Asp Gly Ser Gly Leu Leu Ala 180 185 190

TTC AGC ATG CAG GAC AGC AGC CCC CCA GGC CTG GAC CTG GAC AGC AGC 624

Phe Ser Met Gin Asp Ser Ser Pro Pro Gly Leu Asp Leu Asp Ser Ser

195 200 205

CCA GTG CTC CAA GAC TGG GTG ACC GCC ACC GAC GTC CGT GTA GTG CTC 672

Pro Val Leu Gin Asp Trp Val Thr Ala Thr Asp Val Arg Val Val Leu 210 215 220

ACA AGG CCT AGC ACG GCA GGT GAC CCC AGG GAC ATG GAG GCC GTC GTC 720

Thr Arg Pro Ser Thr Ala Gly Asp Pro Arg Asp Met Glu Ala Val Val 225 230 235 240

CCT TAC TCC TAC GCA GCC ACC GAC CTC CAG GTG GGC GGG CGC TGC AAG 768

Pro Tyr Ser Tyr Ala Ala Thr Asp Leu Gin Val Gly Gly Arg Cys Lys 245 250 255

TGC AAT GGA CAT GCC TCA CGG TGC CTG CTG GAC ACA CAG GGC CAC CTG 816

Cys Asn Gly His Ala Ser Arg Cys Leu Leu Asp Thr Gin Gly His Leu 260 265 270

ATC TGC GAC TGT CGG CAT GGC ACC GAG GGC CCT GAC TGC GGC CGC TGC 864

He Cys Asp Cys Arg His Gly Thr Glu Gly Pro Asp Cys Gly Arg Cys

275 280 285

AAG CCC TTC TAC TGC GAC AGG CCA TGG CAG CGG GCC ACT GCC CGG GAA 912

Lys Pro Phe Tyr Cys Asp Arg Pro Trp Gin Arg Ala Thr Ala Arg Glu 290 295 300

TCC CAC GCC TGC CTC GCT TGC TCC TGC AAC GGC CAT GCC CGC CGC TGC 960

Ser His Ala Cys Leu Ala Cys Ser Cys Asn Gly His Ala Arg Arg Cys 305 310 315 320

CGC TTC AAC ATG GAG CTG TAC CGA CTG TCC GGC CGC CGC AGC GGG GGT 1008

Arg Phe Asn Met Glu Leu Tyr Arg Leu Ser Gly Arg Arg Ser Gly Gly 325 330 335

GTC TGT CTC AAC TGC CGG CAC AAC ACC GCC GGC CGC CAC TGC CAC TAC 1056

Val Cys Leu Asn Cys Arg His Asn Thr Ala Gly Arg His Cys His Tyr 340 345 350

TGC CGG GAG GGC TTC TAT CGA GAC CCT GGC CGT GCC CTG AGT GAC CGT 1104

Cys Arg Glu Gly Phe Tyr Arg Asp Pro Gly Arg Ala Leu Ser Asp Arg

355 360 365

CGG GCT TGC AGG GCC TGC GAC TGT CAC CCG GTT GGT GCT GCT GGC AAG 1152 Arg Ala Cys Arg Ala Cys Asp Cys His Pro Val Gly Ala Ala Gly Lys 370 375 380

ACC TGC AAC CAG ACC ACA GGC CAG TGT CCC TGC AAG GAT GGC GTC ACT 1200

Thr Cys Asn Gin Thr Thr Gly Gin Cys Pro Cys Lys Asp Gly Val Thr 385 390 395 400 GGC CTC ACC TGC AAC CGC TGC GCG CCT GGC TTC CAG CAA AGC CGC TCC 1248 Gly Leu Thr Cys Asn Arg Cys Ala Pro Gly Phe Gin Gin Ser Arg Ser 405 410 415

CCA GTG GCG CCC TGT GTT AAG ACC CCT ATC CCT GGA CCC ACT GAG GAC 1296 Pro Val Ala Pro Cys Val Lys Thr Pro He Pro Gly Pro Thr Glu Asp 420 425 430

AGC AGC CCT GTG CAG CCC CAG GAC TGT GAC TCG CAC TGC AAA CCT GCC 1344 Ser Ser Pro Val Gin Pro Gin Asp Cys Asp Ser His Cys Lys Pro Ala 435 440 445

CGT GGC AGC TAC CGC ATC AGC CTA AAG AAG TTC TGC AAG AAG GAC TAT 1392 Arg Gly Ser Tyr Arg He Ser Leu Lys Lys Phe Cys Lys Lys Asp Tyr 450 455 460

GCG GTG CAG GTG GCG GTG GGT GCG CGC GGC GAG GCG CGC GGC GCG TGG 1440 Ala Val Gin Val Ala Val Gly Ala Arg Gly Glu Ala Arg Gly Ala Trp 465 470 475 480

ACA CGC TTC CCG GTG GCG GTG CTC GCC GTG TTC CGG AGC GGA GAG GAG 1488 Thr Arg Phe Pro Val Ala Val Leu Ala Val Phe Arg Ser Gly Glu Glu 485 490 495

CGC GCG CGG CGC GGG AGT AGC GCG CTG TGG GTG CCC GCC GGG GAT GCG 1536 Arg Ala Arg Arg Gly Ser Ser Ala Leu Trp Val Pro Ala Gly Asp Ala 500 505 510

GCC TGC GGC TGC CCG CGC CTG CTC CCC GGC CGC CGC TAC CTC CTG CTG 1584 Ala Cys Gly Cys Pro Arg Leu Leu Pro Gly Arg Arg Tyr Leu Leu Leu 515 520 525

GGG GGC GGG CCT GGA GCC GCG GCT GGG GGC GCG GGG GGC CGG GGG CCC 1632 Gly Gly Gly Pro Gly Ala Ala Ala Gly Gly Ala Gly Gly Arg Gly Pro 530 535 540

GGG CTC ATC GCC GCC CGC GGA AGC CTC GTG CTA CCC TGG AGG GAC GCG 1680 Gly Leu He Ala Ala Arg Gly Ser Leu Val Leu Pro Trp Arg Asp Ala 545 550 555 560

TGG ACG CGG CGC CTG CGG AGG CTG CAG CGA CGC GAA CGG CGG GGG CGC 1728 Trp Thr Arg Arg Leu Arg Arg Leu Gin Arg Arg Glu Arg Arg Gly Arg 565 570 575

TGC AGC GCC GCC TGA 1743

Cys Ser Ala Ala 580

(2) INFORMATION FOR SEQ ID NO:21:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 580 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:

Met Pro Gly Trp Pro Trp Gly Leu Leu Leu Thr Ala Gly Thr Leu Phe 1 5 10 15

Ala Ala Leu Ser Pro Gly Pro Pro Ala Pro Ala Asp Pro Cys His Asp 20 25 30 Glu Gly Gly Ala Pro Arg Gly Cys Val Pro Gly Leu Val Asn Ala Ala 35 40 45

Leu Gly Arg Glu Val Leu Ala Ser Ser Thr Cys Gly Arg Pro Ala Thr 50 55 60

Arg Ala Cys Asp Ala Ser Asp Pro Arg Arg Ala His Ser Pro Ala Leu 65 70 75 80

Leu Thr Ser Pro Gly Gly Thr Ala Ser Pro Leu Cys Trp Arg Ser Glu 85 90 95

Ser Leu Pro Arg Ala Pro Leu Asn Val Thr Leu Thr Val Pro Leu Gly 100 105 110

Lys Ala Phe Glu Leu Val Phe Val Ser Leu Arg Phe Cys Ser Ala Pro 115 120 125

Pro Ala Ser Val Ala Leu Leu Lys Ser Gin Asp His Gly Arg Ser Trp 130 135 140

Ala Pro Leu Gly Phe Phe Ser Ser His Cys Asp Leu Asp Tyr Gly Arg 145 150 155 160

Leu Pro Ala Pro Ala Asn Gly Pro Ala Gly Pro Gly Pro Glu Ala Leu 165 170 175

Cys Phe Pro Ala Pro Leu Ala Gin Pro Asp Gly Ser Gly Leu Leu Ala 180 185 190

Phe Ser Met Gin Asp Ser Ser Pro Pro Gly Leu Asp Leu Asp Ser Ser 195 200 205

Pro Val Leu Gin Asp Trp Val Thr Ala Thr Asp Val Arg Val Val Leu 210 215 220

Thr Arg Pro Ser Thr Ala Gly Asp Pro Arg Asp Met Glu Ala Val Val 225 230 235 240

Pro Tyr Ser Tyr Ala Ala Thr Asp Leu Gin Val Gly Gly Arg Cys Lys 245 250 255

Cys Asn Gly His Ala Ser Arg Cys Leu Leu Asp Thr Gin Gly His Leu 260 265 270

He Cys Asp Cys Arg His Gly Thr Glu Gly Pro Asp Cys Gly Arg Cys 275 280 285

Lys Pro Phe Tyr Cys Asp Arg Pro Trp Gin Arg Ala Thr Ala Arg Glu 290 295 300

Ser His Ala Cys Leu Ala Cys Ser Cys Asn Gly His Ala Arg Arg Cys 305 310 315 320

Arg Phe Asn Met Glu Leu Tyr Arg Leu Ser Gly Arg Arg Ser Gly Gly 325 330 335

Val Cys Leu Asn Cys Arg His Asn Thr Ala Gly Arg His Cys His Tyr 340 345 350

Cys Arg Glu Gly Phe Tyr Arg Asp Pro Gly Arg Ala Leu Ser Asp Arg 355 360 365

Arg Ala Cys Arg Ala Cys Asp Cys His Pro Val Gly Ala Ala Gly Lys 370 375 380 Thr Cys Asn Gin Thr Thr Gly Gin Cys Pro Cys Lys Asp Gly Val Thr 385 390 395 400

Gly Leu Thr Cys Asn Arg Cys Ala Pro Gly Phe Gin Gin Ser Arg Ser 405 410 415

Pro Val Ala Pro Cys Val Lys Thr Pro He Pro Gly Pro Thr Glu Asp 420 425 430

Ser Ser Pro Val Gin Pro Gin Asp Cys Asp Ser His Cys Lys Pro Ala 435 440 445

Arg Gly Ser Tyr Arg He Ser Leu Lys Lys Phe Cys Lys Lys Asp Tyr 450 455 460

Ala Val Gin Val Ala Val Gly Ala Arg Gly Glu Ala Arg Gly Ala Trp 465 470 475 480

Thr Arg Phe Pro Val Ala Val Leu Ala Val Phe Arg Ser Gly Glu Glu 485 490 495

Arg Ala Arg Arg Gly Ser Ser Ala Leu Trp Val Pro Ala Gly Asp Ala 500 505 510

Ala Cys Gly Cys Pro Arg Leu Leu Pro Gly Arg Arg Tyr Leu Leu Leu 515 520 525

Gly Gly Gly Pro Gly Ala Ala Ala Gly Gly Ala Gly Gly Arg Gly Pro 530 535 540

Gly Leu He Ala Ala Arg Gly Ser Leu Val Leu Pro Trp Arg Asp Ala 545 550 555 560

Trp Thr Arg Arg Leu Arg Arg Leu Gin Arg Arg Glu Arg Arg Gly Arg 565 570 575

Cys Ser Ala Ala 580

(2) INFORMATION FOR SEQ ID NO:22:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 606 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:

Met Pro Arg Arg Gly Ala Glu Gly Pro Leu Ala Leu Leu Leu Ala Ala

1 5 10 15

Ala Trp Leu Ala Gin Pro Leu Arg Gly Gly Tyr Pro Gly Leu Asn Met

20 25 30

Phe Ala Val Gin Thr Ala Gin Pro Asp Pro Cys Tyr Asp Glu His Gly 35 40 45

Leu Pro Arg Arg Cys He Pro Asp Phe Val Asn Ser Ala Phe Gly Lys 50 55 60 Glu Val Lys Val Ser Ser Thr Cys Gly Lys Pro Pro Ser Arg Tyr Cys 65 70 75 80

Val Val Thr Glu Lys Gly Glu Glu Gin Val Arg Ser Cys His Leu Cys 85 90 95

Asn Ala Ser Asp Pro Lys Arg Ala His Pro Pro Ser Phe Leu Thr Asp 100 105 110

Leu Asn Asn Pro His Asn Leu Thr Cys Trp Gin Ser Asp Ser Tyr Val

115 120 125

Gin Tyr Pro His Asn Val Thr Leu Thr Leu Ser Leu Gly Lys Lys Phe 130 135 140

Glu Val Thr Tyr Val Ser Leu Gin Phe Cys Ser Pro Arg Pro Glu Ser 145 150 155 160

Met Ala He Tyr Lys Ser Met Asp Tyr Gly Lys Thr Trp Val Pro Phe 165 170 175

Gin Phe Tyr Ser Thr Gin Cys Arg Lys Met Tyr Asn Lys Pro Ser Arg 180 185 190

Ala Ala He Thr Lys Gin Asn Glu Gin Glu Ala He Cys Thr Asp Ser 195 200 205

His Thr Asp Val Arg Pro Leu Ser Gly G]y Leu He Ala Phe Ser Thr

210 215 220

Leu Asp Gly Arg Pro Thr Ala His Asp Phe Asp Asn Ser Pro Val Leu 225 230 235 240

Gin Asp Trp Val Thr Ala Thr Asp He Lys Val Thr Phe Ser Arg Leu 245 250 255

His Thr Phe Gly Asp Glu Asn Glu Asp Asp Ser Glu Leu Ala Arg Asp 260 265 270

Ser Tyr Phe Tyr Ala Val Ser Asp Leu Gin Val Gly Gly Arg Cys Lys 275 280 285

Cys Asn Gly His Ala Ser Arg Cys Val Arg Asp Arg Asp Asp Asn Leu 290 295 300

Val Cys Asp Cys Lys His Asn Thr Ala Gly Pro Glu Cys Asp Arg Cys 305 310 315 320

Lys Pro Phe His Tyr Asp Arg Pro Trp Gin Arg Ala Thr Ala Arg Glu 325 330 335

Ala Asn Glu Cys Val Ala Cys Asn Cys Asn Leu His Ala Arg Arg Cys 340 345 350

Arg Phe Asn Met Glu Leu Tyr Lys Leu Ser Gly Arg Lys Ser Gly Gly 355 360 365

Val Cys Leu Asn Cys Arg His Asn Thr Ala Gly Arg His Cys His Tyr 370 375 380

Cys Lys Glu Gly Phe Tyr Arg Asp Leu Ser Lys Pro He Ser His Arg 385 390 395 400

Lys Ala Cys Lys Glu Cys Asp Cys His Pro Val Gly Ala Ala Gly Gin 405 410 415 Thr Cys Asn Gin Thr Thr Gly Gin Cys Pro Cys Lys Asp Gly Val Thr 420 425 430

Gly He Thr Cys Asn Arg Cys Ala Lys Gly Tyr Gin Gin Ser Arg Ser 435 440 445

Pro He Ala Pro Cys He Lys He Pro Ala Ala Pro Pro Pro Thr Ala 450 455 460

Ala Ser Ser Thr Glu Glu Pro Ala Asp Cys Asp Ser Tyr Cys Lys Ala 465 470 475 480

Ser Lys Gly Lys Leu Lys He Asn Met Lys Lys Tyr Cys Lys Lys Asp 485 490 495

Tyr Ala Val Gin He His He Leu Lys Ala Glu Lys Asn Ala Asp Trp 500 505 510

Trp Lys Phe Thr Val Asn He He Ser Val Tyr Lys Gin Gly Ser Asn 515 520 525

Arg Leu Arg Arg Gly Asp Gin Thr Leu Trp Val His Ala Lys Asp He 530 535 540

Ala Cys Lys Cys Pro Lys Val Lys Pro Met Lys Lys Tyr Leu Leu Leu 545 550 555 560

Gly Ser Thr Glu Asp Ser Pro Asp Gin Ser Gly He He Ala Asp Lys 565 570 575

Ser Ser Leu Val He Gin Trp Arg Asp Thr Trp Ala Arg Arg Leu Arg 580 585 590

Lys Phe Gin Gin Arg Glu Lys Lys Gly Lys Cys Arg Lys Ala 595 600 605

(2) INFORMATION FOR SEQ ID NO:23:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 581 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(n) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:

Leu Arg Leu Leu Leu Thr Thr Ser Val Leu Arg Leu Ala Arg Ala Ala 1 5 10 15

Asn Pro Glu Val Ala Gin Gin Thr Pro Pro Asp Pro Cys Tyr Asp Glu 20 25 30

Ser Gly Ala Pro Arg Arg Cys He Pro Glu Phe Val Asn Ala Ala Phe 35 40 45

Gly Lys Glu Val Gin Ala Ser Ser Thr Cys Gly Lys Pro Pro Thr Arg 50 55 60

His Cys Asp Ala Ser Asp Pro Arg Arg Ala His Pro Pro Ala Tyr Leu 65 70 75 80 Thr Asp Leu Asn Thr Ala Ala Asn Met Thr Cys Trp Arg Ser Glu Thr 85 90 95

Leu His His Leu Pro His Asn Val Thr Leu Thr Leu Ser Leu Gly Lys 100 105 110

Lys Phe Glu Val Val Tyr Val Ser Leu Gin Phe Cys Ser Pro Arg Pro 115 120 125

Glu Ser Thr Ala He Phe Lys Ser Met Asp Tyr Gly Lys Thr Trp Val 130 135 140

Pro Tyr Gin Tyr Tyr Ser Ser Gin Cys Arg Lys He Tyr Gly Lys Pro 145 150 155 160

Ser Lys Ala Thr Val Thr Lys Gin Asn Glu Gin Glu Ala Leu Cys Thr 165 170 175

Asp Gly Leu Thr Asp Leu Tyr Pro Leu Thr Gly Gly Leu He Ala Phe 180 185 190

Ser Thr Leu Asp Gly Arg Pro Ser Ala Gin Asp Phe Asp Ser Ser Pro 195 200 205

Val Leu Gin Asp Trp Val Thr Ala Thr Asp He Arg Val Val Phe Ser 210 215 220

Arg Pro His Leu Phe Arg Glu Leu Gly Gly Arg Glu Ala Gly Glu Glu 225 230 235 240

Asp Gly Gly Ala Gly Ala Thr Pro Tyr Tyr Tyr Ser Val Gly Glu Leu 245 250 255

Gin Val Gly Gly Arg Cys Lys Cys Asn Gly His Ala Ser Arg Cys Val 260 265 270

Lys Asp Lys Glu Gin Lys Leu Val Cys Asp Cys Lys His Asn Thr Glu 275 280 285

Gly Pro Glu Cys Asp Arg Cys Lys Pro Phe His Tyr Asp Arg Pro Trp 290 295 300

Gin Arg Ala Ser Ala Arg Glu Ala Asn Glu Cys Leu Ala Cys Asn Cys 305 310 315 320

Asn Leu His Ala Arg Arg Cys Arg Phe Asn Met Glu Leu Tyr Lys Leu 325 330 335

Ser Gly Arg Lys Ser Gly Gly Val Cys Leu Asn Cys Arg His Asn Thr 340 345 350

Ala Gly Arg His Cys His Tyr Cys Lys Glu Gly Phe Tyr Arg Asp Leu 355 360 365

Ser Lys Ser He Thr Asp Arg Lys Ala Cys Lys Ala Cys Asp Cys His 370 375 380

Pro Val Gly Ala Ala Gly Lys Thr Cys Asn Gin Thr Thr Gly Gin Cys 385 390 395 400

Pro Cys Lys Asp Gly Val Thr Gly Leu Thr Cys Asn Arg Cys Ala Lys 405 410 415

Gly Phe Gin Gin Ser Arg Ser Pro Val Ala Pro Cys He Lys He Pro 420 425 430 Ala He Asn Pro Thr Ser Leu Val Thr Ser Thr Glu Ala Pro Ala Asp 435 440 445

Cys Asp Ser Tyr Cys Lys Pro Ala Lys Gly Asn Tyr Lys He Asn Met 450 455 460

Lys Lys Tyr Cys Lys Lys Asp Tyr Val Val Gin Val Asn He Leu Glu 465 470 475 480

Met Glu Thr Val Ala Asn Trp Ala Lys Phe Thr He Asn He Leu Ser 485 490 495

Val Tyr Lys Cys Arg Asp Glu Arg Val Lys Arg Gly Asp Asn Phe Leu 500 505 510

Trp He His Leu Lys Asp Leu Ser Cys Lys Cys Pro Lys He Gin He 515 520 525

Ser Lys Lys Tyr Leu Val Met Gly He Ser Glu Asn Ser Thr Asp Arg 530 535 540

Pro Gly Leu Met Ala Asp Lys Asn Ser Leu Val He Gin Trp Arg Asp 545 550 555 560

Ala Trp Thr Arg Arg Leu Arg Lys Leu Gin Arg Arg Glu Lys Lys Gly 565 570 575

Lys Cys Val Lys Pro 580

(2) INFORMATION FOR SEQ ID NO:24:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 5894 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 2..5053

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:

G AAG GTC CTG GTG ACG GTC CTG GAA CTC TTC CTG CCA TTG CTG TTT 46

Lys Val Leu Val Thr Val Leu Glu Leu Phe Leu Pro Leu Leu Phe

1 5 10 15

TCT GGG ATC CTC ATC TGG CTC CGC TTG AAG ATT CAG TCG GAA AAT GTG 94 Ser Gly He Leu He Trp Leu Arg Leu Lys He Gin Ser Glu Asn Val 20 25 30

CCC AAC GCC ACC ATC TAC CCG GGC CAG TCC ATC CAG GAG CTG CCT CTG 142 Pro Asn Ala Thr He Tyr Pro Gly Gin Ser He Gin Glu Leu Pro Leu 35 40 45

TTC TTC ACC TTC CCT CCG CCA GGA GAC ACC TGG GAG CTT GCC TAC ATC 190 Phe Phe Thr Phe Pro Pro Pro Gly Asp Thr Trp Glu Leu Ala Tyr He 50 55 60 CCT TCT CAC AGT GAC GCT GCC AAG GCC GTC ACT GAG ACA GTG CGC AGG 238

