Permissive Cells And Uses Thereof

Abstract

Described are methods for determining the permissiveness of a cell for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular, for Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). Further described are methods and compositions related to the generation of host cells permissive for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular, for PRRSV. Methods of utilzing the cells thus identified or thus generated, in preparing a culture of a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, as well as the use of the virus for the purpose of vaccine production or diagnosis, are also described.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of co-pending U.S. patent application Ser. No. 12/452,675, filed Jan. 13, 2010, U.S. patent Ser. No. ______, which application is a national phase entry under 35 U.S.C. .sctn.371 of International Patent Application PCT/EP2008/006045, filed Jul. 23, 2008, designating the United States of America and published in English as International Patent Publication WO 2009/024239 A2 on Feb. 26, 2009, which claims the benefit under Article 8 of the Patent Cooperation Treaty and under 35 U.S.C. .sctn.119(e) to Great Britain Patent Application Serial No. 0811278.1 filed Jun. 19, 2008, and to European Patent Application Serial No. 07014842.4 filed Jul. 27, 2007, the disclosure of each of which is hereby incorporated herein by this reference in its entirety.

TECHNICAL FIELD

[0002] The disclosure relates generally to the field of virology. More particularly, it relates to methods for determining the permissiveness of a cell for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular, for Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). Further provided are methods and compositions related to the generation of host cells permissive for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular for PRRSV. Methods of utilizing the cells thus identified or thus generated, in preparing a culture of a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, as well as the use of the virus for the purpose of vaccine production or diagnosis, are also provided herein.

BACKGROUND

[0003] A "mystery swine disease" appeared in the 1980s, and is present ever since in pig industry causing important economical damage worldwide (Neumann et al., 2005). The causative agent, designated PRRSV, was first isolated in the Netherlands in 1991 and shortly after in the USA. It is a small enveloped positive-stranded RNA virus that is classified in the order Nidovirales, family Arteriviridae, genus Arterivirus together with equine arteritis