Pro Ser His Ser Asp Ala Ala Lys Ala Val Thr Glu Thr Val Arg Arg

65 70 75

GCA CTT GTG ATC AAC ATG CGA GTG CGC GGC TTT CCC TCC GAG AAG GAC 286

Ala Leu Val He Asn Met Arg Val Arg Gly Phe Pro Ser Glu Lys Asp 80 85 90 95

TTT GAG GAC TAC ATT AGG TAC GAC AAC TGC TCG TCC AGC GTG CTG GCC 334

Phe Glu Asp Tyr He Arg Tyr Asp Asn Cys Ser Ser Ser Val Leu Ala 100 105 110

GCC GTG GTC TTC GAG CAC CCC TTC AAC CAC AGC AAG GAG CCC CTG CCG 382

Ala Val Val Phe Glu His Pro Phe Asn His Ser Lys Glu Pro Leu Pro 115 120 125

CTG GCG GTG AAA TAT CAC CTA CGG TTC AGT TAC ACA CGG AGA AAT TAC 430

Leu Ala Val Lys Tyr His Leu Arg Phe Ser Tyr Thr Arg Arg Asn Tyr

130 135 140

ATG TGG ACC CAA ACA GGC TCC TTT TTC CTG AAA GAG ACA GAA GGC TGG 478

Met Trp Thr Gin Thr Gly Ser Phe Phe Leu Lys Glu Thr Glu Gly Trp

145 150 155

CAC ACT ACT TCC CTT TTC CCG CTT TTC CCA AAC CCA GGA CCA AGG GAA 526

His Thr Thr Ser Leu Phe Pro Leu Phe Pro Asn Pro Gly Pro Arg Glu 160 165 170 175

CTA ACA TCC CCT GAT GGC GGA GAA CCT GGG TAC ATC CGG GAA GGC TTC 574

Leu Thr Ser Pro Asp Gly Gly Glu Pro Gly Tyr He Arg Glu Gly Phe 180 185 190

CTG GCC GTG CAG CAT GCT GTG GAC CGG GCC ATC ATG GAG TAC CAT GCC 622

Leu Ala Val Gin His Ala Val Asp Arg Ala He Met Glu Tyr His Ala 195 200 205

GAT GCC GCC ACA CGC CAG CTG TTC CAG AGA CTG ACG GTG ACC ATC AAG 670

Asp Ala Ala Thr Arg Gin Leu Phe Gin Arg Leu Thr Val Thr He Lys

210 215 220

AGG TTC CCG TAC CCG CCG TTC ATC GCA GAC CCC TTC CTC GTG GCC ATC 718

Arg Phe Pro Tyr Pro Pro Phe He Ala Asp Pro Phe Leu Val Ala He

225 230 235

CAG TAC CAG CTG CCC CTG CTG CTG CTG CTC AGC TTC ACC TAC ACC GCG 766

Gin Tyr Gin Leu Pro Leu Leu Leu Leu Leu Ser Phe Thr Tyr Thr Ala 240 245 250 255

CTC ACC ATT GCC CGT GCT GTC GTG CAG GAG AAG GAA AGG AGG CTG AAG 814

Leu Thr He Ala Arg Ala Val Val Gin Glu Lys Glu Arg Arg Leu Lys 260 265 270

GAG TAC ATG CGC ATG ATG GGG CTC AGC AGC TGG CTG CAC TGG AGT GCC 862

Glu Tyr Met Arg Met Met Gly Leu Ser Ser Trp Leu His Trp Ser Ala 275 280 285

TGG TTC CTC TTG TTC TTC CTC TTC CTC CTC ATC GCC GCC TCC TTC ATG 910

Trp Phe Leu Leu Phe Phe Leu Phe Leu Leu He Ala Ala Ser Phe Met

290 295 300

ACC CTG CTC TTC TGT GTC AAG GTG AAG CCA AAT GTA GCC GTG CTG TCC 958

Thr Leu Leu Phe Cys Val Lys Val Lys Pro Asn Val Ala Val Leu Ser

305 310 315 CGC AGC GAC CCC TCC CTG GTG CTC GCC TTC CTG CTG TGC TTC GCC ATC 1006 Arg Ser Asp Pro Ser Leu Val Leu Ala Phe Leu Leu Cys Phe Ala He 320 325 330 335

TCT ACC ATC TCC TTC AGC TTC ATG GTC AGC ACC TTC TTC AGC AAA GCC 1054

Ser Thr He Ser Phe Ser Phe Met Val Ser Thr Phe Phe Ser Lys Ala

340 345 350

AAC ATG GCA GCA GCC TTC GGA GGC TTC CTC TAC TTC TTC ACC TAC ATC 1102

Asn Met Ala Ala Ala Phe Gly Gly Phe Leu Tyr Phe Phe Thr Tyr He 355 360 365

CCC TAC TTC TTC GTG GCC CCT CGG TAC AAC TGG ATG ACT CTG AGC CAG 1150

Pro Tyr Phe Phe Val Ala Pro Arg Tyr Asn Trp Met Thr Leu Ser Gin 370 375 380

AAG CTC TGC TCC TGC CTC CTG TCT AAT GTC GCC ATG GCA ATG GGA GCC 1198 Lys Leu Cys Ser Cys Leu Leu Ser Asn Val Ala Met Ala Met Gly Ala 385 390 395

CAG CTC ATT GGG AAA TTT GAG GCG AAA GGC ATG GGC ATC CAG TGG CGA 1246

Gin Leu He Gly Lys Phe Glu Ala Lys Gly Met Gly He Gin Trp Arg 400 405 410 415

GAC CTC CTG AGT CCC GTC AAC GTG GAC GAC GAC TTC TGC TTC GGG CAG 1294

Asp Leu Leu Ser Pro Val Asn Val Asp Asp Asp Phe Cys Phe Gly Gin

420 425 430

GTG CTG GGG ATG CTG CTG CTG GAC TCT GTG CTC TAT GGC CTG GTG ACC 1342

Val Leu Gly Met Leu Leu Leu Asp Ser Val Leu Tyr Gly Leu Val Thr 435 440 445

TGG TAC ATG GAG GCC GTC TTC CCA GGG CAG TTC GGC GTG CCT CAG CCC 1390

Trp Tyr Met Glu Ala Val Phe Pro Gly Gin Phe Gly Val Pro Gin Pro 450 455 460

TGG TAC TTC TTC ATC ATG CCC TCC TAT TGG TGT GGG AAG CCA AGG GCG 1438

Trp Tyr Phe Phe He Met Pro Ser Tyr Trp Cys Gly Lys Pro Arg Ala 465 470 475

GTT GCA GGG AAG GAG GAA GAA GAC AGT GAC CCC GAG AAA GCA CTC AGA 1486

Val Ala Gly Lys Glu Glu Glu Asp Ser Asp Pro Glu Lys Ala Leu Arg 480 485 490 495

AAC GAG TAC TTT GAA GCC GAG CCA GAG GAC CTG GTG GCG GGG ATC AAG 1534

Asn Glu Tyr Phe Glu Ala Glu Pro Glu Asp Leu Val Ala Gly He Lys

500 505 510

ATC AAG CAC CTG TCC AAG GTG TTC AGG GTG GGA AAT AAG GAC AGG GCG 1582

He Lys His Leu Ser Lys Val Phe Arg Val Gly Asn Lys Asp Arg Ala 515 520 525

GCC GTC AGA GAC CTG AAC CTC AAC CTG TAC GAG GGA CAG ATC ACC GTC 1630

Ala Val Arg Asp Leu Asn Leu Asn Leu Tyr Glu Gly Gin He Thr Val 530 535 540

CTG CTG GGC CAC AAC GGT GCC GGG AAG ACC ACC ACC CTC TCC ATG CTC 1678

Leu Leu Gly His Asn Gly Ala Gly Lys Thr Thr Thr Leu Ser Met Leu 545 550 555

ACA GGT CTC TTT CCC CCC ACC AGT GGA CGG GCA TAC ATC AGC GGG TAT 1726

Thr Gly Leu Phe Pro Pro Thr Ser Gly Arg Ala Tyr He Ser Gly Tyr 560 565 570 575 GAA ATT TCC CAG GAC ATG GTT CAG ATC CGG AAG AGC CTG GGC CTG TGC 1774

Glu He Ser Gin Asp Met Val Gin He Arg Lys Ser Leu Gly Leu Cys 580 585 590

CCG CAG CAC GAC ATC CTG TTT GAC AAC TTG ACA GTC GCA GAG CAC CTT 1822

Pro Gin His Asp He Leu Phe Asp Asn Leu Thr Val Ala Glu His Leu

595 600 605

TAT TTC TAC GCC CAG CTG AAG GGC CTG TCA CGT CAG AAG TGC CCT GAA 1870

Tyr Phe Tyr Ala Gin Leu Lys Gly Leu Ser Arg Gin Lys Cys Pro Glu

610 615 620

GAA GTC AAG CAG ATG CTG CAC ATC ATC GGC CTG GAG GAC AAG TGG AAC 1918

Glu Val Lys Gin Met Leu His He He Gly Leu Glu Asp Lys Trp Asn

625 630 635

TCA CGG AGC CGC TTC CTG AGC GGG GGC ATG AGG CGC AAG CTC TCC ATC 1966

Ser Arg Ser Arg Phe Leu Ser Gly Gly Met Arg Arg Lys Leu Ser He

640 645 650 655

GGC ATC GCC CTC ATC GCA GGC TCC AAG GTG CTG ATA CTG GAC GAG CCC 2014

Gly He Ala Leu He Ala Gly Ser Lys Val Leu He Leu Asp Glu Pro 660 665 670

ACC TCG GGC ATG GAC GCC ATC TCC AGG AGG GCC ATC TGG GAT CTT CTT 2062

Thr Ser Gly Met Asp Ala He Ser Arg Arg Ala He Trp Asp Leu Leu

675 680 685

CAG CGG CAG AAA AGT GAC CGC ACC ATC GTG CTG ACC ACC CAC TTC ATG 2110

Gin Arg Gin Lys Ser Asp Arg Thr He Val Leu Thr Thr His Phe Met

690 695 700

GAC GAG GCT GAC CTG CTG GGA GAC CGC ATC GCC ATC ATG GCC AAG GGG 2158

Asp Glu Ala Asp Leu Leu Gly Asp Arg He Ala He Met Ala Lys Gly

705 710 715

GAG CTG CAG TGC TGC GGG TCC TCG CTG TTC CTC AAG CAG AAA TAC GGT 2206

Glu Leu Gin Cys Cys Gly Ser Ser Leu Phe Leu Lys Gin Lys Tyr Gly

720 725 730 735

GCC GGC TAT CAC ATG ACG CTG GTG AAG GAG CCG CAC TGC AAC CCG GAA 2254

Ala Gly Tyr His Met Thr Leu Val Lys Glu Pro His Cys Asn Pro Glu 740 745 750

GAC ATC TCC CAG CTG GTC CAC CAC CAC GTG CCC AAC GCC ACG CTG GAG 2302

Asp He Ser Gin Leu Val His His His Val Pro Asn Ala Thr Leu Glu

755 760 765

AGC AGC GCT GGG GCC GAG CTG TCT TTC ATC CTT CCC AGA GAG AGC ACG 2350

Ser Ser Ala Gly Ala Glu Leu Ser Phe He Leu Pro Arg Glu Ser Thr

770 775 780

CAC AGG TTT GAA GGT CTC TTT GCT AAA CTG GAG AAG AAG CAG AAA GAG 2398

His Arg Phe Glu Gly Leu Phe Ala Lys Leu Glu Lys Lys Gin Lys Glu

785 790 795

CTG GGC ATT GCC AGC TTT GGG GCA TCC ATC ACC ACC ATG GAG GAA GTC 2446

Leu Gly He Ala Ser Phe Gly Ala Ser He Thr Thr Met Glu Glu Val

800 805 810 815

TTC CTT CGG GTC GGG AAG CTG GTG GAC AGC AGT ATG GAC ATC CAG GCC 2494

Phe Leu Arg Val Gly Lys Leu Val Asp Ser Ser Met Asp He Gin Ala 820 825 830 ATC CAG CTC CCT GCC CTG CAG TAC CAG CAC GAG AGG CGC GCC AGC GAC 2542

He Gin Leu Pro Ala Leu Gin Tyr Gin His Glu Arg Arg Ala Ser Asp 835 840 845

TGG GCT GTG GAC AGC AAC CTC TGT GGG GCC ATG GAC CCC TCC GAC GGC 2590

Trp Ala Val Asp Ser Asn Leu Cys Gly Ala Met Asp Pro Ser Asp Gly 850 855 860

ATT GGA GCC CTC ATC GAG GAG GAG CGC ACC GCT GTC AAG CTC AAC ACT 2638

He Gly Ala Leu He Glu Glu Glu Arg Thr Ala Val Lys Leu Asn Thr 865 870 875

GGG CTC GCC CTG CAC TGC CAG CAA TTC TGG GCC ATG TTC CTG AAG AAG 2686

Gly Leu Ala Leu His Cys Gin Gin Phe Trp Ala Met Phe Leu Lys Lys

880 885 890 895

GCC GCA TAC AGC TGG CGC GAG TGG AAA ATG GTG GCG GCA CAG GTC CTG 2734

Ala Ala Tyr Ser Trp Arg Glu Trp Lys Met Val Ala Ala Gin Val Leu 900 905 910

GTG CCT CTG ACC TGC GTC ACC CTG GCC CTC CTG GCC ATC AAC TAC TCC 2782

Val Pro Leu Thr Cys Val Thr Leu Ala Leu Leu Ala He Asn Tyr Ser 915 920 925

TCG GAG CTC TTC GAC GAC CCC ATG CTG AGG CTG ACC TTG GGC GAG TAC 2830

Ser Glu Leu Phe Asp Asp Pro Met Leu Arg Leu Thr Leu Gly Glu Tyr 930 935 940

GGC AGA ACC GTC GTG CCC TTC TCA GTT CCC GGG ACC TCC CAG CTG GGT 2878

Gly Arg Thr Val Val Pro Phe Ser Val Pro Gly Thr Ser Gin Leu Gly 945 950 955

CAG CAG CTG TCA GAG CAT CTG AAA GAC GCA CTG CAG GCT GAG GGA CAG 2926

Gin Gin Leu Ser Glu His Leu Lys Asp Ala Leu Gin Ala Glu Gly Gin

960 965 970 975

GAG CCC CGC GAG GTG CTC GGT GAC CTG GAG GAG TTC TTG ATC TTC AGG 2974

Glu Pro Arg Glu Val Leu Gly Asp Leu Glu Glu Phe Leu He Phe Arg 980 985 990

GCT TCT GTG GAG GGG GGC GGC TTT AAT GAG CGG TGC CTT GTG GCA GCG 3022

Ala Ser Val Glu Gly Gly Gly Phe Asn Glu Arg Cys Leu Val Ala Ala 995 1000 1005

TCC TTC AGA GAT GTG GGA GAG CGC ACG GTC GTC AAC GCC TTG TTC AAC 3070

Ser Phe Arg Asp Val Gly Glu Arg Thr Val Val Asn Ala Leu Phe Asn 1010 1015 1020

AAC CAG GCG TAC CAC TCT CCA GCC ACT GCC CTG GCC GTC GTG GAC AAC . 3118

Asn Gin Ala Tyr His Ser Pro Ala Thr Ala Leu Ala Val Val Asp Asn 1025 1030 1035

CTT CTG TTC AAG CTG CTG TGC GGG CCT CAC GCC TCC ATT GTG GTC TCC 3166

Leu Leu Phe Lys Leu Leu Cys Gly Pro His Ala Ser He Val Val Ser

1040 1045 1050 1055

AAC TTC CCC CAG CCC CGG AGC GCC CTG CAG GCT GCC AAG GAC CAG TTT 3214

Asn Phe Pro Gin Pro Arg Ser Ala Leu Gin Ala Ala Lys Asp Gin Phe 1060 1065 1070

AAC GAG GGC CGG AAG GGA TTC GAC ATT GCC CTC AAC CTG CTC TTC GCC 3262

Asn Glu Gly Arg Lys Gly Phe Asp He Ala Leu Asn Leu Leu Phe Ala 1075 1080 1085 ATG GCA TTC TTG GCC AGC ACG TTC TCC ATC CTG GCG GTC AGC GAG AGG 3310 Met Ala Phe Leu Ala Ser Thr Phe Ser He Leu Ala Val Ser Glu Arg 1090 1095 1100

GCC GTG CAG GCC AAG CAT GTG CAG TTT GTG AGT GGA GTC CAC GTG GCC 3358 Ala Val Gin Ala Lys His Val Gin Phe Val Ser Gly Val His Val Ala 1105 1110 1115

AGT TTC TGG CTC TCT GCT CTG CTG TGG GAC CTC ATC TCC TTC CTC ATC 3406 Ser Phe Trp Leu Ser Ala Leu Leu Trp Asp Leu He Ser Phe Leu He 1120 1125 1130 1135

CCC AGT CTG CTG CTG CTG GTG GTG TTT AAG GCC TTC GAC GTG CGT GCC 3454 Pro Ser Leu Leu Leu Leu Val Val Phe Lys Ala Phe Asp Val Arg Ala 1140 1145 1150

TTC ACG CGG GAC GGC CAC ATG GCT GAC ACC CTG CTG CTG CTC CTG CTC 3502 Phe Thr Arg Asp Gly His Met Ala Asp Thr Leu Leu Leu Leu Leu Leu 1155 1160 1165

TAC GGC TGG GCC ATC ATC CCC CTC ATG TAC CTG ATG AAC TTC TTC TTC 3550 Tyr Gly Trp Ala He He Pro Leu Met Tyr Leu Met Asn Phe Phe Phe 1170 1175 1180

TTG GGG GCG GCC ACT GCC TAC ACG AGG CTG ACC ATC TTC AAC ATC CTG 3598 Leu Gly Ala Ala Thr Ala Tyr Thr Arg Leu Thr He Phe Asn He Leu 1185 1190 1195

TCA GGC ATC GCC ACC TTC CTG ATG GTC ACC ATC ATG CGC ATC CCA GCT 3646 Ser Gly He Ala Thr Phe Leu Met Val Thr He Met Arg He Pro Ala 1200 1205 1210 1215

GTA AAA CTG GAA GAA CTT TCC AAA ACC CTG GAT CAC GTG TTC CTG GTG 3694 Val Lys Leu Glu Glu Leu Ser Lys Thr Leu Asp His Val Phe Leu Val 1220 1225 1230

CTG CCC AAC CAC TGT CTG GGG ATG GCA GTC AGC AGT TTC TAC GAG AAC 3742 Leu Pro Asn His Cys Leu Gly Met Ala Val Ser Ser Phe Tyr Glu Asn 1235 1240 1245

TAC GAG ACG CGG AGG TAC TGC ACC TCC TCC GAG GTC GCC GCC CAC TAC 3790 Tyr Glu Thr Arg Arg Tyr Cys Thr Ser Ser Glu Val Ala Ala His Tyr 1250 1255 1260

TGC AAG AAA TAT AAC ATC CAG TAC CAG GAG AAC TTC TAT GCC TGG AGC 3838 Cys Lys Lys Tyr Asn He Gin Tyr Gin Glu Asn Phe Tyr Ala Trp Ser 1265 1270 1275

GCC CCG GGG GTC GGC CGG TTT GTG GCC TCC ATG GCC GCC TCA GGG TGC 3886 Ala Pro Gly Val Gly Arg Phe Val Ala Ser Met Ala Ala Ser Gly Cys 1280 1285 1290 1295

GCC TAC CTC ATC CTG CTC TTC CTC ATC GAG ACC AAC CTG CTT CAG AGA 3934 Ala Tyr Leu He Leu Leu Phe Leu He Glu Thr Asn Leu Leu Gin Arg 1300 1305 1310

CTC AGG GGC ATC CTC TGC GCC CTC CGG AGG AGG CGG ACA CTG ACA GAA 3982 Leu Arg Gly He Leu Cys Ala Leu Arg Arg Arg Arg Thr Leu Thr Glu 1315 1320 1325

TTA TAC ACC CGG ATG CCT GTG CTT CCT GAG GAC CAA GAT GTA GCG GAC 4030 Leu Tyr Thr Arg Met Pro Val Leu Pro Glu Asp Gin Asp Val Ala Asp 1330 1335 1340

GAG AGG ACC CGC ATC CTG GCC CCC AGC CCG GAC TCC CTG CTC CAC ACA 4078 Glu Arg Thr Arg He Leu Ala Pro Ser Pro Asp Ser Leu Leu His Thr 1345 1350 1355

CCT CTG ATT ATC AAG GAG CTC TCC AAG GTG TAC GAG CAG CGG GTG CCC 4126 Pro Leu He He Lys Glu Leu Ser Lys Val Tyr Glu Gin Arg Val Pro 1360 1365 1370 1375

CTC CTG GCC GTG GAC AGG CTC TCC CTC GCG GTG CAG AAA GGG GAG TGC 4174 Leu Leu Ala Val Asp Arg Leu Ser Leu Ala Val Gin Lys Gly Glu Cys 1380 1385 1390

TTC GGC CTG CTG GGC TTC AAT GGA GCC GGG AAG ACC ACG ACT TTC AAA 4222 Phe Gly Leu Leu Gly Phe Asn Gly Ala Gly Lys Thr Thr Thr Phe Lys 1395 1400 1405

ATG CTG ACC GGG GAG GAG AGC CTC ACT TCT GGG GAT GCC TTT GTC GGG 4270 Met Leu Thr Gly Glu Glu Ser Leu Thr Ser Gly Asp Ala Phe Val Gly 1410 1415 1420

GGT CAC AGA ATC AGC TCT GAT GTC GGA AAG GTG CGG CAG CGG ATC GGC 4318 Gly His Arg He Ser Ser Asp Val Gly Lys Val Arg Gin Arg He Gly 1425 1430 1435

TAC TGC CCG CAG TTT GAT GCC TTG CTG GAC CAC ATG ACA GGC CGG GAG 4366 Tyr Cys Pro Gin Phe Asp Ala Leu Leu Asp His Met Thr Gly Arg Glu 1440 1445 1450 1455

ATG CTG GTC ATG TAC GCT CGG CTC CGG GGC ATC CCT GAG CGC CAC ATC 4414 Met Leu Val Met Tyr Ala Arg Leu Arg Gly He Pro Glu Arg His He 1460 1465 1470

GGG GCC TGC GTG GAG AAC ACT CTG CGG GGC CTG CTG CTG GAG CCA CAT 4462 Gly Ala Cys Val Glu Asn Thr Leu Arg Gly Leu Leu Leu Glu Pro His 1475 1480 1485

GCC AAC AAG CTG GTC AGG ACG TAC AGT GGT GGT AAC AAG CGG AAG CTG 4510 Ala Asn Lys Leu Val Arg Thr Tyr Ser Gly Gly Asn Lys Arg Lys Leu 1490 1495 1500

AGC ACC GGC ATC GCC CTG ATC GGA GAG CCT GCT GTC ATC TTC CTG GAC 4558 Ser Thr Gly He Ala Leu He Gly Glu Pro Ala Val He Phe Leu Asp 1505 1510 1515

GAG CCG TCC ACT GGC ATG GAC CCC GTG GCC CGG CGC CTG CTT TGG GAC 4606 Glu Pro Ser Thr Gly Met Asp Pro Val Ala Arg Arg Leu Leu Trp Asp 1520 1525 1530 1535

ACC GTG GCA CGA GCC CGA GAG TCT GGC AAG GCC ATC ATC ATC ACC TCC 4654 Thr Val Ala Arg Ala Arg Glu Ser Gly Lys Ala He He He Thr Ser 1540 1545 1550

CAC AGC ATG GAG GAG TGT GAG GCC CTG TGC ACC CGG CTG GCC ATC ATG 4702 His Ser Met Glu Glu Cys Glu Ala Leu Cys Thr Arg Leu Ala He Met 1555 1560 1565

GTG CAG GGG CAG TTC AAG TGC CTG GGC AGC CCC CAG CAC CTC AAG AGC 4750 Val Gin Gly Gin Phe Lys Cys Leu Gly Ser Pro Gin His Leu Lys Ser 1570 1575 1580

AAG TTC GGC AGC GGC TAC TCC CTG CGG GCC AAG GTG CAG AGT GAA GGG 4798 Lys Phe Gly Ser Gly Tyr Ser Leu Arg Ala Lys Val Gin Ser Glu Gly 1585 1590 1595 CAA CAG GAG GCG CTG GAG GAG TTC AAG GCC TTC GTG GAC CTG ACC TTT 4846 Gin Gin Glu Ala Leu Glu Glu Phe Lys Ala Phe Val Asp Leu Thr Phe 1600 1605 1610 1615

CCA GGC AGC GTC CTG GAA GAT GAG CAC CAA GGC ATG GTC CAT TAC CAC 4894 Pro Gly Ser Val Leu Glu Asp Glu His Gin Gly Met Val His Tyr His 1620 1625 1630

CTG CCG GGC CGT GAC CTC AGC TGG GCG AAG GTT TTC GGT ATT CTG GAG 4942 Leu Pro Gly Arg Asp Leu Ser Trp Ala Lys Val Phe Gly He Leu Glu 1635 1640 1645

AAA GCC AAG GAA AAG TAC GGC GTG GAC GAC TAC TCC GTG AGC CAG ATC 4990 Lys Ala Lys Glu Lys Tyr Gly Val Asp Asp Tyr Ser Val Ser Gin He 1650 1655 1660

TCG CTG GAA CAG GTC TTC CTG AGC TTC GCC CAC CTG CAG CCG CCC ACC 5038 Ser Leu Glu Gin Val Phe Leu Ser Phe Ala His Leu Gin Pro Pro Thr 1665 1670 1675

GCA GAG GAG GGG CGA TGAGGGGTGG CGGCTGTCTC GCCATCAGGC AGGGACAGGA 5093

Ala Glu Glu Gly Arg

1680

CGGGCAAGCA GGGCCCATCT TACATCCTCT CTCTCCAAGT TTATCTCATC CTTTATTTTT 5153

AATCACTTTT TTCTATGATG GATATGAAAA ATTCAAGGCA GTATGCACAG AATGGACGAG 5213

TGCAGCCCAG CCCTCATGCC CAGGATCAGC ATGCGCATCT CCATGTCTGC ATACTCTGGA 5273

GTTCACTTTC CCAGAGCTGG GGCAGGCCGG GCAGTCTGCG GGCAAGCTCC GGGGTCTCTG 5333

GGTGGAGAGC TGACCCAGGA AGGGCTGCAG CTGAGCTGGG GGTTGAATTT CTCCAGGCAC 5393

TCCCTGGAGA GAGGACCCAG TGACTTGTCC AAGTTTACAC ACGACACTAA TCTCCCCTGG 5453

GGAGGAAGCG GGAAGCCAGC CAGGTTGAAC TGTAGCGAGG CCCCCAGGCC GCCAGGAATG 5513

GACCATGCAG ATCACTGTCA GTGGAGGGAA GCTGCTGACT GTGATTAGGT GCTGGGGTCT 5573

TAGCGTCCAG CGCAGCCCGG GGGCATCCTG GAGGCTCTGC TCCTTAGGGC ATGGTAGTCA 5633

CCGCGAAGCC GGGCACCGTC CCACAGCATC TCCTAGAAGC AGCCGGCACA GGAGGGAAGG 5693

TGGCCAGGCT CGAAGCAGTC TCTGTTTCCA GCACTGCACC CTCAGGAAGT CGCCCGCCCC 5753

AGGACACGCA GGGACCACCC TAAGGGCTGG GTGGCTGTCT CAAGGACACA TTGAATACGT 5813

TGTGACCATC CAGAAAATAA ATGCTGAGGG GACACAAAAA AAAAAAAAAA AAAAAAAAAA 5873

AAAAAAAAAA AAAAAAAAAA A 5894

(2) INFORMATION FOR SEQ ID NO:25:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1684 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(n) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:

Lys Val Leu Val Thr Val Leu Glu Leu Phe Leu Pro Leu Leu Phe Ser

1 5 10 15

Gly He Leu He Trp Leu Arg Leu Lys He Gin Ser Glu Asn Val Pro 20 25 30

Asn Ala Thr He Tyr Pro Gly Gin Ser He Gin Glu Leu Pro Leu Phe 35 40 45

Phe Thr Phe Pro Pro Pro Gly Asp Thr Trp Glu Leu Ala Tyr He Pro 50 55 60

Ser His Ser Asp Ala Ala Lys Ala Val Thr Glu Thr Val Arg Arg Ala 65 70 75 80

Leu Val He Asn Met Arg Val Arg Gly Phe Pro Ser Glu Lys Asp Phe 85 90 95

Glu Asp Tyr He Arg Tyr Asp Asn Cys Ser Ser Ser Val Leu Ala Ala 100 105 110

Val Val Phe Glu His Pro Phe Asn His Ser Lys Glu Pro Leu Pro Leu 115 120 125

Ala Val Lys Tyr His Leu Arg Phe Ser Tyr Thr Arg Arg Asn Tyr Met 130 135 140

Trp Thr Gin Thr Gly Ser Phe Phe Leu Lys Glu Thr Glu Gly Trp His 145 150 155 160

Thr Thr Ser Leu Phe Pro Leu Phe Pro Asn Pro Gly Pro Arg Glu Leu 165 170 175

Thr Ser Pro Asp Gly Gly Glu Pro Gly Tyr He Arg Glu Gly Phe Leu 180 185 190

Ala Val Gin His Ala Val Asp Arg Ala He Met Glu Tyr His Ala Asp 195 200 205

Ala Ala Thr Arg Gin Leu Phe Gin Arg Leu Thr Val Thr He Lys Arg 210 215 220

Phe Pro Tyr Pro Pro Phe He Ala Asp Pro Phe Leu Val Ala He Gin 225 230 235 240

Tyr Gin Leu Pro Leu Leu Leu Leu Leu Ser Phe Thr Tyr Thr Ala Leu 245 250 255

Thr He Ala Arg Ala Val Val Gin Glu Lys Glu Arg Arg Leu Lys Glu 260 265 270

Tyr Met Arg Met Met Gly Leu Ser Ser Trp Leu His Trp Ser Ala Trp 275 280 285

Phe Leu Leu Phe Phe Leu Phe Leu Leu He Ala Ala Ser Phe Met Thr 290 295 300

Leu Leu Phe Cys Val Lys Val Lys Pro Asn Val Ala Val Leu Ser Arg 305 310 315 320

Ser Asp Pro Ser Leu Val Leu Ala Phe Leu Leu Cys Phe Ala He Ser 325 330 335 Thr He Ser Phe Ser Phe Met Val Ser Thr Phe Phe Ser Lys Ala Asn 340 345 350

Met Ala Ala Ala Phe Gly Gly Phe Leu Tyr Phe Phe Thr Tyr He Pro 355 360 365

Tyr Phe Phe Val Ala Pro Λrg Tyr Asn Trp Met Thr Leu Ser Gin Lys 370 375 380

Leu Cys Ser Cys Leu Leu Ser Asn Val Ala Met Ala Met Gly Ala Gin 385 390 395 400

Leu He Gly Lys Phe Glu Ala Lys Gly Met Gly He Gin Trp Arg Asp 405 410 415

Leu Leu Ser Pro Val Asn Val Asp Asp Asp Phe Cys Phe Gly Gin Val 420 425 430

Leu Gly Met Leu Leu Leu Asp Ser Val Leu Tyr Gly Leu Val Thr Trp 435 440 445

Tyr Met Glu Ala Val Phe Pro Gly Gin Phe Gly Val Pro Gin Pro Trp 450 455 460

Tyr Phe Phe He Met Pro Ser Tyr Trp Cys Gly Lys Pro Arg Ala Val 465 470 475 480

Ala Gly Lys Glu Glu Glu Asp Ser Asp Pro Glu Lys Ala Leu Arg Asn 485 490 495

Glu Tyr Phe Glu Ala Glu Pro Glu Asp Leu Val Ala Gly He Lys He 500 505 510

Lys His Leu Ser Lys Val Phe Arg Val Gly Asn Lys Asp Arg Ala Ala 515 520 525

Val Arg Asp Leu Asn Leu Asn Leu Tyr Glu Gly Gin He Thr Val Leu 530 535 540

Leu Gly His Asn Gly Ala Gly Lys Thr Thr Thr Leu Ser Met Leu Thr 545 550 555 560

Gly Leu Phe Pro Pro Thr Ser Gly Arg Ala Tyr He Ser Gly Tyr Glu 565 570 575

He Ser Gin Asp Met Val Gin He Arg Lys Ser Leu Gly Leu Cys Pro 580 585 590

Gin His Asp He Leu Phe Asp Asn Leu Thr Val Ala Glu His Leu Tyr 595 600 605

Phe Tyr Ala Gin Leu Lys Gly Leu Ser Arg Gin Lys Cys Pro Glu Glu 610 615 620

Val Lys Gin Met Leu His He He Gly Leu Glu Asp Lys Trp Asn Ser 625 630 635 640

Arg Ser Arg Phe Leu Ser Gly Gly Met Arg Arg Lys Leu Ser He Gly 645 650 655

He Ala Leu He Ala Gly Ser Lys Val Leu He Leu Asp Glu Pro Thr 660 665 670

Ser Gly Met Asp Ala He Ser Arg Arg Ala He Trp Asp Leu Leu Gin 675 680 685 Arg Gin Lys Ser Asp Arg Thr He Val Leu Thr Thr His Phe Met Asp 690 695 700

Glu Ala Asp Leu Leu Gly Asp Arg He Ala He Met Ala Lys Gly Glu 705 710 715 720

Leu Gin Cys Cys Gly Ser Ser Leu Phe Leu Lys Gin Lys Tyr Gly Ala 725 730 735

Gly Tyr His Met Thr Leu Val Lys Glu Pro His Cys Asn Pro Glu Asp 740 745 750

He Ser Gin Leu Val His His His Val Pro Asn Ala Thr Leu Glu Ser 755 760 765

Ser Ala Gly Ala Glu Leu Ser Phe He Leu Pro Arg Glu Ser Thr His 770 775 780

Arg Phe Glu Gly Leu Phe Ala Lys Leu Glu Lys Lys Gin Lys Glu Leu 785 790 795 800

Gly He Ala Ser Phe Gly Ala Ser He Thr Thr Met Glu Glu Val Phe 805 810 815

Leu Arg Val Gly Lys Leu Val Asp Ser Ser Met Asp He Gin Ala He 820 825 830

Gin Leu Pro Ala Leu Gin Tyr Gin His Glu Arg Arg Ala Ser Asp Trp 835 840 845

Ala Val Asp Ser Asn Leu Cys Gly Ala Met Asp Pro Ser Asp Gly He 850 855 860

Gly Ala Leu He Glu Glu Glu Arg Thr Ala Val Lys Leu Asn Thr Gly 865 870 875 880

Leu Ala Leu His Cys Gin Gin Phe Trp Ala Met Phe Leu Lys Lys Ala 885 890 895

Ala Tyr Ser Trp Arg Glu Trp Lys Met Val Ala Ala Gin Val Leu Val 900 905 910

Pro Leu Thr Cys Val Thr Leu Ala Leu Leu Ala He Asn Tyr Ser Ser 915 920 925

Glu Leu Phe Asp Asp Pro Met Leu Arg Leu Thr Leu Gly Glu Tyr Gly 930 935 940

Arg Thr Val Val Pro Phe Ser Val Pro Gly Thr Ser Gin Leu Gly Gin 945 950 955 960

Gin Leu Ser Glu His Leu Lys Asp Ala Leu Gin Ala Glu Gly Gin Glu 965 970 975

Pro Arg Glu Val Leu Gly Asp Leu Glu Glu Phe Leu He Phe Arg Ala 980 985 990

Ser Val Glu Gly Gly Gly Phe Asn Glu Arg Cys Leu Val Ala Ala Ser 995 1000 1005

Phe Arg Asp Val Gly Glu Arg Thr Val Val Asn Ala Leu Phe Asn Asn 1010 1015 1020

Gin Ala Tyr His Ser Pro Ala Thr Ala Leu Ala Val Val Asp Asn Leu 1025 1030 1035 1040 Leu Phe Lys Leu Leu Cys Gly Pro His Ala Ser He Val Val Ser Asn 1045 1050 1055

Phe Pro Gin Pro Arg Ser Ala Leu Gin Ala Ala Lys Asp Gin Phe Asn 1060 1065 1070

Glu Gly Arg Lys Gly Phe Asp He Ala Leu Asn Leu Leu Phe Ala Met 1075 1080 1085

Ala Phe Leu Ala Ser Thr Phe Ser He Leu Ala Val Ser Glu Arg Ala 1090 1095 1100

Val Gin Ala Lys His Val Gin Phe Val Ser Gly Val His Val Ala Ser 1105 1110 1115 1120

Phe Trp Leu Ser Ala Leu Leu Trp Asp Leu He Ser Phe Leu He Pro 1125 1130 1135

Ser Leu Leu Leu Leu Val Val Phe Lys Ala Phe Asp Val Arg Ala Phe 1140 1145 1150

Thr Arg Asp Gly His Met Ala Asp Thr Leu Leu Leu Leu Leu Leu Tyr 1155 1160 1165

Gly Trp Ala He He Pro Leu Met Tyr Leu Met Asn Phe Phe Phe Leu 1170 1175 1180

Gly Ala Ala Thr Ala Tyr Thr Arg Leu Thr He Phe Asn He Leu Ser 1185 1190 1195 1200

Gly He Ala Thr Phe Leu Met Val Thr He Met Arg He Pro Ala Val 1205 1210 1215

Lys Leu Glu Glu Leu Ser Lys Thr Leu Asp His Val Phe Leu Val Leu 1220 1225 1230

Pro Asn His Cys Leu Gly Met Ala Val Ser Ser Phe Tyr Glu Asn Tyr 1235 1240 1245

Glu Thr Arg Arg Tyr Cys Thr Ser Ser Glu Val Ala Ala His Tyr Cys 1250 1255 1260

Lys Lys Tyr Asn He Gin Tyr Gin Glu Asn Phe Tyr Ala Trp Ser Ala 1265 1270 1275 1280

Pro Gly Val Gly Arg Phe Val Ala Ser Met Ala Ala Ser Gly Cys Ala 1285 1290 1295

Tyr Leu He Leu Leu Phe Leu He Glu Thr Asn Leu Leu Gin Arg Leu 1300 1305 1310

Arg Gly He Leu Cys Ala Leu Arg Arg Arg Arg Thr Leu Thr Glu Leu 1315 1320 1325

Tyr Thr Arg Met Pro Val Leu Pro Glu Asp Gin Asp Val Ala Asp Glu 1330 1335 1340

Arg Thr Arg He Leu Ala Pro Ser Pro Asp Ser Leu Leu His Thr Pro 1345 ^" 1350 1355 1360

Leu He He Lys Glu Leu Ser Lys Val Tyr Glu Gin Arg Val Pro Leu 1365 1370 1375

Leu Ala Val Asp Arg Leu Ser Leu Ala Val Gin Lys Gly Glu Cys Phe 1380 1385 1390 Gly Leu Leu Gly Phe Asn Gly Ala Gly Lys Thr Thr Thr Phe Lys Met 1395 1400 1405

Leu Thr Gly Glu Glu Ser Leu Thr Ser Gly Asp Ala Phe Val Gly Gly 1410 1415 1420

His Arg He Ser Ser Asp Val Gly Lys Val Arg Gin Arg He Gly Tyr 1425 1430 1435 1440

Cys Pro Gin Phe Asp Ala Leu Leu Asp His Met Thr Gly Arg Glu Met 1445 1450 1455

Leu Val Met Tyr Ala Arg Leu Λrg Gly He Pro Glu Arg His He Gly 1460 1465 1470

Ala Cys Val Glu Asn Thr Leu Arg Gly Leu Leu Leu Glu Pro His Ala 1475 1480 1485

Asn Lys Leu Val Arg Thr Tyr Ser Gly Gly Asn Lys Arg Lys Leu Ser 1490 1495 1500

Thr Gly He Ala Leu He Gly Glu Pro Ala Val He Phe Leu Asp Glu 1505 1510 1515 1520

Pro Ser Thr Gly Met Asp Pro Val Ala Arg Arg Leu Leu Trp Asp Thr 1525 1530 1535

Val Ala Arg Ala Arg Glu Ser Gly Lys Ala He He He Thr Ser His 1540 1545 1550

Ser Met Glu Glu Cys Glu Ala Leu Cys Thr Arg Leu Ala He Met Val 1555 1560 1565

Gin Gly Gin Phe Lys Cys Leu Gly Ser Pro Gin His Leu Lys Ser Lys 1570 1575 1580

Phe Gly Ser Gly Tyr Ser Leu Arg Ala Lys Val Gin Ser Glu Gly Gin 1585 1590 1595 1600

Gin Glu Ala Leu Glu Glu Phe Lys Ala Phe Val Asp Leu Thr Phe Pro 1605 1610 1615

Gly Ser Val Leu Glu Asp Glu His Gin Gly Met Val His Tyr His Leu 1620 1625 1630

Pro Gly Arg Asp Leu Ser Trp Ala Lys Val Phe Gly He Leu Glu Lys 1635 1640 1645

Ala Lys Glu Lys Tyr Gly Val Asp Asp Tyr Ser Val Ser Gin He Ser 1650 1655 1660

Leu Glu Gin Val Phe Leu Ser Phe Ala His Leu Gin Pro Pro Thr Ala 1665 1670 1675 1680

Glu Glu Gly Arg

(2) INFORMATION FOR SEQ ID NO: 26:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1375 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:

Cys Met Glu Glu Glu Pro Thr His Leu Arg Leu Gly Val Ser He Gin 1 5 10 15

Asn Leu Val Lys Val Tyr Arg Asp Gly Met Lys Val Ala Val Asp Gly 20 25 30

Leu Ala Leu Asn Phe Tyr Glu Gly Gin He Thr Ser Phe Leu Gly His 35 40 45

Asn Gly Ala Gly Lys Thr Thr Thr Met Ser lie Leu Thr Gly Leu Phe 50 55 60

Pro Pro Thr Ser Gly Thr Ala Tyr He Leu Gly Lys Asp He Arg Ser 65 70 75 80

Glu Met Ser Ser He Arg Gin Asn Leu Gly Val Cys Pro Gin His Asn 85 90 95

Val Leu Phe Asp Met Leu Thr Val Glu Glu His He Trp Phe Tyr Ala 100 105 110

Arg Leu Lys Gly Leu Ser Glu Lys His Val Lys Ala Glu Met Glu Gin 115 120 125

Met Ala Leu Asp Val Gly Leu Pro Pro Ser Lys Leu Lys Ser Lys Thr 130 135 140

Ser Gin Leu Ser Gly Gly Met Gin Arg Lys Leu Ser Val Ala Leu Ala 145 150 155 160

Phe Val Gly Gly Ser Lys Val Val He Leu Asp Glu Pro Thr Ala Gly 165 170 175

Val Asp Pro Tyr Ser Arg Arg Gly He Trp Glu Leu Leu Leu Lys Tyr 180 185 190

Arg Gin Gly Arg Thr He He Leu Ser Thr His His Met Asp Glu Ala 195 200 205

Asp He Leu Gly Asp Arg He Ala He He Ser His Gly Lys Leu Cys 210 215 220

Cys Val Gly Ser Ser Leu Phe Leu Lys Asn Gin Leu Gly Thr Gly Tyr 225 230 235 240

Tyr Leu Thr Leu Val Lys Lys Asp Val Glu Ser Ser Leu Ser Ser Cys 245 250 255

Arg Asn Ser Ser Ser Thr Val Ser Cys Leu Lys Lys Glu Asp Ser Val 260 265 270

Ser Gin Ser Ser Ser Asp Ala Gly Leu Gly Ser Asp His Glu Ser Asp 275 280 285

Thr Leu Thr He Asp Val Ser Ala He Ser Asn Leu He Arg Lys His 290 295 300

Val Ser Glu Ala Arg Leu Val Glu Asp He Gly His Glu Leu Thr Tyr 305 310 315 320 Val Leu Pro Tyr Glu Ala Ala Lys Glu Gly Ala Phe Val Glu Leu Phe 325 330 335

His Glu He Asp Asp Arg Leu Ser Asp Leu Gly He Ser Ser Tyr Gly 340 345 350

He Ser Glu Thr Thr Leu Glu Glu He Phe Leu Lys Val Ala Glu Glu 355 360 365

Ser Gly Val Asp Ala Glu Thr Ser Asp Gly Thr Leu Pro Ala Arg Arg 370 375 380

Asn Arg Arg Ala Phe Gly Asp Lys Gin Ser Cys Leu His Pro Phe Thr 385 390 395 400

Glu Asp Asp Ala Val Asp Pro Asn Asp Ser Asp He Asp Pro Glu Ser 405 410 415

Arg Glu Thr Asp Leu Leu Ser Gly Met Asp Gly Lys Gly Ser Tyr Gin 420 425 430

Leu Lys Gly Trp Lys Leu Thr Gin Gin Gin Phe Val Ala Leu Leu Trp 435 440 445

Lys Arg Leu Leu He Ala Arg Arg Ser Arg Lys Gly Phe Phe Ala Gin 450 455 460

He Val Leu Pro Ala Val Phe Val Cys He Ala Leu Val Phe Ser Leu 465 470 475 480

He Val Pro Pro Phe Gly Lys Tyr Pro Ser Leu Glu Leu Gin Pro Trp 485 490 495

Met Tyr Asn Glu Gin Tyr Thr Phe Val Ser Asn Asp Ala Pro Glu Asp 500 505 510

Met Gly Thr Gin Glu Leu Leu Asn Ala Leu Thr Lys Asp Pro Gly Phe 515 520 525

Gly Thr Arg Cys Met Glu Gly Asn Pro He Pro Asp Thr Pro Cys Leu 530 535 540

Ala Gly Glu Glu Asp Trp Thr He Ser Pro Val Pro Gin Ser He Val 545 550 555 560

Asp Leu Phe Gin Asn Gly Asn Trp Thr Met Lys Asn Pro Ser Pro Ala 565 570 575

Cys Gin Cys Ser Ser Asp Lys He Lys Lys Met Leu Pro Val Cys Pro 580 585 590

Pro Gly Ala Gly Gly Leu Pro Pro Pro Gin Arg Lys Gin Lys Thr Ala 595 600 605

Asp He Leu Gin Asn Leu Thr Gly Arg Asn He Ser Asp Tyr Leu Val 610 615 620

Lys Thr Tyr Val Gin He He Ala Lys Ser Leu Lys Asn Lys He Trp 625 630 635 640

Val Asn Glu Phe Arg Tyr Gly Gly Phe Ser Leu Gly Val Ser Asn Ser 645 650 655

Gin Ala Leu Pro Pro Ser His Glu Val Asn Asp Ala He Lys Gin Met 660 665 670 Lys Lys Leu Leu Lys Leu Thr Lys Asp Thr Ser Ala Asp Arg Phe Leu 675 680 685

Ser Ser Leu Gly Arg Phe Met Ala Gly Leu Asp Thr Lys Asn Asn Val 690 695 700

Lys Val Trp Phe Asn Asn Lys Gly Trp His Ala He Ser Ser Phe Leu 705 710 715 720

Asn Val He Asn Asn Ala He Leu Arg Ala Asn Leu Gin Lys Gly Glu 725 730 735

Asn Pro Ser Gin Tyr Gly He Thr Ala Phe Asn His Pro Leu Asn Leu 740 745 750

Thr Lys Gin Gin Leu Ser Glu Val Ala Leu Met Thr Thr Ser Val Asp 755 760 765

Val Leu Val Ser He Cys Val He Phe Ala Met Ser Phe Val Pro Ala 770 775 780

Ser Phe Val Val Phe Leu He Gin Glu Arg Val Ser Lys Ala Lys His 785 790 795 800

Leu Gin Phe He Ser Gly Val Lys Pro Val He Tyr Trp Leu Ser Asn 805 810 815

Phe Val Trp Asp Met Cys Asn Tyr Val Val Pro Ala Thr Leu Val He 820 825 830

He He Phe He Cys Phe Gin Gin Lys Ser Tyr Val Ser Ser Thr Asn 835 840 845

Leu Pro Val Leu Ala Leu Leu Leu Leu Leu Tyr Gly Trp Ser He Thr 850 855 860

Pro Leu Met Tyr Pro Ala Ser Phe Val Phe Lys He Pro Ser Thr Ala 865 870 875 880

Tyr Val Val Leu Thr Ser Val Asn Leu Phe He Gly He Asn Gly Ser 885 890 895

Val Ala Thr Phe Val Leu Glu Leu Phe Thr Asn Asn Lys Leu Asn Asp 900 905 910

He Asn Asp He Leu Lys Ser Val Phe Leu He Phe Pro His Phe Cys 915 920 925

Leu Gly Arg Gly Leu He Asp Met Val Lys Asn Gin Ala Met Ala Asp 930 935 940

Ala Leu Glu Arg Phe Gly Glu Asn Arg Phe Val Ser Pro Leu Ser Trp 945 950 955 960

Asp Leu Val Gly Arg Asn Leu Phe Ala Met Ala Val Glu Gly Val Val 965 970 975

Phe Phe Leu He Thr Val Leu He Gin Tyr Arg Phe Phe He Arg Pro 980 985 990

Arg Pro Val Lys Ala Lys Leu Pro Pro Leu Asn Asp Glu Asp Glu Asp 995 1000 1005

Val Arg Arg Glu Arg Gin Arg He Leu Asp Gly Gly Gly Gin Asn Asp 1010 1015 ^" 1020 He Leu Glu He Lys Glu Leu Thr Lys He Tyr Arg Arg Lys Arg Lys 1025 1030 1035 1040

Pro Ala Val Asp Arg He Cys He Gly He Pro Pro Gly Glu Cys Phe 1045 1050 1055

Gly Leu Leu Gly Val Asn Gly Ala Gly Lys Ser Thr Thr Phe Lys Met 1060 1065 1070

Leu Thr Gly Asp Thr Pro Val Thr Arg Gly Asp Ala Phe Leu Asn Lys

1075 1080 1085

Asn Ser He Leu Ser Asn He His Glu Val His Gin Asn Met Gly Tyr 1090 1095 1100

Cys Pro Gin Phe Asp Ala He Thr Glu Leu Leu Thr Gly Arg Glu His 1105 1110 1115 1120

Val Glu Phe Phe Ala Leu Leu Arg Gly Val Pro Glu Lys Glu Val Gly 1125 1130 1135

Lys Phe Gly Glu Trp Ala He Arg Lys Leu Gly Leu Val Lys Tyr Gly 1140 1145 1150

Glu Lys Tyr Ala Ser Asn Tyr Ser Gly Gly Asn Lys Arg Lys Leu Ser

1155 1160 1165

Thr Ala Met Ala Leu He Gly Gly Pro Pro Val Val Phe Leu Asp Glu 1170 1175 1180

Pro Thr Thr Gly Met Asp Pro Lys Ala Arg Arg Phe Leu Trp Asn Cys 1185 1190 1195 1200

Ala Leu Ser He Val Lys Glu Gly Arg Ser Val Val Leu Thr Ser His 1205 1210 1215

Ser Met Glu Glu Cys Glu Ala Leu Cys Thr Arg Met Ala He Met Val 1220 1225 1230

Asn Gly Arg Phe Arg Cys Leu Gly Ser Val Gin His Leu Lys Asn Arg

1235 1240 1245

Phe Gly Asp Gly Tyr Thr He Val Val Arg He Ala Gly Ser Asn Pro 1250 1255 1260

Asp Leu Lys Pro Val Gin Glu Phe Phe Gly Leu Ala Phe Pro Gly Ser 1265 1270 1275 1280

Val Leu Lys Glu Lys His Arg Asn Met Leu Gin Tyr Gin Leu Pro Ser 1285 1290 1295

Ser Leu Ser Ser Leu Ala Arg He Phe Ser He Leu Ser Gin Ser Lys 1300 1305 1310

Lys Arg Leu His He Glu Asp Tyr Ser Val Ser Gin Thr Thr Leu Asp

1315 1320 1325

Gin Val Phe Val Asn Phe Ala Lys Asp Gin Ser Asp Asp Asp His Leu 1330 1335 1340

Lys Asp Leu Ser Leu His Lys Asn Gin Thr Val Val Asp Val Ala Val 1345 1350 1355 1360

Leu Thr Ser Phe Leu Gin Asp Glu Lys Val Lys Glu Ser Tyr Val 1365 1370 1375 NFORMATION FOR SEQ ID NO: 27:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1457 amino acids

(B) TYPE: ammo acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(n) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27:

Met Glu Glu Glu Pro Thr His Leu Pro Leu Val Val Cys Val Asp Lys

1 5 10 15

Leu Thr Lys Val Tyr Lys Asn Asp Lys Lys Leu Ala Leu Asn Lys Leu 20 25 30

Ser Leu Asn Leu Tyr Glu Asn Gin Val Val Ser Phe Leu Gly His Asn 35 40 45

Gly Ala Gly Lys Thr Thr Thr Met Ser He Leu Thr Gly Leu Phe Pro 50 55 60

Pro Thr Ser Gly Ser Ala Thr He Tyr Gly His Asp He Arg Thr Glu 65 70 75 80

Met Asp Glu He Arg Lys Asn Leu Gly Met Cys Pro Gin His Asn Val 85 90 95

Leu Phe Asp Arg Leu Thr Val Glu Glu His Leu Trp Phe Tyr Ser Arg 100 105 110

Leu Lys Ser Met Ala Gin Glu Glu He Arg Lys Glu Thr Asp Lys Met 115 120 125

He Glu Asp Leu Glu Leu Ser Asn Lys Arg His Ser Leu Val Gin Thr 130 135 140

Leu Ser Gly Gly Met Lys Arg Lys Leu Ser Val Ala He Ala Phe Val 145 150 155 160

Gly Gly Ser Arg Ala He He Leu Asp Glu Pro Thr Ala Gly Val ASD 165 170 175

Pro Tyr Ala Arg Arg Ala He Trp Asp Leu He Leu Lys Tyr Lys Pro 180 185 190

Gly Arg Thr He Leu Leu Ser Thr His His Met Asp Glu Ala Asp Leu 195 200 205

Leu Gly Asp Arg He Ala He He Ser His Gly Lys Leu Lys Cys Cys 210 215 220

Gly Ser Pro Leu Phe Leu Lys Gly Ala Tyr Xaa Asp Gly Tyr Arg Leu 225 230 235 240

Thr Leu Val Lys Gin Pro Ala Glu Pro Gly Thr Ser Gin Glu Pro Gly 245 250 255

Leu Ala Ser Ser Pro Ser Gly Cys Pro Arg Leu Ser Ser Cys Ser Glu 260 265 270 Pro Gin Val Ser Gin Phe He Arg Lys His Val Ala Ser Ser Leu Leu 275 280 285

Val Ser Asp Thr Ser Thr Glu Leu Ser Tyr He Leu Pro Ser Glu Ala 290 295 300

Val Lys Lys Gly Ala Phe Glu Arg Leu Phe Gin Gin Leu Glu His Ser 305 310 315 320

Leu Asp Ala Leu His Leu Ser Ser Phe Gly Leu Met Asp Thr Thr Leu 325 330 335

Glu Glu Val Phe Leu Lys Val Ser Glu Glu Asp Gin Ser Leu Glu Asn 340 345 350

Ser Glu Ala Asp Val Lys Glu Ser Arg Lys Asp Val Leu Pro Gly Ala 355 360 365

Glu Gly Leu Thr Ala Val Gly Gly Gin Ala Gly Asn Leu Ala Arg Cys 370 375 380

Ser Glu Leu Ala Gin Ser Gin Ala Ser Leu Gin Ser Ala Ser Ser Val 385 390 395 400

Gly Ser Ala Arg Gly Glu Glu Gly Thr Gly Tyr Ser Asp Gly Tyr Gly 405 410 415

Asp Tyr Arg Pro Leu Phe Asp Asn Leu Gin Asp Pro Asp Asn Val Ser 420 425 430

Leu Gin Glu Ala Glu Met Glu Ala Leu Ala Gin Val Gly Gin Gly Ser 435 440 445

Arg Lys Leu Glu Gly Trp Trp Leu Lys Met Arg Gin Phe His Gly Leu 450 455 460

Leu Val Lys Arg Phe His Cys Ala Arg Arg Asn Ser Lys Ala Leu Cys 465 470 475 480

Ser Gin He Leu Leu Pro Ala Phe Phe Val Cys Val Ala Met Thr Val 485 490 495

Ala Leu Ser Val Pro Glu He Gly Asp Leu Pro Pro Leu Val Leu Ser 500 505 510

Pro Ser Gin Tyr His Asn Tyr Thr Gin Pro Arg Gly Asn Phe He Pro 515 520 525

Tyr Ala Asn Glu Glu Arg Gin Glu Tyr Arg Leu Arg Leu Ser Pro Asp 530 535 540

Ala Ser Pro Gin Gin Leu Val Ser Thr Phe Arg Leu Pro Ser Gly Val 545 550 555 560

Gly Ala Thr Cys Val Leu Lys Ser Pro Ala Asn Gly Ser Leu Gly Pro 565 570 575

Met Leu Asn Leu Ser Ser Gly Glu Ser Arg Leu Leu Ala Ala Arg Phe 580 585 590

Phe Asp Ser Met Cys Leu Glu Ser Phe Thr Gin Gly Leu Pro Leu Ser 595 600 605

Asn Phe Val Pro Pro Pro Pro Ser Pro Ala Pro Ser Asp Ser Pro Val 610 615 620 Xaa Pro Asp Glu Asp Ser Leu Gin Ala Trp Asn Met Ser Leu Pro Pro 625 630 635 640

Thr Ala Gly Pro Glu Thr Trp Thr Ser Ala Pro Ser Leu Pro Arg Leu 645 650 655

Val His Glu Pro Val Arg Cys Thr Cys Ser Ala Gin Gly Thr Gly Phe 660 665 670

Ser Cys Pro Ser Ser Val Gly Gly His Pro Pro Gin Met Arg Val Val 675 680 685

Thr Gly Asp He Leu Thr Asp He Thr Gly His Asn Val Ser Glu Tyr 690 695 700

Leu Leu Phe Thr Ser Asp Arg Phe Arg Leu His Arg Tyr Gly Ala He 705 710 715 720

Thr Phe Gly Asn Val Gin Lys Ser He Pro Ala Ser Phe Gly Ala Arg 725 730 735

Val Pro Pro Met Val Arg Lys He Ala Val Arg Arg Val Ala Gin Val 740 745 750

Leu Tyr Asn Asn Lys Gly Tyr His Ser Met Pro Thr Tyr Leu Asn Ser 755 760 765

Leu Asn Asn Ala He Leu Arg Ala Asn Leu Pro Lys Ser Lys Gly Asn 770 775 780

Pro Ala Ala Tyr Xaa He Thr Val Thr Asn His Pro Met Asn Lys Thr 785 790 795 800

Ser Ala Ser Leu Ser Leu Asp Tyr Leu Leu Gin Gly Thr Asp Val Val 805 810 815

He Ala He Phe He He Val Ala Met Ser Phe Val Pro Ala Ser Phe 820 825 830

Val Val Phe Leu Val Ala Glu Lys Ser Thr Lys Ala Lys His Leu Gin 835 840 845

Phe Val Ser Gly Cys Asn Pro Val He Tyr Trp Leu Ala Asn Tyr Val 850 855 860

Trp Asp Met Leu Asn Tyr Leu Val Pro Ala Thr Cys Cys Val He He 865 870 875 880

Leu Phe Val Phe Asp Leu Pro Ala Tyr Thr Ser Pro Thr Asn Phe Pro 885 890 895

Ala Val Leu Ser Leu Phe Leu Leu Tyr Gly Trp Ser He Thr Pro He 900 905 910

Met Tyr Pro Ala Ser Phe Trp Phe Glu Val Pro Ser Ser Ala Tyr Val 915 920 925

Phe Leu He Val He Asn Leu Phe He Gly He Thr Ala Thr Val Ala 930 935 940

Thr Phe Leu Leu Gin Leu Phe Glu His Asp Lys Asp Leu Lys Val Val 945 950 955 960

Asn Ser Tyr Leu Lys Ser Cys Phe Leu He Phe Pro Asn Tyr Asn Leu 965 970 975 Gly His Gly Leu Met Glu Met Ala Tyr Asn Glu Tyr He Asn Glu Tyr 980 985 990

Tyr Ala Lys He Gly Gin Phe ASD Lys Met Lys Ser Pro Phe Glu Trp 995 1000 1005

Asp He Val Thr Arg Gly Leu Val Ala Met Thr Val Glu Gly Phe Val 1010 1015 1020

Gly Phe Phe Leu Thr He Met Cys Gin Tyr Asn Phe Leu Arg Gin Pro 1025 1030 1035 1040

Gin Arg Leu Pro Val Ser Thr Lys Pro Val Glu Asp Asp Val Asp Val 1045 1050 1055

Ala Ser Glu Arg Gin Arg Val Leu Arg Gly Asp Ala Asp Asn Asp Met 1060 1065 1070

Val Lys He Glu Asn Leu Thr Lys Val Tyr Lys Ser Arg Lys He Gly 1075 1080 1085

Arg He Leu Ala Val Asp Arg Leu Cys Leu Gly Val Cys Val Pro Gly 1090 1095 1100

Glu Cys Phe Gly Leu Leu Gly Val Asn Gly Ala Gly Lys Thr Ser Thr 1105 1110 1115 1120

Phe Lys Met Leu Thr Gly Asp Glu Ser Thr Thr Gly Gly Glu Ala Phe 1125 1130 1135

Val Asn Gly His Ser Val Leu Lys Asp Leu Leu Gin Val Gin Gin Ser 1140 1145 1150

Leu Gly Tyr Cys Pro Gin Phe Asp Val Pro Val Asp Glu Leu Thr Ala 1155 1160 1165

Arg Glu His Leu Gin Leu Tyr Thr Arg Leu Arg Cys He Pro Trp Lys 1170 1175 1180

Asp Glu Ala Gin Val Val Lys Trp Ala Leu Glu Lys Leu Glu Leu Thr 1185 1190 1195 1200

Lys Tyr Ala Asp Lys Pro Ala Gly Thr Tyr Ser Gly Gly Asn Lys Arg 1205 1210 1215

Lys Leu Ser Thr Ala He Ala Leu He Gly Tyr Pro Ala Phe He Phe 1220 1225 1230

Leu Asp Glu Pro Thr Thr Gly Met Asp Pro Lys Ala Arg Arg Phe Leu 1235 1240 1245

Trp Asn Leu He Leu Asp Leu He Lys Thr Gly Arg Ser Val Val Leu 1250 1255 1260

Thr Ser His Ser Met Glu Glu Cys Glu Ala Leu Cys Thr Arg Leu Ala 1265 1270 1275 1280

He Met Val Asn Gly Arg Leu His Cys Leu Gly Ser He Gin His Leu 1285 1290 1295

Lys Asn Arg Phe Gly Asp Gly Tyr Met He Thr Val Arg Thr Lys Ser 1300 1305 1310

Ser Gin Asn Val Lys Asp Val Val Arg Phe Phe Asn Arg Asn Phe Pro 1315 1320 1325 Glu Ala His Ala Gin Gly Lys Thr Pro Tyr Lys Val Gin Tyr Gin Leu 1330 1335 1340

Lys Ser Glu His He Ser Leu Ala Gin Val Pne Ser Lys Met Glu Gin 1345 1350 1355 1360

Val Val Gly Val Leu Gly He Glu Asp Tyr Ser Val Ser Gin Thr Thr 1365 1370 1375

Leu Asp Asn Val Phe Val Asn Phe Ala Lys Lys Gin Ser Asp Asn Val 1380 1385 1390

Glu Gin Gin Glu Ala Glu Pro Ser Ser Leu Pro Ser Pro Leu Gly Leu 1395 1400 1405

Leu Ser Leu Leu Arg Pro Arg Pro Ala Pro Thr Glu Leu Arg Ala Leu 1410 1415 1420

Val Ala Asp Glu Pro Glu Asp Leu Asp Thr Glu Asp Glu Gly Leu He 1425 1430 1435 1440

Ser Phe Glu Glu Glu Arg Ala Gin Leu Ser Phe Asn Thr Asp Thr Leu 1445 1450 1455

Cys

(2) INFORMATION FOR SEQ ID NO.28-

(l) SEQUENCE CHARACTERISTICS.

(A) LENGTH- 1548 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS smgle

(D) TOPOLOGY: linear

(ll) MOLECULE TYPE: cDNA

(IX) FEATURE.

(A) NAME/KEY: CDS

(B) LOCATION: 49..1271

(xi) SEQUENCE DESCRIPTION. SEQ ID NO:28-

GGCGGCTAGC GGCGAGGCCC CTTCCTGTAC CTTCAGGGAT CGGCCACC ATG TCC CAC 57

Met Ser His 1

CGG AAG TTT TCC GCC CCT CGG CAC GGA CAC CTG GGC TTC CTG CCC CAT 105 Arg Lys Phe Ser Ala Pro Arg His Gly His Leu Gly Phe Leu Pro His

5 10 15

AAG AGG AGC CAC CGG CAC CGG GGC AAG GTG AAG ACG TGG CCG CGG GAT 153 Lys Arg Ser His Arg His Arg Gly Lys Val Lys Thr Trp Pro Arg Asp 20 25 30 35

GAC CCC AGC CAG CCC GTG CAC CTC ACG GCC TTC CTG GGC TAC AAG GCG 201 Asp Pro Ser Gin Pro Val His Leu Thr Ala Phe Leu Gly Tyr Lys Ala 40 45 50

GGC ATG ACC CAC ACC CTG CGG GAG GTG CAC CGG CCG GGG CTC AAA ATT 249 Gly Met Thr His Thr Leu Arg Glu Val His Arg Pro Gly Leu Lys He 55 60 65 TCC AAA CGG GAG GAG GTG GAG GCG GTG ACA ATT GTA GAA ACG CCG CCC 297 Ser Lys Arg Glu Glu Val Glu Ala Val Thr He Val Glu Thr Pro Pro 70 75 80

CTA GTG GTG GTG GGC GTG GTG GGC TAC GTG GCC ACC CCT CGA GGT CTC 345 Leu Val Val Val Gly Val Val Gly Tyr Val Ala Thr Pro Arg Gly Leu 85 90 95

CGG AGC TTC AAG ACC ATC TTT GCA GAA CAC CTC AGT GAT GAG TGC CGG 393 Arg Ser Phe Lys Thr He Phe Ala Glu His Leu Ser Asp Glu Cys Arg 100 105 110 115

CGC CGA TTC TAC AAG GAC TGG CAC AAG AGC AAG AAG AAA GCC TTC ACC 441 Arg Arg Phe Tyr Lys Asp Trp His Lys Ser Lys Lys Lys Ala Phe Thr 120 125 130

AAG GCC TGC AAG AGG TGG CGG GAC ACA GAC GGG AAA AAG CAG CTA CAG 489 Lys Ala Cys Lys Arg Trp Arg Asp Thr Asp Gly Lys Lys Gin Leu Gin 135 140 145

AAG GAC TTC GCC GCC ATG AAG AAG TAC TGC AAG GTC ATT CGG GTC ATT 537 Lys Asp Phe Ala Ala Met Lys Lys Tyr Cys Lys Val He Arg Val He 150 155 160

GTC CAC ACT CAG ATG AAA CTG CTG CCC TTC CGG CAG AAG AAG GCC CAC 585 Val His Thr Gin Met Lys Leu Leu Pro Phe Arg Gin Lys Lys Ala His 165 170 175

ATC ATG GAG ATC CAG CTG AAC GGT GGC ACG GTG GCC GAG AAG GTG GCC 633 He Met Glu He Gin Leu Asn Gly Gly Thr Val Ala Glu Lys Val Ala 180 185 190 195

TGG GCC CAG GCC CGG CTG GAG AAG CAG GTG CCC GTG CAC AGC GTG TTC 681 Trp Ala Gin Ala Arg Leu Glu Lys Gin Val Pro Val His Ser Val Phe 200 205 210

AGC CAG AGT GAG GTC ATT GAT GTC ATT GCT GTC ACC AAG GGT CGA GGC 729 Ser Gin Ser Glu Val He Asp Val He Ala Val Thr Lys Gly Arg Gly 215 220 225

GTC AAA GGG GTC ACA AGC CGC TGG CAT ACC AAG AAG CTG CCG CGC AAG 777 Val Lys Gly Val Thr Ser Arg Trp His Thr Lys Lys Leu Pro Arg Lys 230 235 240

ACC CAT AAG GGC CTG CGC AAG GTG GCC TGC ATT GGC GCC TGG CAC CCC 825 Thr His Lys Gly Leu Arg Lys Val Ala Cys He Gly Ala Trp His Pro 245 250 255

GCC CGC GTG GGC TGC TCC ATT GCT CGG GCC GGG CAG AAG GGC TAT CAC 873 Ala Arg Val Gly Cys Ser He Ala Arg Ala Gly Gin Lys Gly Tyr His 260 265 270 275

CAC CGC ACG GAG CTC AAC AAG AAG ATC TTC CGC ATC GGC AGG GGC CCG 921 His Arg Thr Glu Leu Asn Lys Lys He Phe Arg He Gly Arg Gly Pro 280 285 290

CAC ATG GAG GAC GGG AAG CTG GTG AAG AAC AAT GCA TCC ACC AGC TAC 969 His Met Glu Asp Gly Lys Leu Val Lys Asn Asn Ala Ser Thr Ser Tyr 295 300 305

GAC GTG ACT GCC AAG TCC ATC ACA CCG CTG GGT GGC TTC CCC CAC TAC 1017 Asp Val Thr Ala Lys Ser He Thr Pro Leu Gly Gly Phe Pro His Tyr 310 315 320 GGG GAA GTG AAC AAC GAC TTC GTC ATG CTG AAG GGT TGT ATT GCT GGT 1065 Gly Glu Val Asn Asn Asp Pne Val Met Leu Lys Gly Cys He Ala Gly 325 330 335

ACC AAG AAG CGG GTC ATT ACG CTG AGA AAG TCC CTC CTG GTG CAT CAC 1113 Thr Lys Lys Arg Val He Thr Leu Arg Lys Ser Leu Leu Val His His 340 345 350 355

AGT CGC CAA GCC GTG GAG AAT ATT GAG CTC AAG TTC ATT GAC ACC ACC 1161 Ser Arg Gin Ala Val Glu Asn He Glu Leu Lys Phe He Asp Thr Thr 360 365 370

TCC AAG TTC GGC CAT GGC CGC TTC CAG ACA GCC CAA GAG AAG AGG GCC 1209 Ser Lys Phe Gly His Gly Arg Phe Gin Thr Ala Gin Glu Lys Arg Ala 375 380 385

TTC ATG GGC CCC CAA AAG AAG CAT CTG GAG AAG GAA ACG CCG GAG ACC 1257 Phe Met Gly Pro Gin Lys Lys His Leu Glu Lys Glu Thr Pro Glu Thr 390 395 400

TCG GGA GAC TTG TA GGCTGTGTGG GGTGGATGAA CCCTGAAGCG CACCGCACTG 1311 Ser Gly Asp Leu 405

TCTGCCCCAA TGTCTAACAA AGGCCGGAGG CGACTCTTCC TGCGAGGTCT CAGAGCGCTG 1371

TGTAACCGCC CAAGGGGTTC ACCTTGCCTG CTGCCTAGAC AAAGCCGATT CATTAAGACA 1431

GGGGAATTGC AATAGAGAAA GAGTAATTCA CACAGAGCTG GCTGTGCGGG AGACCGGAGT 1491

TTTATGTTTT ATTATTACTC AAATCGATCT CTTTGAGCAA AAAAAAAAAA AAAAAAA 1548

(2) INFORMATION FOR SEQ ID NO:29

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 407 ammo acids

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION- SEQ ID NO:29.

Met Ser His Arg Lys Phe Ser Ala Pro Arg His Gly His Leu Gly Phe 1 5 10 15

Leu Pro His Lys Arg Ser His Arg His Arg Gly Lys Val Lys Thr Trp 20 25 30

Pro Arg Asp Asp Pro Ser Gin Pro Val His Leu Thr Ala Phe Leu Gly 35 40 45

Tyr Lys Ala Gly Met Thr His Thr Leu Arg Glu Val His Arg Pro Gly 50 55 60

Leu Lys He Ser Lys Arg Glu Glu Val Glu Ala Val Thr He Val Glu 65 70 75 80

Thr Pro Pro Leu Val Val Val Gly Val Val Gly Tyr Val Ala Thr Pro 85 90 95

Arg Gly Leu Arg Ser Phe Lys Thr He Phe Ala Glu His Leu Ser Asp 100 105 110

16 Glu Cys Arg Arg Arg Phe Tyr Lys Asp Trp His Lys Ser Lys Lys Lys

115 120 125

Ala Phe Thr Lys Ala Cys Lys Arg Trp Arg Asp Thr Asp Gly Lys Lys 130 135 140

Gin Leu Gin Lys Asp Phe Ala Ala Met Lys Lys Tyr Cys Lys Val He 145 150 155 160

Arg Val He Val His Thr Gin Met Lys Leu Leu Pro Phe Arg Gin Lys 165 170 175

Lys Ala His He Met Glu He Gin Leu Asn Gly Gly Thr Val Ala Glu 180 185 190

Lys Val Ala Trp Ala Gin Ala Arg Leu Glu Lys Gin Val Pro Val His 195 200 205

Ser Val Phe Ser Gin Ser Glu Val He Asp Val He Ala Val Thr Lys 210 215 220

Gly Arg Gly Val Lys Gly Val Thr Ser Arg Trp His Thr Lys Lys Leu 225 230 235 240

Pro Arg Lys Thr His Lys Gly Leu Arg Lys Val Ala Cys He Gly Ala 245 250 255

Trp His Pro Ala Arg Val Gly Cys Ser He Ala Arg Ala Gly Gin Lys 260 265 270

Gly Tyr His His Arg Thr Glu Leu Asn Lys Lys He Phe Arg He Gly 275 280 285

Arg Gly Pro His Met Glu Asp Gly Lys Leu Val Lys Asn Asn Ala Ser 290 295 300

Thr Ser Tyr Asp Val Thr Ala Lys Ser He Thr Pro Leu Gly Gly Phe 305 310 315 320

Pro His Tyr Gly Glu Val Asn Asn Asp Phe Val Met Leu Lys Gly Cys 325 330 335

He Ala Gly Thr Lys Lys Arg Val He Thr Leu Arg Lys Ser Leu Leu 340 345 350

Val His His Ser Arg Gin Ala Val Glu Asn He Glu Leu Lys Phe He 355 360 365

Asp Thr Thr Ser Lys Phe Gly His Gly Arg Phe Gin Thr Ala Gin Glu 370 375 380

Lys Arg Ala Phe Met Gly Pro Gin Lys Lys His Leu Glu Lys Glu Thr 385 390 395 400

Pro Glu Thr Ser Gly Asp Leu 405

(2) INFORMATION FOR SEQ ID NO: 30:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 403 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY, unknown

(ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30:

Met Ser His Arg Lys Phe Ser Ala Pro Arg His Gly Ser Leu Gly Phe 1 5 10 15

Leu Pro Arg Lys Arg Ser Ser Λrg His Arg Gly Lys Val Lys Ser Phe 20 25 30

Pro Lys Asp Asp Pro Ser Lys Pro Val His Leu Thr Ala Phe Leu Gly 35 40 45

Tyr Lys Ala Gly Met Thr His He Val Arg Glu Val Asp Arg Pro Gly 50 55 60

Ser Lys Val Asn Lys Lys Glu Val Val Glu Ala Val Thr He Val Glu 65 70 75 80

Thr Pro Pro Met Val Val Val Gly He Val Gly Tyr Val Glu Thr Pro 85 90 95

Arg Gly Leu Arg Thr Phe Lys Thr Val Phe Ala Glu His He Ser Asp 100 105 110

Glu Cys Lys Arg Arg Phe Tyr Lys Asn Trp His Lys Ser Lys Lys Lys 115 120 125

Ala Phe Thr Lys Tyr Cys Lys Lys Trp Gin Asp Glu Asp Gly Lys Lys 130 135 140

Gin Leu Glu Lys Asp Phe Ser Ser Met Lys Lys Tyr Cys Gin Val He 145 150 155 160

Arg Val He Ala His Thr Gin Met Arg Leu Leu Pro Leu Arg Gin Lys 165 170 175

Lys Ala His Leu Met Glu He Gin Val Asn Gly Gly Thr Val Ala Glu 180 185 190

Lys Leu Asp Trp Ala Arg Glu Arg Leu Glu Gin Gin Val Pro Val Asn 195 200 205

Gin Val Phe Gly Gin Asp Glu Met He Asp Val He Gly Val Thr Lys 210 215 220

Gly Lys Gly Tyr Lys Gly Val Thr Ser Arg Trp His Thr Lys Lys Leu 225 230 235 240

Pro Arg Lys Thr His Arg Gly Leu Arg Lys Val Ala Cys He Gly Ala 245 250 255

Trp His Pro Ala Arg Val Ala Phe Ser Val Ala Arg Ala Gly Gin Lys 260 265 270

Gly Tyr His His Arg Thr Glu He Asn Lys Lys He Tyr Lys He Gly 275 280 285

Gin Gly Tyr Leu He Lys Asp Gly Lys Leu He Lys Asn Asn Ala Ser 290 295 300

Thr Asp Tyr Asp Leu Ser Asp Lys Ser He Asn Pro Leu Gly Gly Phe 305 310 315 320 Val His Tyr Gly Glu Val Thr Asn Asp Phe Val Met Leu Lys Gly Cys 325 330 335

Val Val Gly Thr Lys Lys Arg Val Leu Thr Leu Arg Lys Ser Leu Leu 340 345 350

Val Gin Thr Lys Arg Arg Ala Leu Glu Lys He Asp Leu Lys Phe He 355 360 365

Asp Thr Thr Ser Lys Phe Gly His Gly Arg Phe Gin Thr Met Glu Glu 370 375 380

Lys Lys Ala Phe Met Gly Pro Leu Lys Lys Asp Arg He Ala Lys Glu 385 390 395 400

Glu Gly Ala

(2) INFORMATION FOR SEQ ID NO:31:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 403 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:

Met Ser His Arg Lys Phe Ser Ala Pro Arg His Gly Ser Leu Gly Phe 1 5 10 15

Leu Pro Arg Lys Arg Ser Ser Arg His Arg Gly Lys Val Lys Ser Phe 20 25 30

Pro Lys Asp Asp Ser Ser Lys Pro Val His Leu Thr Ala Phe Leu Gly 35 40 45

Tyr Lys Ala Gly Met Thr His He Val Arg Glu Val Asp Arg Pro Gly 50 55 60

Ser Lys Val Asn Lys Lys Glu Val Val Glu Ala Val Thr He Val Glu 65 70 75 80

Thr Pro Pro Met Val He Val Gly He Val Gly Tyr Val Glu Thr Pro 85 90 95

Arg Gly Leu Arg Thr Phe Lys Thr He Phe Ala Glu His He Ser Asp 100 105 110

Glu Cys Lys Arg Arg Phe Tyr Lys Asn Trp His Lys Ser Lys Lys Lys 115 120 125

Ala Phe Thr Lys Tyr Cys Lys Lys Trp Gin Asp Ala Asp Gly Lys Lys 130 135 140

Gin Leu Glu Arg Asp Phe Ser Ser Met Lys Lys Tyr Cys Gin Val He 145 150 155 160

Arg Val He Ala His Thr Gin Met^"Arg Leu Leu Pro Leu Arg Gin Lys 165 170 175 Lys Ala His Leu Met Glu Val Gin Val Asn Gly Gly Thr Val Ala Glu 180 185 190

Lys Leu Asp Trp Ala Arg Glu Arg Leu Glu Gin Gin Val Pro Val Asn 195 200 205

Gin Val Phe Gly Gin Asp Glu Met He Asp Val He Gly Val Thr Lys 210 215 220

Gly Lys Gly Tyr Lys Gly Val Thr Ser Arg Trp His Thr Lys Lys Leu 225 230 235 240

Pro Arg Lys Thr His Arg Gly Leu Arg Lys Val Ala Cys He Gly Ala 245 250 255

Trp His Pro Ala Arg Val Ala Phe Ser Val Ala Arg Ala Gly Gin Lys 260 265 270

Gly Tyr His His Arg Thr Glu He Asn Lys Lys He Tyr Lys He Gly 275 280 285

Gin Gly Tyr Leu He Lys Asp Gly Lys Leu He Lys Asn Asn Ala Ser 290 295 300

Thr Asp Tyr ASD Leu Ser Asp Lys Ser He Asn Pro Leu Gly Gly Phe

305 310 315 320

Val His Tyr Gly Glu Val Thr Asn Asp Phe Val Met Leu Lys Gly Cys 325 330 335

Val Val Gly Thr Lys Lys Arg Val Leu Thr Leu Arg Lys Ser Leu Leu 340 345 350

Val Gin Thr Lys Arg Arg Ala Leu Glu Lys He Asp Leu Lys Phe He 355 360 365

Asp Thr Thr Ser Lys Phe Gly His Gly Arg Phe Gin Thr Val Glu Glu 370 375 380

Lys Lys Ala Phe Met Gly Pro Leu Lys Lys Asp Arg He Ala Lys Glu 385 390 395 400

Glu Gly Ala

(2) INFORMATION FOR SEQ ID NO: 32:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 403 ammo acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(n) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32.

Met Ser His Arg Lys Phe Ser Ala Pro Arg His Gly Ser Leu Gly Phe 1 5 10 15

Leu Pro Arg Lys Arg Ser Ser Arg His Arg Gly Lys Val Lys Ser Phe 20 25 30 Pro Lys Asp Asp Ala Ser Lys Pro Val His Leu Thr Ala Phe Leu Gly

35 40 45

Tyr Lys Ala Gly Met Thr His He Val Arg Glu Val Asp Arg Pro Gly 50 55 60

Ser Lys Val Asn Lys Lys Glu Val Val Glu Ala Val Thr He Val Glu 65 70 75 80

Thr Pro Pro Met Val Val Val Gly He Val Gly Tyr Val Glu Thr Pro 85 90 95

Arg Gly Leu Arg Thr Phe Lys Thr Val Phe Ala Glu His He Ser Asp 100 105 110

Glu Cys Lys Arg Arg Phe Tyr Lys Asn Trp His Lys Ser Lys Lys Lys 115 120 125

Ala Phe Thr Lys Tyr Cys Lys Lys Trp Gin Asp Asp Thr Gly Lys Lys 130 135 140

Gin Leu Glu Lys Asp Phe Asn Ser Met Lys Lys Tyr Cys Gin Val He 145 150 155 160

Arg He He Ala His Thr Gin Met Arg Leu Leu Pro Leu Arg Gin Lys 165 170 175

Lys Ala His Leu Met Glu He Gin Val Asn Gly Gly Thr Val Ala Glu 180 185 190

Lys Leu Asp Trp Ala Arg Glu Arg Leu Glu Gin Gin Val Pro Val Ser 195 200 205

Gin Val Phe Gly Gin Asp Glu Met He Asp Val He Gly Val Thr Lys 210 215 220

Gly Lys Gly Tyr Lys Gly Val Thr Ser Arg Trp His Thr Lys Lys Leu 225 230 235 240

Pro Arg Lys Thr His Arg Gly Leu Arg Lys Val Ala Cys He Gly Ala 245 250 255

Trp His Pro Ala Arg Val Ala Phe Thr Val Ala Arg Ala Gly Gin Lys 260 265 270

Gly Tyr His His Arg Thr Glu He Asn Lys Lys He Tyr Lys He Gly 275 280 285

Gin Gly Tyr Leu He Lys Asp Gly Lys Leu He Lys Asn Asn Ala Ser 290 295 300

Thr Asp Tyr Asp Leu Ser Asp Lys Ser He Asn Pro Leu Gly Gly Phe 305 310 315 320

Val His Tyr Gly Glu Val Thr Asn Asp Phe He Met Leu Lys Gly Cys 325 330 335

Val Val Gly Thr Lys Lys Arg Val Leu Thr Leu Arg Lys Ser Leu Leu 340 345 350

Val Gin Thr Lys Arg Arg Ala Leu Glu Lys He Asp Leu Lys Phe He 355 360 365

Asp Thr Thr Ser Lys Phe Gly His Gly Arg Phe Gin Thr Met Glu Glu 370 375 380 Lys Lys Ala Phe Met Gly Pro Leu Lys Lvs Asp Arg He Ala Lys Glu 385 390 39b 400

Glu Gly Ala

(2) INFORMATION FOR SEQ ID NO:33:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 468 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: smgle

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(lx) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 1..357

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:

CGG GAC ACC AAG TTT AGG GAG GAC TGC CCG CCG GAT CGC GAG GAA CTG 48 Arg ASD Thr Lys Phe Arg Glu Asp Cys Pro Pro ASD Arg Glu Glu Leu l b 10 15

GGC CGC CAC AGC TGG GCT GTC CTC CAC ACC CTG GCC GCC TAC TAC CCC 96 Gly Arg His Ser Trp Ala Val Leu His Thr Leu Ala Ala Tyr Tyr Pro 20 25 30

GAC CTG CCC ACC CCA GAA CAG CAG CAA GAC ATG GCC CAG TTC ATA CAT 144 Asp Leu Pro Thr Pro Glu Gin Gin Gin Asp Met Ala Gin Phe He His 35 40 45

TTA TTT TCT AAG TTT TAC CCC TGT GAG GAG TGT GCT GAA GAC CTA AGA 192 Leu Phe Ser Lys Phe Tyr Pro Cys Glu Glu Cys Ala Glu Asp Leu Arg 50 55 60

AAA AGG CTG TGC AGG AAC CAC CCA GAC ACC CGC ACC CGG GCA TGC TTC 240 Lys Arg Leu Cys Arg Asn His Pro Asp Thr Arg Thr Arg Ala Cys Phe 65 70 75 80

ACA CAG TGG CTG TGC CAC CTG CAC AAT GAA GTG AAC CGC AAG CTG GGC 288 Thr Gin Trp Leu Cys His Leu His Asn Glu Val Asn Arg Lys Leu Gly 85 90 95

AAG CCT GAC TTC GAC TGC TCA AAA GTG GAT GAG CGC TGG CGC GAC GGC 336 Lys Pro Asp Phe Asp Cys Ser Lys Val Asp Glu Arg Trp Arg Asp Gly 100 105 110

TGG AAG GAT GGC TCC TGT GAC TAGAGGGTGG TCAGCCAGAG CTCATGGGAC 387

Trp Lys Asp Gly Ser Cys Asp 115

AGCTAGCCAG GCATGGTTGG ATAGGGGCAG GGCACTCATT AAAGTGCATC ACAGCCAGAA 447

AAAAAAAAAA AAAAAAAAAA A 468

(2) INFORMATION FOR SEQ ID NO:34:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 119 amino acids

(B) TYPE: amino acid ( D ) TOPOLOGY , l inear ( n ) MOLECULE TYPE , prote in ( xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 34

Arg Asp Tnr Lys Phe Arg Glu Asp Cys Pro Pro Asp Arg Glu Gl u Leu

1 5 10 15

Gly Arg His Ser Trp Ala Val Lou His Thr Leu Ala Ala Tyr Tyr Pro 20 25 30

Asp Leu Pro Thr Pro Glu Gin Gin Gin Asp Met Ala Gin Phe He His 35 40 45

Leu Phe Ser Lys Phe Tyr Pro Cys Glu Glu Cys Ala Glu Asp Leu Arg 50 55 60

Lys Arg Leu Cys Arg Asn His Pro Asp Thr Arg Thr Arg Ala Cys Phe 65 70 75 80

Thr Gin Trp Leu Cys His Leu His Asn Glu Val Asn Arg Lys Leu Gly 85 90 95

Lys Pro Asp Phe Asp Cys Ser Lys Val Asp Glu Arg Trp Arg Asp Gly 100 105 110

Trp Lys Asp Gly Ser Cys Asp 115

(2) INFORMATION FOR SEQ ID NO: 35:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH. 125 ammo acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(n) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO- 35-

Met Arg Thr Gin Gin Lys Arg Asp He Lys Phe Arg Glu Asp Cys Pro 1 5 10 15

Gin Asp Arg Glu Glu Leu Gly Arg Asn Thr Trp Ala Phe Leu His Thr 20 25 30

Leu Ala Ala Tyr Tyr Pro Asp Met Pro Thr Pro Glu Gin Gin Gin Asp 35 40 45

Met Ala Gin Phe He His He Phe Ser Lys Phe Tyr Pro Cys Glu Glu 50 55 60

Cys Ala Glu Asp He Arg Lys Arg He Asp Arg Ser Gin Pro Asp Thr 65 70 75 80

Ser Thr Arg Val Ser Phe Ser Gin Trp Leu Cys Arg Leu His Asn Glu 85 90 95 Val Asn Arg Lys Leu Gly Lys Pro Asp Phe Asp Cys Ser Arg Val Asp 100 105 110

Glu Arg Trp Arg Asp Gly Trp Lys Asp Gly Ser Cys Asp 115 120 125

(2) INFORMATION FOR SEQ ID NO: 36

(l) SEQUENCE CHARACTERISTICS

(A) LENGTH: 20 base pairs

(B) TYPE, nucleic acid

(C) STRANDEDNESS single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE- other nucleic acid

(A) DESCRIPTION /desc - "oligonucleotide primer"

(XI) SEQUENCE DESCRIPTION. SEQ ID NO:36 TGACGCCGTG CCCATCCAGT 20

(2) INFORMATION FOR SEQ ID NO- 37

(l) SEQUENCE CHARACTERISTICS.

(A) LENGTH- 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION- SEQ ID NO: 37: CAGCGTGGTG TTATGTTCCT 20

(2) INFORMATION FOR SEQ ID NO: 38-

(l) SEQUENCE CHARACTERISTICS.

(A) LENGTH: 20 base pairs

(B) TYPE, nucleic acid

(C) STRANDEDNESS- single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: TTGGGCCTGT GCTGAACTAC 20

(2) INFORMATION FOR SEQ ID NO: 39:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS. smgle (D) TOPOLOGY: linear

(11) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION, /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39: CGGCAAGCTG GTGATTAACA 20

(2) INFORMATION FOR SEQ ID NO: 40:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 18 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: Single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 40: CGGCAGAGGA TGCTGTGT (2) INFORMATION FOR SEQ ID NO: 41:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 18 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41: GCGGAGCCAC CTTCATCA (2) INFORMATION FOR SEQ ID NO: 42:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: Single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: GACGCTGGTG AAGGAGC 17 (2) INFORMATION FOR SEQ ID NO:43:

(l) SEQUENCE CHARACTERISTICS

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: smgle

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43: TCGCTGACCG CCAGGAT 17

(2) INFORMATION FOR SEQ ID NO: 44:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: smgle

(D) TOPOLOGY: linear

(ii ) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc - "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44: CTGTCGGGAA GGTCTCACTG 20

(2) INFORMATION FOR SEQ ID NO: 45:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: smgle

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45: GTTCACCGCC TTGGAGGATT 20

(2) INFORMATION FOR SEQ ID NO: 46:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: smgle

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc - "oligonucleotide primer" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46 GTGTGGGGAA GACCTGTCTG 20

(2) INFORMATION FOR SEQ ID NO.47

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH- 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION, /desc = "oligonucleotide primer"

(XI) SEQUENCE DESCRIPTION: SEQ ID NO:47: AGGAGGCCTT GTTGGTGACA 20

(2) INFORMATION FOR SEQ ID NO: 48:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: smgle

(D) TOPOLOGY, linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: ACGGACACCT GGGCTTC 17

(2) INFORMATION FOR SEQ ID NO:49:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: AAACGGGAGG AGGTGGA 17

(2) INFORMATION FOR SEQ ID NO: 50:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (11) MOLECULE TYPE- other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO:50: TGTGGCTATG AGCTGTTCTC 20

(2) INFORMATION FOR SEQ ID NO: 51:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY, linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51: GCAGTCCCGA TTCTGAATAT 20

(2) INFORMATION FOR SEQ ID NO: 52:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52: CATTGCCCGT GCTGTCGTG 19

(2) INFORMATION FOR SEQ ID NO:53:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(XI) SEQUENCE DESCRIPTION: SEQ ID NO: 53: CATCGCCGCC TCCTTCATG 19

(2) INFORMATION FOR SEQ ID NO:54: (l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 18 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: Single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54: GCGGAGCCAC CTTCATCA (2) INFORMATION FOR SEQ ID NO: 55:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer'

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 55: GACGCTGGTG AAGGAGC 17

(2) INFORMATION FOR SEQ ID NO: 56:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: ATCCTGGCGG TCAGCGA 17

(2) INFORMATION FOR SEQ ID NO: 57:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57- AGGGATTCGA CATTGCC 17

(2) INFORMATION FOR SEQ ID NO:58

(l) SEQUENCE CHARACTERISTICS.

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS. smgle

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58: CTTCAGAGAC TCAGGGGCAT 20

(2) INFORMATION FOR SEQ ID NO: 59:

(l) SEQUENCE CHARACTERISTICS.

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59- GCCTGTCATC GCTCTAG 17

(2) INFORMATION FOR SEQ ID NO: 60:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60: CAGTCGCAGG CCCTGCA 17

(2) INFORMATION FOR SEQ ID NO: 61.

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (11) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION /desc - "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61: GAGGACGCGC CAACATC 17

(2) INFORMATION FOR SEQ ID NO: 62:

(l) SEQUENCE CHARACTERISTICS.

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY, linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION, /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: CGGCAGTAGT GGCAGTG 17

(2) INFORMATION FOR SEQ ID NO: 63:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63: CCTGCCTCGC TTGCTCCTGC 20

(2) INFORMATION FOR SEQ ID NO: 64:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY, linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64: CGGGCAGCCG CAGGCCGCAT 20

(2) INFORMATION FOR SEQ ID NO:65: (l) SEQUENCE CHARACTERISTICS.

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65: CCTGCAACGG CCATGCCCGC 20

(2) INFORMATION FOR SEQ ID NO: 66:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH. 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY, linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(XI) SEQUENCE DESCRIPTION: SEQ ID NO: 66: GCATCCCCGG CGGGCACCCA 20

(2) INFORMATION FOR SEQ ID NO: 67:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 18 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO: 67: GTTCGTACGA GAATCGCT (2) INFORMATION FOR SEQ ID NO: 68:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 9 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(li) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "Kozak Initiation Sequence' (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68: CCACCATGT 9

(2) INFORMATION FOR SEQ ID NO: 69:

(l) SEQUENCE CHARACTERISTICS :

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:69: TGGCCCAGTT CATACATTTA 20

(2) INFORMATION FOR SEQ ID NO:70:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: smgle

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(XI) SEQUENCE DESCRIPTION: SEQ ID NO:70: TTACCCCTGT GAGGAGTGTG 20

(2) INFORMATION FOR SEQ ID NO:71:

(l) SEQUENCE CHARACTERISTICS.

(A) LENGTH: 8 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:71;

His Arg Asp Leu Lys Pro Glu Asn 1 5

(2) INFORMATION FOR SEQ ID NO:72:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (11) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc - "oligonucleotide primer'

(Xl) SEQUENCE DESCRIPTION. SEQ ID NO.72: GTCCTTCTTG CAGAACT 17

(2) INFORMATION FOR SEQ ID NO:73:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73: AGACAGCCCA AGAGAAGAGG 20

(2) INFORMATION FOR SEQ ID NO: 74:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 6525 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(IX) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 573..5684

(Xl) SEQUENCE DESCRIPTION: SEQ ID NO: 74:

CACATAAAAT ACACCGCCCC GGCGCCCAGG CTCGGTGCTG GAGAGTCATG CCTGTGAGCC 60

CTGGGCACCT CCTGATGTCC TGCGAGGTCA CGGTGTTCCC AAACCTCAGG GTTGCCCTGC 120

CCCACTCCAG AGGCTCTCAG GCCCCACCCC GGAGCCCTCT GTGCGGAGCC GCCTCCTCCT 180

GGCCAGTTCC CCAGTAGTCC TGAAGGGAGA CCTGCTGTGT GGAGCCTCTT CTGGGACCCA 240

GCCATGAGTG TGGAGCTGAG CAACTGAACC TGAAACTCTT CCACTGTGAG TCAAGGAGGC 300

TTTTCCGCAC ATGAAGGACG CTGAGCGGGA AGGACTCCTC TCTGCCTGCA GTTGTAGCGA 360

GTGGACCAGC ACCAGGGGCT CTCTAGACTG CCCCTCCTCC ATCGCCTTCC CTGCCTCTCC 420

AGGACAGAGC AGCCACGTCT GCACACCTCG CCCTCTTTAC ACTCAGTTTT CAGAGCACGT 480

TTCTCCTATT TCCTGCGGGT TGCAGCGCCT ACTTGAACTT ACTCAGACCA CCTACTTCTC 540 TAGCAGCACT GGGCGTCCCT TTCAGCAAGA CG ATG GCT GTG CTC AGG CAG CTG 593

Met Ala Val Leu Arg Gin Leu

1 5

GCG CTC CTC CTC TGG AAG AAC TAC ACC CTG CAG AAG CGG AAG GTC CTG 641 Ala Leu Leu Leu Trp Lys Asn Tyr Thr Leu Gin Lys Arg Lys Val Leu 10 15 20

GTG ACG GTC CTG GAA CTC TTC CTG CCA TTG CTG TTT TCT GGG ATC CTC 689 Val Thr Val Leu Glu Leu Phe Leu Pro Leu Leu Phe Ser Gly He Leu 25 30 35

ATC TGG CTC CGC TTG AAG ATT CAG TCG GAA AAT GTG CCC AAC GCC ACC 737 He Trp Leu Arg Leu Lys He Gin Ser Glu Asn Val Pro Asn Ala Thr 40 45 50 55

ATC TAC CCG GGC CAG TCC ATC CAG GAG CTG CCT CTG TTC TTC ACC TTC 785 He Tyr Pro Gly Gin Ser He Gin Glu Leu Pro Leu Phe Phe Thr Phe 60 65 70

CCT CCG CCA GGA GAC ACC TGG GAG CTT GCC TAC ATC CCT TCT CAC AGT 833 Pro Pro Pro Gly Asp Thr Trp Glu Leu Ala Tyr He Pro Ser His Ser 75 80 85

GAC GCT GCC AAG GCC GTC ACT GAG ACA GTG CGC AGG GCA CTT GTG ATC 881 Asp Ala Ala Lys Ala Val Thr Glu Thr Val Arg Arg Ala Leu Val He 90 95 100

AAC ATG CGA GTG CGC GGC TTT CCC TCC GAG AAG GAC TTT GAG GAC TAC 929 Asn Met Arg Val Arg Gly Phe Pro Ser Glu Lys Asp Phe Glu Asp Tyr 105 110 115

ATT AGG TAC GAC AAC TGC TCG TCC AGC GTG CTG GCC GCC GTG GTC TTC 977 He Arg Tyr Asp Asn Cys Ser Ser Ser Val Leu Ala Ala Val Val Phe 120 125 130 135

GAG CAC CCC TTC AAC CAC AGC AAG GAG CCC CTG CCG CTG GCG GTG AAA 1025 Glu His Pro Phe Asn His Ser Lys Glu Pro Leu Pro Leu Ala Val Lys 140 145 150

TAT CAC CTA CGG TTC AGT TAC ACA CGG AGA AAT TAC ATG TGG ACC CAA 1073 Tyr His Leu Arg Phe Ser Tyr Thr Arg Arg Asn Tyr Met Trp Thr Gin 155 160 165

ACA GGC TCC TTT TTC CTG AAA GAG ACA GAA GGC TGG CAC ACT ACT TCC 1121 Thr Gly Ser Phe Phe Leu Lys Glu Thr Glu Gly Trp His Thr Thr Ser 170 175 180

CTT TTC CCG CTT TTC CCA AAC CCA GGA CCA AGG GAA CTA ACA TCC CCT 1169 Leu Phe Pro Leu Phe Pro Asn Pro Gly Pro Arg Glu Leu Thr Ser Pro 185 190 195

GAT GGC GGA GAA CCT GGG TAC ATC CGG GAA GGC TTC CTG GCC GTG CAG 1217 Asp Gly Gly Glu Pro Gly Tyr He Arg Glu Gly Phe Leu Ala Val Gin 200 205 210 215

CAT GCT GTG GAC CGG GCC ATC ATG GAG TAC CAT GCC GAT GCC GCC ACA 1265 His Ala Val Asp Arg Ala He Met Glu Tyr His Ala Asp Ala Ala Thr 220 225 230

CGC CAG CTG TTC CAG AGA CTG ACG GTG ACC ATC AAG AGG TTC CCG TAC 1313 Arg Gin Leu Phe Gin Arg Leu Thr Val Thr He Lys Arg Phe Pro Tyr 235 240 245 CCG CCG TTC ATC GCA GAC CCC TTC CTC GTG GCC ATC CAG TAC CAG CTG 1361

Pro Pro Phe He Ala Asp Pro Phe Leu Val Ala He Gin Tyr Gin Leu

250 255 260

CCC CTG CTG CTG CTG CTC AGC TTC ACC TAC ACC GCG CTC ACC ATT GCC 1409

Pro Leu Leu Leu Leu Leu Ser Phe Thr Tyr Thr Ala Leu Thr He Ala 265 270 275

CGT GCT GTC GTG CAG GAG AAG GAA AGG AGG CTG AAG GAG TAC ATG CGC 1457

Arg Ala Val Val Gin Glu Lys Glu Arg Arg Leu Lys Glu Tyr Met Arg 280 285 290 295

ATG ATG GGG CTC AGC AGC TGG CTG CAC TGG AGT GCC TGG TTC CTC TTG 1505

Met Met Gly Leu Ser Ser Trp Leu His Trp Ser Ala Trp Phe Leu Leu 300 305 310

TTC TTC CTC TTC CTC CTC ATC GCC GCC TCC TTC ATG ACC CTG CTC TTC 1553

Phe Phe Leu Phe Leu Leu He Ala Ala Ser Phe Met Thr Leu Leu Phe

315 320 325

TGT GTC AAG GTG AAG CCA AAT GTA GCC GTG CTG TCC CGC AGC GAC CCC 1601

Cys Val Lys Val Lys Pro Asn Val Ala Val Leu Ser Arg Ser Asp Pro

330 335 340

TCC CTG GTG CTC GCC TTC CTG CTG TGC TTC GCC ATC TCT ACC ATC TCC 1649

Ser Leu Val Leu Ala Phe Leu Leu Cys Phe Ala He Ser Thr He Ser 345 350 355

TTC AGC TTC ATG GTC AGC ACC TTC TTC AGC AAA GCC AAC ATG GCA GCA 1697

Phe Ser Phe Met Val Ser Thr Phe Phe Ser Lys Ala Asn Met Ala Ala 360 365 370 375

GCC TTC GGA GGC TTC CTC TAC TTC TTC ACC TAC ATC CCC TAC TTC TTC 1745

Ala Phe Gly Gly Phe Leu Tyr Phe Phe Thr Tyr He Pro Tyr Phe Phe 380 385 390

GTG GCC CCT CGG TAC AAC TGG ATG ACT CTG AGC CAG AAG CTC TGC TCC 1793

Val Ala Pro Arg Tyr Asn Trp Met Thr Leu Ser Gin Lys Leu Cys Ser

395 400 405

TGC CTC CTG TCT AAT GTC GCC ATG GCA ATG GGA GCC CAG CTC ATT GGG 1841

Cys Leu Leu Ser Asn Val Ala Met Ala Met Gly Ala Gin Leu He Gly

410 415 420

AAA TTT GAG GCG AAA GGC ATG GGC ATC CAG TGG CGA GAC CTC CTG AGT 1889

Lys Phe Glu Ala Lys Gly Met Gly He Gin Trp Arg Asp Leu Leu Ser 425 430 435

CCC GTC AAC GTG GAC GAC GAC TTC TGC TTC GGG CAG GTG CTG GGG ATG 1937

Pro Val Asn Val Asp Asp Asp Phe Cys Phe Gly Gin Val Leu Gly Met 440 445 450 455

CTG CTG CTG GAC TCT GTG CTC TAT GGC CTG GTG ACC TGG TAC ATG GAG 1985

Leu Leu Leu Asp Ser Val Leu Tyr Gly Leu Val Thr Trp Tyr Met Glu 460 465 470

GCC GTC TTC CCA GGG CAG TTC GGC GTG CCT CAG CCC TGG TAC TTC TTC 2033

Ala Val Phe Pro Gly Gin Phe Gly Val Pro Gin Pro Trp Tyr Phe Phe

475 480 485

ATC ATG CCC TCC TAT TGG TGT GGG AAG CCA AGG GCG GTT GCA GGG AAG 2081

He Met Pro Ser Tyr Trp Cys Gly Lys Pro Arg Ala Val Ala Gly Lys

490 495 500 GAG GAA GAA GAC AGT GAC CCC GAG AAA GCA CTC AGA AAC GAG TAC TTT 2129 Glu Glu Glu Asp Ser Asp Pro Glu Lys Ala Leu Arg Asn Glu Tyr Phe 505 510 515

GAA GCC GAG CCA GAG GAC CTG GTG GCG GGG ATC AAG ATC AAG CAC CTG 2177 Glu Ala Glu Pro Glu Asp Leu Val Ala Gly He Lys He Lys His Leu 520 525 530 535

TCC AAG GTG TTC AGG GTG GGA AAT AAG GAC AGG GCG GCC GTC AGA GAC 2225 Ser Lys Val Phe Arg Val Gly Asn Lys Asp Arg Ala Ala Val Arg Asp 540 545 550

CTG AAC CTC AAC CTG TAC GAG GGA CAG ATC ACC GTC CTG CTG GGC CAC 2273 Leu Asn Leu Asn Leu Tyr Glu Gly Gin He Thr Val Leu Leu Gly His 555 560 565

AAC GGT GCC GGG AAG ACC ACC ACC CTC TCC ATG CTC ACA GGT CTC TTT 2321 Asn Gly Ala Gly Lys Thr Thr Thr Leu Ser Met Leu Thr Gly Leu Phe 570 575 580

CCC CCC ACC AGT GGA CGG GCA TAC ATC AGC GGG TAT GAA ATT TCC CAG 2369 Pro Pro Thr Ser Gly Arg Ala Tyr He Ser Gly Tyr Glu He Ser Gin 585 590 595

GAC ATG GTT CAG ATC CGG AAG AGC CTG GGC CTG TGC CCG CAG CAC GAC 2417 Asp Met Val Gin He Arg Lys Ser Leu Gly Leu Cys Pro Gin His Asp 600 605 610 615

ATC CTG TTT GAC AAC TTG ACA GTC GCA GAG CAC CTT TAT TTC TAC GCC 2465 He Leu Phe Asp Asn Leu Thr Val Ala Glu His Leu Tyr Phe Tyr Ala 620 625 630

CAG CTG AAG GGC CTG TCA CGT CAG AAG TGC CCT GAA GAA GTC AAG CAG 2513 Gin Leu Lys Gly Leu Ser Arg Gin Lys Cys Pro Glu Glu Val Lys Gin 635 640 645

ATG CTG CAC ATC ATC GGC CTG GAG GAC AAG TGG AAC TCA CGG AGC CGC 2561 Met Leu His He He Gly Leu Glu Asp Lys Trp Asn Ser Arg Ser Arg 650 655 660

TTC CTG AGC GGG GGC ATG AGG CGC AAG CTC TCC ATC GGC ATC GCC CTC 2609 Phe Leu Ser Gly Gly Met Arg Arg Lys Leu Ser He Gly He Ala Leu 665 670 675

ATC GCA GGC TCC AAG GTG CTG ATA CTG GAC GAG CCC ACC TCG GGC ATG 2657 He Ala Gly Ser Lys Val Leu He Leu Asp Glu Pro Thr Ser Gly Met 680 685 690 695

GAC GCC ATC TCC AGG AGG GCC ATC TGG GAT CTT CTT CAG CGG CAG AAA 2705 Asp Ala He Ser Arg Arg Ala He Trp Asp Leu Leu Gin Arg Gin Lys 700 705 710

AGT GAC CGC ACC ATC GTG CTG ACC ACC CAC TTC ATG GAC GAG GCT GAC 2753 Ser Asp Arg Thr He Val Leu Thr Thr His Phe Met Asp Glu Ala Asp 715 720 725

CTG CTG GGA GAC CGC ATC GCC ATC ATG GCC AAG GGG GAG CTG CAG TGC 2801 Leu Leu Gly Asp Arg He Ala He Met Ala Lys Gly Glu Leu Gin Cys 730 735 740

TGC GGG TCC TCG CTG TTC CTC AAG CAG AAA TAC GGT GCC GGC TAT CAC 2849 Cys Gly Ser Ser Leu Phe Leu Lys Gin Lys Tyr Gly Ala Gly Tyr His 745 750 755 ATG ACG CTG GTG AAG GAG CCG CAC TGC AAC CCG GAA GAC ATC TCC CAG 2897 Met Thr Leu Val Lys Glu Pro His Cys Asn Pro Glu Asp Ho Ser Gin 760 765 770 775

CTG GTC CAC CAC CAC GTG CCC AAC GCC ACG CTG GΛG AGC AGC GCT GGG 2945 Leu Val His His His Val Pro Asn Ala Thr Lou Glu Ser Ser Ala Gly 780 785 790

GCC GAG CTG TCT TTC ATC CTT CCC AGA GAG AGC ACG CAC AGG TTT GAA 2993 Ala Glu Leu Ser Phe He Leu Pro Arg Glu Ser Thr His Arg Phe Glu 795 800 805

GGT CTC TTT GCT AAA CTG GAG AAG AAG CAG AAA GAG CTG GGC ATT GCC 3041 Gly Leu Phe Ala Lys Leu Glu Lys Lys Gin Lys Glu Leu Gly He Ala 810 815 820

AGC TTT GGG GCA TCC ATC ACC ACC ATG GAG GAA GTC TTC CTT CGG GTC 3089 Ser Phe Gly Ala Ser He Thr Thr Met Glu Glu Val Phe Leu Arg Val 825 830 835

GGG AAG CTG GTG GAC AGC AGT ATG GAC ATC CAG GCC ATC CAG CTC CCT 3137 Gly Lys Leu Val Asp Ser Ser Met Asp He Gin Ala He Gin Leu Pro 840 845 850 855

GCC CTG CAG TAC CAG CAC GAG AGG CGC GCC AGC GAC TGG GCT GTG GAC 3185 Ala Leu Gin Tyr Gin His Glu Arg Arg Ala Ser Asp Trp Ala Val Asp 860 865 870

AGC AAC CTC TGT GGG GCC ATG GAC CCC TCC GAC GGC ATT GGA GCC CTC 3233 Ser Asn Leu Cys Gly Ala Met Asp Pro Ser Asp Gly He Gly Ala Leu 875 880 885

ATC GAG GAG GAG CGC ACC GCT GTC AAG CTC AAC ACT GGG CTC GCC CTG 3281 He Glu Glu Glu Arg Thr Ala Val Lys Leu Asn Thr Gly Leu Ala Leu 890 895 900

CAC TGC CAG CAA TTC TGG GCC ATG TTC CTG AAG AAG GCC GCA TAC AGC 3329 His Cys Gin Gin Phe Trp Ala Met Phe Leu Lys Lys Ala Ala Tyr Ser 905 910 915

TGG CGC GAG TGG AAA ATG GTG GCG GCA CAG GTC CTG GTG CCT CTG ACC 3377 Trp Arg Glu Trp Lys Met Val Ala Ala Gin Val Leu Val Pro Leu Thr 920 925 930 935

TGC GTC ACC CTG GCC CTC CTG GCC ATC AAC TAC TCC TCG GAG CTC TTC 3425 Cys Val Thr Leu Ala Leu Leu Ala He Asn Tyr Ser Ser Glu Leu Phe 940 945 950

GAC GAC CCC ATG CTG AGG CTG ACC TTG GGC GAG TAC GGC AGA ACC GTC 3473 Asp Asp Pro Met Leu Arg Leu Thr Leu Gly Glu Tyr Gly Arg Thr Val 955 960 965

GTG CCC TTC TCA GTT CCC GGG ACC TCC CAG CTG GGT CAG CAG CTG TCA 3521 Val Pro Phe Ser Val Pro Gly Thr Ser Gin Leu Gly Gin Gin Leu Ser 970 975 980

GAG CAT CTG AAA GAC GCA CTG CAG GCT GAG GGA CAG GAG CCC CGC GAG 3569 Glu His Leu Lys Asp Ala Leu Gin Ala Glu Gly Gin Glu Pro Arg Glu 985 990 995

GTG CTC GGT GAC CTG GAG GAG TTC TTG ATC TTC AGG GCT TCT GTG GAG 3617 Val Leu Gly Asp Leu Glu Glu Phe Leu He Phe Arg Ala Ser Val Glu 1000 1005 1010 1015 GGG GGC GGC TTT AAT GAG CGG TGC CTT GTG GCA GCG TCC TTC AGA GAT 3665 Gly Gly Gly Phe Asn Glu Arg Cys Leu Val Ala Ala Ser Phe Arg Asp 1020 1025 1030

GTG GGA GAG CGC ACG GTC GTC AAC GCC TTG TTC AAC AAC CAG GCG TAC 3713 Val Gly Glu Arg Thr Val Val Asn Ala Leu Phe Asn Asn Gin Ala Tyr 1035 1040 1045

CAC TCT CCA GCC ACT GCC CTG GCC GTC GTG GAC AAC CTT CTG TTC AAG 3761 His Ser Pro Ala Thr Ala Leu Ala Val Val Asp Asn Leu Leu Phe Lys 1050 1055 1060

CTG CTG TGC GGG CCT CAC GCC TCC ATT GTG GTC TCC AAC TTC CCC CAG 3809 Leu Leu Cys Gly Pro His Ala Ser He Val Val Ser Asn Phe Pro Gin 1065 1070 1075

CCC CGG AGC GCC CTG CAG GCT GCC AAG GAC CAG TTT AAC GAG GGC CGG 3857 Pro Arg Ser Ala Leu Gin Ala Ala Lys Asp Gin Phe Asn Glu Gly Arg 1080 1085 1090 1095

AAG GGA TTC GAC ATT GCC CTC AAC CTG CTC TTC GCC ATG GCA TTC TTG 3905 Lys Gly Phe Asp He Ala Leu Asn Leu Leu Phe Ala Met Ala Phe Leu 1100 1105 1110

GCC AGC ACG TTC TCC ATC CTG GCG GTC AGC GAG AGG GCC GTG CAG GCC 3953 Ala Ser Thr Phe Ser He Leu Ala Val Ser Glu Arg Ala Val Gin Ala 1115 1120 1125

AAG CAT GTG CAG TTT GTG AGT GGA GTC CAC GTG GCC AGT TTC TGG CTC 4001 Lys His Val Gin Phe Val Ser Gly Val His Val Ala Ser Phe Trp Leu 1130 1135 1140

TCT GCT CTG CTG TGG GAC CTC ATC TCC TTC CTC ATC CCC AGT CTG CTG 4049 Ser Ala Leu Leu Trp Asp Leu He Ser Phe Leu He Pro Ser Leu Leu 1145 1150 1155

CTG CTG GTG GTG TTT AAG GCC TTC GAC GTG CGT GCC TTC ACG CGG GAC 4097 Leu Leu Val Val Phe Lys Ala Phe Asp Val Arg Ala Phe Thr Arg Asp 1160 1165 1170 1175

GGC CAC ATG GCT GAC ACC CTG CTG CTG CTC CTG CTC TAC GGC TGG GCC 4145 Gly His Met Ala Asp Thr Leu Leu Leu Leu Leu Leu Tyr Gly Trp Ala 1180 1185 1190

ATC ATC CCC CTC ATG TAC CTG ATG AAC TTC TTC TTC TTG GGG GCG GCC 4193 He He Pro Leu Met Tyr Leu Met Asn Phe Phe Phe Leu Gly Ala Ala 1195 1200 1205

ACT GCC TAC ACG AGG CTG ACC ATC TTC AAC ATC CTG TCA GGC ATC GCC 4241 Thr Ala Tyr Thr Arg Leu Thr He Phe Asn He Leu Ser Gly He Ala 1210 1215 1220

ACC TTC CTG ATG GTC ACC ATC ATG CGC ATC CCA GCT GTA AAA CTG GAA 4289 Thr Phe Leu Met Val Thr He Met Arg He Pro Ala Val Lys Leu Glu 1225 1230 1235

GAA CTT TCC AAA ACC CTG GAT CAC GTG TTC CTG GTG CTG CCC AAC CAC 4337 Glu Leu Ser Lys Thr Leu Asp His Val Phe Leu Val Leu Pro Asn His 1240 1245 1250 1255

TGT CTG GGG ATG GCA GTC AGC AGT TTC TAC GAG AAC TAC GAG ACG CGG 4385 Cys Leu Gly Met Ala Val Ser Ser Phe Tyr Glu Asn Tyr Glu Thr Arg 1260 1265 1270 AGG TAC TGC ACC TCC TCC GAG GTC GCC GCC CAC TAC TGC AAG AAA TAT 4433 Arg Tyr Cys Thr Ser Ser Glu Val Ala Ala His Tyr Cys Lys Lys Tyr 1275 1280 1285

AAC ATC CAG TAC CAG GAG AAC TTC TAT GCC TGG AGC GCC CCG GGG GTC 4481 Asn He Gin Tyr Gin Glu Asn Phe Tyr Ala Trp Ser Ala Pro Gly Val 1290 1295 1300

GGC CGG TTT GTG GCC TCC ATG GCC GCC TCA GGG TGC GCC TAC CTC ATC 4529 Gly Arg Phe Val Ala Ser Met Ala Ala Ser Gly Cys Ala Tyr Leu He 1305 1310 1315

CTG CTC TTC CTC ATC GAG ACC AAC CTG CTT CAG AGA CTC AGG GGC ATC 4577 Leu Leu Phe Leu He Glu Thr Asn Leu Leu Gin Arg Leu Arg Gly He 1320 1325 1330 1335

CTC TGC GCC CTC CGG AGG AGG CGG ACA CTG ACA GAA TTA TAC ACC CGG 4625 Leu Cys Ala Leu Arg Arg Arg Arg Thr Leu Thr Glu Leu Tyr Thr Arg 1340 1345 1350

ATG CCT GTG CTT CCT .GAG GAC CAA GAT GTA GCG GAC GAG AGG ACC CGC 4673 Met Pro Val Leu Pro Glu Asp Gin Asp Val Ala Asp Glu Arg Thr Arg 1355 1360 1365

ATC CTG GCC CCC AGC CCG GAC TCC CTG CTC CAC ACA CCT CTG ATT ATC 4721 He Leu Ala Pro Ser Pro Asp Ser Leu Leu His Thr Pro Leu He He 1370 1375 1380

AAG GAG CTC TCC AAG GTG TAC GAG CAG CGG GTG CCC CTC CTG GCC GTG 4769 Lys Glu Leu Ser Lys Val Tyr Glu Gin Arg Val Pro Leu Leu Ala Val 1385 1390 1395

GAC AGG CTC TCC CTC GCG GTG CAG AAA GGG GAG TGC TTC GGC CTG CTG 4817 Asp Arg Leu Ser Leu Ala Val Gin Lys Gly Glu Cys Phe Gly Leu Leu 1400 1405 1410 1415

GGC TTC AAT GGA GCC GGG AAG ACC ACG ACT TTC AAA ATG CTG ACC GGG 4865 Gly Phe Asn Gly Ala Gly Lys Thr Thr Thr Phe Lys Met Leu Thr Gly 1420 1425 1430

GAG GAG AGC CTC ACT TCT GGG GAT GCC TTT GTC GGG GGT CAC AGA ATC 4913 Glu Glu Ser Leu Thr Ser Gly Asp Ala Phe Val Gly Gly His Arg He 1435 1440 1445

AGC TCT GAT GTC GGA AAG GTG CGG CAG CGG ATC GGC TAC TGC CCG CAG 4961 Ser Ser Asp Val Gly Lys Val Arg Gin Arg He Gly Tyr Cys Pro Gin 1450 1455 1460

TTT GAT GCC TTG CTG GAC CAC ATG ACA GGC CGG GAG ATG CTG GTC ATG 5009 Phe Asp Ala Leu Leu Asp His Met Thr Gly Arg Glu Met Leu Val Met 1465 1470 1475

TAC GCT CGG CTC CGG GGC ATC CCT GAG CGC CAC ATC GGG GCC TGC GTG 5057 Tyr Ala Arg Leu Arg Gly He Pro Glu Arg His He Gly Ala Cys Val 1480 1485 1490 1495

GAG AAC ACT CTG CGG GGC CTG CTG CTG GAG CCA CAT GCC AAC AAG CTG 5105 Glu Asn Thr Leu Arg Gly Leu Leu Leu Glu Pro His Ala Asn Lys Leu 1500 1505 1510

GTC AGG ACG TAC AGT GGT GGT AAC AAG CGG AAG CTG AGC ACC GGC ATC 5153 Val Arg Thr Tyr Ser Gly Gly Asn Lys Arg Lys Leu Ser Thr Gly He 1515 1520 1525 GCC CTG ATC GGA GAG CCT GCT GTC ATC TTC CTG GAC GAG CCG TCC ACT 5201 Ala Leu He Gly Glu Pro Ala Val He Phe Leu Asp Glu Pro Ser Thr 1530 1535 1540

GGC ATG GAC CCC GTG GCC CGG CGC CTG CTT TGG GAC ACC GTG GCA CGA 5249 Gly Met Asp Pro Val Ala Arg Arg Leu Leu Trp Asp Thr Val Ala Arg 1545 1550 1555

GCC CGA GAG TCT GGC AAG GCC ATC ATC ATC ACC TCC CAC AGC ATG GAG 5297 Ala Arg Glu Ser Gly Lys Ala He He He Thr Ser His Ser Met Glu 1560 1565 1570 1575

GAG TGT GAG GCC CTG TGC ACC CGG CTG GCC ATC ATG GTG CAG GGG CAG 5345 Glu Cys Glu Ala Leu Cys Thr Arg Leu Ala He Met Val Gin Gly Gin 1580 1585 1590

TTC AAG TGC CTG GGC AGC CCC CAG CAC CTC AAG AGC AAG TTC GGC AGC 5393 Phe Lys Cys Leu Gly Ser Pro Gin His Leu Lys Ser Lys Phe Gly Ser 1595 1600 1605

GGC TAC TCC CTG CGG GCC AAG GTG CAG AGT GAA GGG CAA CAG GAG GCG 5441 Gly Tyr Ser Leu Arg Ala Lys Val Gin Ser Glu Gly Gin Gin Glu Ala 1610 1615 1620

CTG GAG GAG TTC AAG GCC TTC GTG GAC CTG ACC TTT CCA GGC AGC GTC 5489 Leu Glu Glu Phe Lys Ala Phe Val Asp Leu Thr Phe Pro Gly Ser Val 1625 1630 1635

CTG GAA GAT GAG CAC CAA GGC ATG GTC CAT TAC CAC CTG CCG GGC CGT 5537 Leu Glu Asp Glu His Gin Gly Met Val His Tyr His Leu Pro Gly Arg 1640 1645 1650 1655

GAC CTC AGC TGG GCG AAG GTT TTC GGT ATT CTG GAG AAA GCC AAG GAA 5585 Asp Leu Ser Trp Ala Lys Val Phe Gly He Leu Glu Lys Ala Lys Glu 1660 1665 1670

AAG TAC GGC GTG GAC GAC TAC TCC GTG AGC CAG ATC TCG CTG GAA CAG 5633 Lys Tyr Gly Val Asp Asp Tyr Ser Val Ser Gin He Ser Leu Glu Gin 1675 1680 1685

GTC TTC CTG AGC TTC GCC CAC CTG CAG CCG CCC ACC GCA GAG GAG GGG 5681 Val Phe Leu Ser Phe Ala His Leu Gin Pro Pro Thr Ala Glu Glu Gly 1690 1695 1700

CGA TGAGGGGTGG CGGCTGTCTC GCCATCAGGC AGGGACAGGA CGGGCAAGCA 5734

Arg

GGGCCCATCT TACATCCTCT CTCTCCAAGT TTATCTCATC CTTTATTTTT AATCACTTTT 5794

TTCTATGATG GATATGAAAA ATTCAAGGCA GTATGCACAG AATGGACGAG TGCAGCCCAG 5854

CCCTCATGCC CAGGATCAGC ATGCGCATCT CCATGTCTGC ATACTCTGGA GTTCACTTTC 5914

CCAGAGCTGG GGCAGGCCGG GCAGTCTGCG GGCAAGCTCC GGGGTCTCTG GGTGGAGAGC 5974

TGACCCAGGA AGGGCTGCAG CTGAGCTGGG GGTTGAATTT CTCCAGGCAC TCCCTGGAGA 6034

GAGGACCCAG TGACTTGTCC AAGTTTACAC ACGACACTAA TCTCCCCTGG GGAGGAAGCG 6094

GGAAGCCAGC CAGGTTGAAC TGTAGCGAGG CCCCCAGGCC GCCAGGAATG GACCATGCAG 6154

ATCACTGTCA GTGGAGGGAA GCTGCTGACT GTGATTAGGT GCTGGGGTCT TAGCGTCCAG 6214

CGCAGCCCGG GGGCATCCTG GAGGCTCTGC TCCTTAGGGC ATGGTAGTCA CCGCGAAGCC 6274 GGGCACCGTC CCACAGCATC TCCTAGAAGC AGCCGGCACA GGAGGGAAGG TGGCCAGGCT 6334

CGAAGCAGTC TCTGTTTCCA GCACTGCACC CTCAGGAAGT CGCCCGCCCC AGGACACGCA 6394

GGGACCACCC TAAGGGCTGG GTGGCTGTCT CAAGGACACA TTGAATACGT TGTGACCATC 6454

CAGAAAATAA ATGCTGAGGG GACACAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA 6514

AAAAAAAAAA A 6525

(2) INFORMATION FOR SEQ ID NO:75:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1704 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:

Met Ala Val Leu Arg Gin Leu Ala Leu Leu Leu Trp Lys Asn Tyr Thr 1 5 10 15

Leu Gin Lys Arg Lys Val Leu Val Thr Val Leu Glu Leu Phe Leu Pro 20 25 30

Leu Leu Phe Ser Gly He Leu He Trp Leu Arg Leu Lys He Gin Ser 35 40 45

Glu Asn Val Pro Asn Ala Thr He Tyr Pro Gly Gin Ser He Gin Glu 50 55 60

Leu Pro Leu Phe Phe Thr Phe Pro Pro Pro Gly Asp Thr Trp Glu Leu 65 70 75 80

Ala Tyr He Pro Ser His Ser Asp Ala Ala Lys Ala Val Thr Glu Thr 85 90 95

Val Arg Arg Ala Leu Val He Asn Met Arg Val Arg Gly Phe Pro Ser 100 105 110

Glu Lys Asp Phe Glu Asp Tyr He Arg Tyr Asp Asn Cys Ser Ser Ser 115 120 125

Val Leu Ala Ala Val Val Phe Glu His Pro Phe Asn His Ser Lys Glu 130 135 140

Pro Leu Pro Leu Ala Val Lys Tyr His Leu Arg Phe Ser Tyr Thr Arg 145 150 155 160

Arg Asn Tyr Met Trp Thr Gin Thr Gly Ser Phe Phe Leu Lys Glu Thr 165 170 175

Glu Gly Trp His Thr Thr Ser Leu Phe Pro Leu Phe Pro Asn Pro Gly 180 185 190

Pro Arg Glu Leu Thr Ser Pro Asp Gly Gly Glu Pro Gly Tyr He Arg 195 200 205

Glu Gly Phe Leu Ala Val Gin His Ala Val Asp Arg Ala He Met Glu 210 215 220

Tyr His Ala Asp Ala Ala Thr Arg Gin Leu Phe Gin Arg Leu Thr Val 225 230 235 240 Thr He Lys Arg Phe Pro Tyr Pro Pro Phe He Ala Asp Pro Phe Leu 245 250 255

Val Ala He Gin Tyr Gin Leu Pro Leu Leu Leu Leu Leu Ser Phe Thr 260 265 270

Tyr Thr Ala Leu Thr He Ala Arg Ala Val Val Gin Glu Lys Glu Arg 275 280 285

Arg Leu Lys Glu Tyr Met Arg Met Met Gly Leu Ser Ser Trp Leu His 290 295 300

Trp Ser Ala Trp Phe Leu Leu Phe Phe Leu Phe Leu Leu He Ala Ala 305 310 315 320

Ser Phe Met Thr Leu Leu Phe Cys Val Lys Val Lys Pro Asn Val Ala 325 330 335

Val Leu Ser Arg Ser Asp Pro Ser Leu Val Leu Ala Phe Leu Leu Cys 340 345 350

Phe Ala He Ser Thr He Ser Phe Ser Phe Met Val Ser Thr Phe Phe 355 360 365

Ser Lys Ala Asn Met Ala Ala Ala Phe Gly Gly Phe Leu Tyr Phe Phe 370 375 380

Thr Tyr He Pro Tyr Phe Phe Val Ala Pro Arg Tyr Asn Trp Met Thr 385 390 395 400

Leu Ser Gin Lys Leu Cys Ser Cys Leu Leu Ser Asn Val Ala Met Ala 405 410 415

Met Gly Ala Gin Leu He Gly Lys Phe Glu Ala Lys Gly Met Gly He 420 425 430

Gin Trp Arg Asp Leu Leu Ser Pro Val Asn Val Asp Asp Asp Phe Cys 435 440 445

Phe Gly Gin Val Leu Gly Met Leu Leu Leu Asp Ser Val Leu Tyr Gly 450 455 460

Leu Val Thr Trp Tyr Met Glu Ala Val Phe Pro Gly Gin Phe Gly Val 465 470 475 480

Pro Gin Pro Trp Tyr Phe Phe He Met Pro Ser Tyr Trp Cys Gly Lys 485 490 495

Pro Arg Ala Val Ala Gly Lys Glu Glu Glu Asp Ser Asp Pro Glu Lys 500 505 510

Ala Leu Arg Asn Glu Tyr Phe Glu Ala Glu Pro Glu Asp Leu Val Ala 515 520 525

Gly He Lys He Lys His Leu Ser Lys Val Phe Arg Val Gly Asn Lys 530 535 540

Asp Arg Ala Ala Val Arg Asp Leu Asn Leu Asn Leu Tyr Glu Gly Gin 545 550 555 560

He Thr Val Leu Leu Gly His Asn Gly Ala Gly Lys Thr Thr Thr Leu 565 570 575

Ser Met Leu Thr Gly Leu Phe Pro Pro Thr Ser Gly Arg Ala Tyr He 580 585 590 Ser Gly Tyr Glu He Ser Gin Asp Met Val Gin He Arg Lys Ser Leu 595 600 605

Gly Leu Cys Pro Gin His Asp He Leu Phe Asp Asn Leu Thr Val Ala 610 615 620

Glu His Leu Tyr Phe Tyr Ala Gin Leu Lys Gly Leu Ser Arg Gin Lys 625 630 635 640

Cys Pro Glu Glu Val Lys Gin Met Leu His He He Gly Leu Glu Asp 645 650 655

Lys Trp Asn Ser Arg Ser Arg Phe Leu Ser Gly Gly Met Arg Arg Lys 660 665 670

Leu Ser He Gly He Ala Leu He Ala Gly Ser Lys Val Leu He Leu 675 680 685

Asp Glu Pro Thr Ser Gly Met Asp Ala He Ser Arg Arg Ala He Trp 690 695 700

Asp Leu Leu Gin Arg Gin Lys Ser Asp Arg Thr He Val Leu Thr Thr 705 710 715 720

His Phe Met Asp Glu Ala Asp Leu Leu Gly Asp Arg He Ala He Met 725 730 735

Ala Lys Gly Glu Leu Gin Cys Cys Gly Ser Ser Leu Phe Leu Lys Gin 740 745 750

Lys Tyr Gly Ala Gly Tyr His Met Thr Leu Val Lys Glu Pro His Cys 755 760 765

Asn Pro Glu Asp He Ser Gin Leu Val His His His Val Pro Asn Ala 770 775 780

Thr Leu Glu Ser Ser Ala Gly Ala Glu Leu Ser Phe He Leu Pro Arg 785 790 795 800

Glu Ser Thr His Arg Phe Glu Gly Leu Phe Ala Lys Leu Glu Lys Lys 805 810 815

Gin Lys Glu Leu Gly He Ala Ser Phe Gly Ala Ser He Thr Thr Met 820 825 830

Glu Glu Val Phe Leu Arg Val Gly Lys Leu Val Asp Ser Ser Met Asp 835 840 845

He Gin Ala He Gin Leu Pro Ala Leu Gin Tyr Gin His Glu Arg Arg 850 855 860

Ala Ser Asp Trp Ala Val Asp Ser Asn Leu Cys Gly Ala Met Asp Pro 865 870 875 880

Ser Asp Gly He Gly Ala Leu He Glu Glu Glu Arg Thr Ala Val Lys 885 890 895

Leu Asn Thr Gly Leu Ala Leu His Cys Gin Gin Phe Trp Ala Met Phe 900 905 910

Leu Lys Lys Ala Ala Tyr Ser Trp Arg Glu Trp Lys Met Val Ala Ala 915 920 925

Gin Val Leu Val Pro Leu Thr Cys Val Thr Leu Ala Leu Leu Ala He 930 935 940 Asn Tyr Ser Ser Glu Leu Phe Asp Asp Pro Met Leu Arg Leu Thr Leu 945 950 955 960

Gly Glu Tyr Gly Arg Thr Val Val Pro Phe Ser Val Pro Gly Thr Ser 965 970 975

Gin Leu Gly Gin Gin Leu Ser Glu His Leu Lys Asp Ala Leu Gin Ala 980 985 990

Glu Gly Gin Glu Pro Arg Glu Val Leu Gly Asp Leu Glu Glu Phe Leu 995 1000 1005

He Phe Arg Ala Ser Val Glu Gly Gly Gly Phe Asn Glu Arg Cys Leu 1010 1015 1020

Val Ala Ala Ser Phe Arg Asp Val Gly Glu Arg Thr Val Val Asn Ala 1025 1030 1035 1040

Leu Phe Asn Asn Gin Ala Tyr His Ser Pro Ala Thr Ala Leu Ala Val 1045 1050 1055

Val Asp Asn Leu Leu Phe Lys Leu Leu Cys Gly Pro His Ala Ser He 1060 1065 1070

Val Val Ser Asn Phe Pro Gin Pro Arg Ser Ala Leu Gin Ala Ala Lys 1075 1080 1085

Asp Gin Phe Asn Glu Gly Arg Lys Gly Phe Asp He Ala Leu Asn Leu 1090 1095 1100

Leu Phe Ala Met Ala Phe Leu Ala Ser Thr Phe Ser He Leu Ala Val 1105 1110 1115 1120

Ser Glu Arg Ala Val Gin Ala Lys His Val Gin Phe Val Ser Gly Val 1125 1130 1135

His Val Ala Ser Phe Trp Leu Ser Ala Leu Leu Trp Asp Leu He Ser 1140 1145 1150

Phe Leu He Pro Ser Leu Leu Leu Leu Val Val Phe Lys Ala Phe Asp 1155 1160 1165

Val Arg Ala Phe Thr Arg Asp Gly His Met Ala Asp Thr Leu Leu Leu 1170 1175 1180

Leu Leu Leu Tyr Gly Trp Ala He He Pro Leu Met Tyr Leu Met Asn 1185 1190 1195 1200

Phe Phe Phe Leu Gly Ala Ala Thr Ala Tyr Thr Arg Leu Thr He Phe 1205 1210 1215

Asn He Leu Ser Gly He Ala Thr Phe Leu Met Val Thr He Met Arg 1220 1225 1230

He Pro Ala Val Lys Leu Glu Glu Leu Ser Lys Thr Leu Asp His Val 1235 1240 1245

Phe Leu Val Leu Pro Asn His Cys Leu Gly Met Ala Val Ser Ser Phe 1250 1255 1260

Tyr Glu Asn Tyr Glu Thr Arg Arg Tyr Cys Thr Ser Ser Glu Val Ala 1265 1270 1275 1280

Ala His Tyr Cys Lys Lys Tyr Asn He Gin Tyr Gin Glu Asn Phe Tyr 1285 1290 1295 Ala Trp Ser Ala Pro Gly Val Gly Arg Phe Val Ala Ser Met Ala Ala 1300 1305 1310

Ser Gly Cys Ala Tyr Leu He Leu Leu Phe Leu He Glu Thr Asn Leu 1315 1320 1325

Leu Gin Arg Leu Arg Gly He Leu Cys Ala Leu Arg Arg Arg Arg Thr 1330 1335 1340

Leu Thr Glu Leu Tyr Thr Arg Met Pro Val Leu Pro Glu Asp Gin Asp 1345 1350 1355 1360

Val Ala Asp Glu Arg Thr Arg He Leu Ala Pro Ser Pro Asp Ser Leu 1365 1370 1375

Leu His Thr Pro Leu He He Lys Glu Leu Ser Lys Val Tyr Glu Gin 1380 1385 1390

Arg Val Pro Leu Leu Ala Val Asp Arg Leu Ser Leu Ala Val Gin Lys 1395 1400 1405

Gly Glu Cys Phe Gly Leu Leu Gly Phe Asn Gly Ala Gly Lys Thr Thr 1410 1415 1420

Thr Phe Lys Met Leu Thr Gly Glu Glu Ser Leu Thr Ser Gly Asp Ala 1425 1430 1435 1440

Phe Val Gly Gly His Arg He Ser Ser Asp Val Gly Lys Val Arg Gin 1445 1450 1455

Arg He Gly Tyr Cys Pro Gin Phe Asp Ala Leu Leu Asp His Met Thr 1460 1465 1470

Gly Arg Glu Met Leu Val Met Tyr Ala Arg Leu Arg Gly He Pro Glu 1475 1480 1485

Arg His He Gly Ala Cys Val Glu Asn Thr Leu Arg Gly Leu Leu Leu 1490 1495 1500

Glu Pro His Ala Asn Lys Leu Val Arg Thr Tyr Ser Gly Gly Asn Lys 1505 1510 1515 1520

Arg Lys Leu Ser Thr Gly He Ala Leu He Gly Glu Pro Ala Val He 1525 1530 1535

Phe Leu Asp Glu Pro Ser Thr Gly Met Asp Pro Val Ala Arg Arg Leu 1540 1545 1550

Leu Trp Asp Thr Val Ala Arg Ala Arg Glu Ser Gly Lys Ala He He 1555 1560 1565

He Thr Ser His Ser Met Glu Glu Cys Glu Ala Leu Cys Thr Arg Leu 1570 1575 1580

Ala He Met Val Gin Gly Gin Phe Lys Cys Leu Gly Ser Pro Gin His 1585 1590 1595 1600

Leu Lys Ser Lys Phe Gly Ser Gly Tyr Ser Leu Arg Ala Lys Val Gin 1605 1610 1615

Ser Glu Gly Gin Gin Glu Ala Leu Glu Glu Phe Lys Ala Phe Val Asp 1620 1625 1630

Leu Thr Phe Pro Gly Ser Val Leu Glu Asp Glu His Gin Gly Met Val 1635 1640 1645 His Tyr His Leu Pro Gly Arg Asp Leu Ser Trp Ala Lys Val Phe Gly 1650 1655 1660

He Leu Glu Lys Ala Lys Glu Lys Tyr Gly Val Asp Asp Tyr Ser Val 1665 1670 1675 1680

Ser Gin He Ser Leu Glu Gin Val Phe Leu Ser Phe Ala His Leu Gin 1685 1690 1695

Pro Pro Thr Ala Glu Glu Gly Arg 1700

(2) INFORMATION FOR SEQ ID NO:76:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 18 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "Oligonucleotide primer"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:76 AGCTGGCGCT CCTCCTCT (2) INFORMATION FOR SEQ ID NO:77:

(l) SEQUENCE CHARACTERISTICS :

(A) LENGTH: 349 ammo acids

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77:

Gly Gin Leu Leu Gly His Asn Gly Ala Gly Lys Thr Thr Ser He Gly 1 5 10 15

Arg Pro Thr Gly He Gly Tyr Asp Arg Gly Cys Pro Gin Leu Asp Leu 20 25 30

Thr Val Glu His Leu Leu Lys Gly Lys Leu Leu Lys Asn Leu Ser Gly 35 40 45

Gly Met Arg Lys Leu Gly Leu Asp Glu Pro Thr Ala Gly Met Asp Arg 50 55 60

Leu Arg Lys Arg Thr He Leu Thr Thr His Met Asp Glu Ala Leu Gly 65 70 75 80

Asp He Met His Gly Leu Gly Leu Lys Gin Lys Gly Gly Tyr Thr Val 85 90 95

Glu Gin Pro Ala Arg Phe Leu Leu Ser Phe Gly Ser Thr Glu Val Phe 100 105 110 He Gly Asp His Arg Gly Ala Gin Phe Lys Lys Tyr Ser Arg Tro Gin

115 120 125

Val Leu Pro Leu Asp Leu Thr Glu Val Phe Pro Leu Pro Gly Ala Leu 130 135 140

Phe Asn Tyr His Thr Ser Val Ser Gin Ala Leu Ala Ser Thr Phe Glu 145 150 155 160

Arg Gin Ala His Gin Phe Gly Phe Leu Asp He Ser Leu Leu Phe Asp 165 170 175

His Ala Leu Leu Tyr Ser Pro Tyr Phe Phe Ala Leu He Ala Leu Val 180 185 190

Glu Leu Leu Phe Leu Pro Gly Ala Asn Trp Gly Phe Leu Arg Met Leu 195 200 205

Pro Val Glu Arg Arg Asn Leu He Lys Leu Lys Ala Val Leu Leu Ala 210 215 220

Val Glu Cys Phe Gly Leu Leu Gly Asn Gly Ala Gly Lys Thr Thr Thr 225 230 235 240

Phe Leu Thr Gly Ser Ser Gly Ala Gly Gly Asp Val He Gly Tyr Cys 245 250 255

Pro Gin Phe Asp Ala Leu Thr Gly Arg Glu Leu Ala Gly Ala Glu Leu 260 265 270

His Ala Lys Leu Val Arg Tyr Ser Gly Gly Lys Arg Lys Ser Gly Ala 275 280 285

Leu Leu Pro Gin He Leu Asp Glu Pro Gly Asp Pro Ala Arg Arg Trp 290 295 300

Glu Ser Ala Thr Ser His Ser Met Glu Cys Glu Ala Leu Cys Arg Ala 305 310 315 320

Gly Gly Ser Gin Leu Lys Ser Gly Tyr Val Pro Ser Val Leu Leu Pro 325 330 335

Trp Phe Gly Val Asp Gin Ser Leu Glu Phe Leu Ala Leu 340 345

(2) INFORMATION FOR SEQ ID NO:78:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1974 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:

CAGCGGGAGG ACGCGCCAAC ATCCCCGCTG CTGTGCTGGG CCCGGGGCGT GCCCGCCGCT 60

GCTCCCACCT CTGGGCCGGG CTGGGGCCGC CCGGGGGCCC TGTTCCTCGG CATTGCGGGC 120

CTGGTGGGCA GAACCGCGGA GAGGGCTTCT TTTCCCCAAG GGCAGCGTCT TGGGGCCCGG 180 CCACTGGCTG ACCCGCAGCG GCTCCGGCCA TGCCTGGCTG GCCCTGGGGG CTGCTGCTGA 240

CGGCAGGCAC GCTCTTCGCC GCCCTGAGTC CTGGGCCGCC GGCGCCCGCC GACCCCTGCC 300

ACGATGAGGG GGGTGCGCCC CGCGGCTGCG TGCCAGGACT GGTGAACGCC GCCCTGGGCC 360

GCGAGGTGCT GGCTTCCAGC ACGTGCGGGC GGCCGGCCAC TCGGGCCTGC GACGCCTCCG 420

ACCCGCGACG GGCACACTCC CCCGCCCTCC TTACTTCCCC AGGGGGCACG GCCAGCCCTC 480

TGTGCTGGCG CTCGGAGTCC CTGCCTCGGG CGCCCCTCAA CGTGACTCTC ACGGTGCCCC 540

TGGGCAAGGC TTTTGAGCTG GTCTTCGTGA GCCTGCGCTT CTGCTCAGCT CCCCCAGCCT 600

CCGTGGCCCT GCTCAAGTCT CAGGACCATG GCCGCAGCTG GGCCCCGCTG GGCTTCTTCT 660

CCTCCCACTG TGACCTGGAC TATGGCCGTC TGCCTGCCCC TGCCAATGGC CCAGCTGGCC 720

CAGGGCCTGA GGCCCTGTGC TTCCCCGCAC CCCTGGCCCA GCCTGATGGC AGCGGCCTTC 780

TGGCCTTCAG CATGCAGGAC AGCAGCCCCC CAGGCCTGGA CCTGGACAGC AGCCCAGTGC 840

TCCAAGACTG GGTGACCGCC ACCGACGTCC GTGTAGTGCT CACAAGGCCT AGCACGGCAG 900

GTGACCCCAG GGACATGGAG GCCGTCGTCC CTTACTCCTA CGCAGCCACC GACCTCCAGG 960

TGGGCGGGCG CTGCAAGTGC AATGGACATG CCTCACGGTG CCTGCTGGAC ACACAGGGCC 1020

ACCTGATCTG CGACTGTCGG CATGGCACCG AGGGCCCTGA CTGCGGCCGC TGCAAGCCCT 1080

TCTACTGCGA CAGGCCATGG CAGCGGGCCA CTGCCCGGGA ATCCCACGCC TGCCTCGCTT 1140

GCTCCTGCAA CGGCCATGCC CGCCGCTGCC GCTTCAACAT GGAGCTGTAC CGACTGTCCG 1200

GCCGCCGCAG CGGGGGTGTC TGTCTCAACT GCCGGCACAA CACCGCCGGC CGCCACTGCC 1260

ACTACTGCCG GGAGGGCTTC TATCGAGACC CTGGCCGTGC CCTGAGTGAC CGTCGGGCTT 1320

GCAGGGCCTG CGACTGTCAC CCGGTTGGTG CTGCTGGCAA GACCTGCAAC CAGACCACAG 1380

GCCAGTGTCC CTGCAAGGAT GGCGTCACTG GCCTCACCTG CAACCGCTGC GCGCCTGGCT 1440

TCCAGCAAAG CCGCTCCCCA GTGGCGCCCT GTGTTAAGAC CCCTATCCCT GGACCCACTG 1500

AGGACAGCAG CCCTGTGCAG CCCCAGGACT GTGACTCGCA CTGCAAACCT GCCCGTGGCA 1560

GCTACCGCAT CAGCCTAAAG AAGTTCTGCA AGAAGGACTA TGCGGTGCAG GTGGCGGTGG 1620

GTGCGCGCGG CGAGGCGCGC GGCGCGTGGA CACGCTTCCC GGTGGCGGTG CTCGCCGTGT 1680

TCCGGAGCGG AGAGGAGCGC GCGCGGCGCG GGAGTAGCGC GCTGTGGGTG CCCGCCGGGG 1740

ATGCGGCCTG CGGCTGCCCG CGCCTGCTCC CCGGCCGCCG CTACCTCCTG CTGGGGGGCG 1800

GGCCTGGAGC CGCGGCTGGG GGCGCGGGGG GCCGGGGGCC CGGGCTCATC GCCGCCCGCG 1860

GAAGCCTCGT GCTACCCTGG AGGGACGCGT GGACGCGGCG CCTGCGGAGG CTGCAGCGAC 1920

GCGAACGGCG GGGGCGCTGC AGCGCCGCCT GAGCCCGCCG GCTGGGCAAG GCGC 1974 (2) INFORMATION FOR SEQ ID NO: 79:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 612 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: not relevant

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:

Met He Thr Ser Val Leu Arg Tyr Val Leu Ala Leu Tyr Phe Cys Met 1 5 10 15

Gly He Ala His Gly Ala Tyr Phe Ser Gin Phe Ser Met Arg Ala Pro 20 25 30

Asp His Asp Pro Cys His Asp His Thr Gly Arg Pro Val Arg Cys Val 35 40 45

Pro Glu Phe He Asn Ala Ala Phe Gly Lys Pro Val He Ala Ser Asp 50 55 60

Thr Cys Gly Thr Asn Arg Pro Asp Lys Tyr Cys Thr Val Lys Glu Gly 65 70 75 80

Pro Asp Gly He He Arg Glu Gin Cys Asp Thr Cys Asp Ala Arg Asn 85 90 95

His Phe Gin Ser His Pro Ala Ser Leu Leu Thr Asp Leu Asn Ser He 100 105 110

Gly Asn Met Thr Cys Trp Val Ser Thr Pro Ser Leu Ser Pro Gin Asn 115 120 125

Val Ser Leu Thr Leu Ser Leu Gly Lys Lys Phe Glu Leu Thr Tyr Val 130 135 140

Ser Met His Phe Cys Ser Arg Leu Pro Asp Ser Met Ala Leu Tyr Lys 145 150 155 160

Ser Ala Asp Phe Gly Lys Thr Trp Thr Pro Phe Gin Phe Tyr Ser Ser 165 170 175

Glu Cys Arg Arg He Phe Gly Arg Asp Pro Asp Val Ser He Thr Lys 180 185 190

Ser Asn Glu Gin Glu Ala Val Cys Thr Ala Ser His He Met Gly Pro 195 200 205

Gly Gly Asn Arg Val Ala Phe Pro Phe Leu Glu Asn Arg Pro Ser Ala 210 215 220

Gin Asn Phe Glu Asn Ser Pro Val Leu Gin Asp Trp Val Thr Ala Thr 225 230 235 240

Asp He Lys Val Val Phe Ser Arg Leu Ser Pro Asp Gin Ala Glu Leu 245 250 255

Tyr Gly Leu Ser Asn Asp Val Asn Ser Tyr Gly Asn Glu Thr Asp Asp 260 265 270 Glu Val Lys Gin Arg Tyr Phe Tyr Ser Met Gly Glu Leu Ala Val Gly 275 280 285

Gly Arg Cys Lys Cys Asn Gly His Ala Ser Arg Cys He Phe Asp Lys 290 295 300

Met Gly Arg Tyr Thr Cys Asp Cys Lys His Asn Thr Ala Gly Thr Glu 305 310 315 320

Cys Glu Met Cys Lys Pro Phe His Tyr Asp Arg Pro Trp Gly Arg Ala 325 330 335

Thr Ala Asn Ser Ala Asn Ser Cys Val Ala Cys Asn Cys Asn Gin His 340 345 350

Ala Lys Arg Cys Arg Phe Asp Ala Glu Leu Phe Arg Leu Ser Gly Asn 355 360 365

Arg Ser Gly Gly Val Cys Leu Asn Cys Arg His Asn Thr Ala Gly Arg 370 375 380

Asn Cys His Leu Cys Lys Pro Gly Phe Val Arg Asp Thr Ser Leu Pro 385 390 395 400

Met Thr His Arg Arg Ala Cys Lys Ser Cys Gly Cys His Pro Val Gly 405 410 415

Ser Leu Gly Lys Ser Cys Asn Gin Ser Ser Gly Gin Cys Val Cys Lys 420 425 430

Pro Gly Val Thr Gly Thr Thr Cys Asn Arg Cys Ala Lys Gly Tyr Gin 435 440 445

Gin Ser Arg Ser Thr Val Thr Pro Cys He Lys He Pro Thr Lys Ala 450 455 460

Asp Phe He Gly Ser Ser His Ser Glu Glu Gin Asp Gin Cys Ser Lys 465 470 475 480

Cys Arg He Val Pro Lys Arg Leu Asn Gin Lys Lys Phe Cys Lys Arg 485 490 495

Asp His Ala Val Gin Met Val Val Val Ser Arg Glu Met Val Asp Gly 500 505 510

TΓD Ala Lys Tyr Lys He Val Val Glu Ser Val Phe Lys Arg Thr Glu 515 520 525

Asn Met Gin Arg Arg Gly Glu Thr Ser Leu Trp He Ser Pro Gin Gly 530 535 540

Val He Cys Lys Cys Pro Lys Leu Arg Val Gly Arg Arg Tyr Leu Leu 545 550 555 560

Leu Gly Lys Asn Asp Ser Asp His Glu Arg Asp Gly Leu Met Val Asn 565 570 575

Pro Gin Thr Val Leu Val Glu Trp Glu Asp Asp He Met Asp Lys Val 580 585 590

Leu Arg Phe Ser Lys Lys Asp Lys Leu Gly Gin Cys Pro Glu He Thr 595 600 605

(2) INFORMATION FOR SEQ ID NO: 80:

(l) SEQUENCE CHARACTERISTICS.

(A) LENGTH. 17 base pairs

(B) TYPE- nucleic acid

(C) STRANDEDNESS smgle

(D) TOPOLOGY, linear

(n) MOLECULE TYPE other nucleic acid

(A) DESCRIPTION: /desc - "Oligonucleotide primer - sense strand"

(xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 80- CTTGCAGGGC CTGCGAC 17

(2) INFORMATION FOR SEQ ID NO: 81:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE, nucleic acid

(C) STRANDEDNESS: smgle

(D) TOPOLOGY linear

(ii) MOLECULE TYPE, other nucleic acid

(A) DESCRIPTION: /desc = "Oligonucleotide primer - antisense strand"

(xi) SEQUENCE DESCRIPTION SEQ ID NO: 81: GAAGGCACAG GGTGAAC 17

(2) INFORMATION FOR SEQ ID NO: 82:

(l) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(n) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "Oligonucleotide primer - sense strand"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82: CTGCAACCAG ACCACAG 17

(2) INFORMATION FOR SEQ ID NO: 83:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: other nucleic acid

(A) DESCRIPTION: /desc = "Oligonucleotide primer - antisense strand"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83: TAGATGTGGG AGCAGCG 17

Claims

What is claimed is:

1. Isolated nucleic acid encoding human netrin (hNET) or its complement.

2. Isolated nucleic acid according to claim 1, wherein said nucleic acid is mRNA.

3. Isolated nucleic acid according to claim 1, wherein said nucleic acid is DNA comprising the sequence set forth in SEQ ID NO: 19.

4. Isolated nucleic acid according to claim 1, wherein said nucleic acid is DNA comprising the sequence set forth in SEQ ID NO:20.

5. Isolated nucleic acid according to claim 1, wherein said nucleic acid is DNA comprising the sequence set forth in SEQ ID NO:78.

6. Isolated nucleic acid that hybridizes under stringent conditions to the nucleic acid of claim 1.

7. Isolated nucleic acid according to claim 6, comprising the sequence: 5'-GCCTGTCATCGCTCTAG-3 ' (SEQ ID NO:59) .

8. Isolated nucleic acid according to claim 6, comprising the sequence: 5' -CAGTCGCAGGCCCTGCA-3 ' (SEQ ID NO:60) .

9. Isolated nucleic acid according to claim 6, comprising the sequence: 5' -GAGGACGCGCCAACATC-3 ' (SEQ ID NO:61) .

10. Isolated nucleic acid according to claim 6, comprising the sequence: 5' -CGGCAGTAGTGGCAGTG-3 ' (SEQ ID NO: 62) .

11. Isolated nucleic acid according to claim 6, comprising the sequence: 5' -CCTGCCTCGCTTGCTCCTGC-3 ' (SEQ ID NO: 63) .

12. Isolated nucleic acid according to claim 6, comprising the sequence: 5' -CGGGCAGCCGCAGGCCGCAT-3 ' (SEQ ID NO: 64) .

13. Isolated nucleic acid according to claim 6, comprising the sequence: 5' -CCTGCAACGGCCATGCCCGC-3 ' (SEQ ID NO: 65) .

14. Isolated nucleic acid according to claim 6, comprising the sequence: 5' -GCATCCCCGGCGGGCACCCA-3 ' (SEQ ID NO:66) .

15. Isolated nucleic acid according to claim 6, comprising the sequence: 5' -CTTGCAGGGCCTGCGAC-3 ' (SEQ ID NO:80) .

16. Isolated nucleic acid according to claim 6, comprising the sequence 5 ' -GAAGGCACAGGGTGAAC-3 ' (SEQ ID NO:81) .

17. Isolated nucleic acid according to claim 6, comprising the sequence 5' -CTGCAACCAGACCACAG-3 ' (SEQ ID NO: 82) .

18. Isolated nucleic acid according to claim 6, comprising the sequence 5 ' -TAGATGTGGGAGCAGCG-3 ' (SEQ ID NO: 83) .

19. An antisense oligonucleotide that specifically binds to and modulates translation of mRNA according to claim 2.

20. Isolated human netrin (hNET) and biologically active fragments thereof.

21. Isolated hNET according to claim 20 comprising the amino acid sequence set forth in SEQ ID NO:21.

22. A vector comprising the isolated nucleic acid of claim 1.

23. A host cell comprising the vector of claim

22

24. A method for producing human netrin protein, said method comprising:

(a) culturing the host cell of claim 23 in a medium and under conditions suitable for expression of said protein, and

(b) isolating said expressed protein.

25. An antibody that specifically binds to human netrin (hNET) .

26. A composition comprising an amount of the oligonucleotide according to claim 19, effective to modulate expression of hNET by passing through a cell membrane and binding specifically with mRNA encoding hNET in the cell so as to prevent its translation and an acceptable hydrophobic carrier capable of passing through a cell membrane.

27. A composition comprising an amount of the antibody according to claim.25, effective to block binding of naturally occurring ligands to hNET and an acceptable carrier.

28. A transgenic non-human mammal expressing DNA encoding human netrin (hNET) .

29. A method for identifying compounds which bind to human netrin (hNET) , said method comprising a competitive binding assay wherein the cells according to claim 23 are exposed to a plurality of compounds and identifying compounds which bind thereto.

30. Isolated nucleic acid encoding human ATP Binding Cassette transporter (hABC3) or its complement.

31. Isolated nucleic acid according to claim 30, wherein said nucleic acid is mRNA.

32. Isolated nucleic acid according to claim 30, wherein said nucleic acid is DNA comprising the sequence set forth in SEQ ID NO:24.

33. Isolated nucleic acid according to claim 30, wherein said nucleic acid is DNA comprising the sequence set forth in SEQ ID NO:74.

34. Isolated nucleic acid that hybridizes under stringent conditions to the nucleic acid of claim 30.

35. Isolated nucleic acid according to claim 34, comprising the sequence: 5'-GACGCTGGTGAAGGAGC-3 ' (SEQ ID NO:42) .

36. Isolated nucleic acid according to claim 34, comprising the sequence: 5' -TCGCTGACCGCCAGGAT-3 ' (SEQ ID NO:43) .

37. Isolated nucleic acid according to claim 34, comprising the sequence: 5' -CATTGCCCGTGCTGTCGTG-3 ' (SEQ ID NO:52) .

38. Isolated nucleic acid according to claim 34, comprising the sequence: 5' -CATCGCCGCCTCCTTCATG-3 ' (SEQ ID NO:53) .

39. Isolated nucleic acid according to claim 34, comprising the sequence: 5' -GCGGAGCCACCTTCATCA-3 ' (SEQ ID NO:54) .

40. Isolated nucleic acid according to claim 34, comprising the sequence: 5 ' -GACGCTGGTGAAGGAGC-3 ' (SEQ ID NO:55) .

41. Isolated nucleic acid according to claim 34, comprising the sequence: 5 '-ATCCTGGCGGTCAGCGA-3 ' (SEQ ID NO:56) .

42. Isolated nucleic acid according to claim 34, comprising the sequence: 5 ' -AGGGATTCGACATTGCC-3 ' (SEQ ID NO:57) .

43. Isolated nucleic acid according to claim

34, comprising the sequence: 5 ' -CTTCAGAGACTCAGGGGCAT-3 ' (SEQ ID NO: 58) .

44. Isolated nucleic acid according to claim 34, comprising the sequence 5' -AGCTGGCGCTCCTCCTCT-3 ' (SEQ ID NO:76) .

45. An antisense oligonucleotide that specifically binds to and modulates translation of mRNA according to claim 31.

46. Isolated human ATP binding cassette transporter (hABC3) and biologically active fragments thereof .

47. Isolated hABC3 according to claim 46 comprising the amino acid sequence set forth in SEQ ID NO: 25.

48. Isolated hABC3 according to claim 46 comprising the amino acid sequence set forth in SEQ ID NO:75.

49. A vector comprising the isolated nucleic acid of claim 30.

50. A host cell comprising the vector of claim 49.

51. A method for producing human ATP binding cassette transporter (hABC3), said method comprising:

(a) culturing the host cell of claim 50 in a medium and under conditions suitable for expression of said protein, and

(b) isolating said expressed protein.

52. An antibody that specifically binds to human ATP binding cassette transporter (hABC3) .

53. A composition comprising an amount of the oligonucleotide according to claim 45, effective to modulate expression of hABC3 by passing through a cell membrane and binding specifically with mRNA encoding hABC3 in the cell so as to prevent its translation and an acceptable hydrophobic carrier capable of passing through a cell membrane.

54. A composition comprising an amount of the antibody according to claim 52 , effective to block binding of naturally occurring ligands to hABC3 and an acceptable carrier.

55. A transgenic non-human mammal expressing DNA encoding human ATP binding cassette transporter

(hABC3) .

56. A method for identifying compounds which bind to human ATP binding cassette transporter (hABC3), said method comprising a competitive binding assay wherein the cells according to claim 50 are exposed to a plurality of compounds and identifying compounds which bind thereto.

57. Isolated nucleic acid encoding human ribosomal L3 (RPL3L) or its complement.

58. Isolated nucleic acid according to claim 57, wherein said nucleic acid is mRNA.

59. Isolated nucleic acid according to claim 57, wherein said nucleic acid is DNA comprising the sequence set forth in SEQ ID NO:28.

60. Isolated nucleic acid that hybridizes under stringent conditions to the nucleic acid of claim 57.

61. Isolated nucleic acid according to claim 60, comprising the sequence: 5 ' -ACGGACACCTGGGCTTC-3 ' (SEQ ID NO:48) .

62. Isolated nucleic acid according to claim 60, comprising the sequence: 5 ' -AAACGGGAGGAGGTGGA-3 ' (SEQ ID NO:49) .

63. Isolated nucleic acid according to claim 60, comprising the sequence: 5 ' -AGACAGCCCAAGAGAAGAGG-3 ' (SEQ ID NO: 73) .

64. An antisense oligonucleotide that specifically binds to and modulates translation of mRNA according to claim 58.

65. Isolated human ribosomal L3 (RPL3L) and biologically active fragments thereof.

66. Isolated RPL3L according to claim 65 comprising the amino acid sequence set forth in SEQ ID NO:29.

67. A vector comprising the isolated nucleic acid of claim 57.

68. A host cell comprising the vector of claim

67.

69. A method for producing human ribosomal L3 (RPL3L) , said method comprising:

(a) culturing the host cell of claim 68 in a medium and under conditions suitable for expression of said protein, and

(b) isolating said expressed protein.

70. An antibody that specifically binds to human ribosomal L3 (RPL3L) .

71. A composition comprising an amount of the oligonucleotide according to claim 64, effective to modulate expression of RPL3L by passing through a cell membrane and binding specifically with mRNA encoding RPL3L in the cell so as to prevent its translation and an acceptable hydrophobic carrier capable of passing through a cell membrane.

72. A composition comprising an amount of the antibody according to claim 70, effective to block binding of naturally occurring ligands to RPL3L and an acceptable carrier.

73. A transgenic non-human mammal expressing DNA encoding human ribosomal L3 (RPL3L) .

74. A method for identifying compounds which bind to human ribosomal L3 (RPL3L) , said method comprising a competitive binding assay wherein the cells according to claim 68 are exposed to a plurality of compounds and identifying compounds which bind thereto.

75. Isolated nucleic acid encoding human augmenter of liver regeneration (hALR) or its complement.

76. Isolated nucleic acid according to claim 75, wherein said nucleic acid is mRNA.

77. Isolated nucleic acid according to claim 75, wherein said nucleic acid is DNA comprising the sequence set forth in SEQ ID NO:33.

78. Isolated nucleic acid that hybridizes under stringent conditions to the nucleic acid of claim 75.

79. Isolated nucleic acid according to claim 78, comprising the sequence: 5' -TGGCCCAGTTCATACATTTA-3 ' (SEQ ID NO: 69) .

80. Isolated nucleic acid according to claim 78, comprising the sequence: 5 ' -TTACCCCTGTGAGGAGTGTG-3 ' (SEQ ID NO:70) .

81. An antisense oligonucleotide that specifically binds to and modulates translation of mRNA according to claim 76.

82. Isolated human augmenter of liver regeneration (hALR) and biologically active fragments thereof.

83. Isolated hALR according to claim 82 comprising the amino acid sequence set forth in SEQ ID NO:34.

84. A vector comprising the isolated nucleic acid of claim 75.

85. A host cell comprising the vector of claim 84.

86 . A method for producing human augmenter of liver regeneration (hALR) , said method comprising:

(a) culturing the host cell of claim 85 in a medium and under conditions suitable for expression of said protein, and

(b) isolating said expressed protein.

87 . An antibody that specifically binds to human augmenter of liver regeneration (hALR) .

88 . A composition comprising an amount of the oligonucleotide according to claim 81, effective to modulate expression of hALR by passing through a cell membrane and binding specifically with mRNA encoding hALR in the cell so as to prevent its translation and an acceptable hydrophobic carrier capable of passing through a cell membrane.

89 . A composition comprising an amount of the antibody according to claim 87, effective to block binding of naturally occurring ligands to hALR and an acceptable carrier.

90 . A transgenic non-human mammal expressing DNA encoding human augmenter of liver regeneration (hALR) .

91 . A method for identifying compounds which bind to human augmenter of liver regeneration (hALR) , said method comprising a competitive binding assay wherein the cells according to claim 85 are exposed to a plurality of compounds and identifying compounds which bind thereto.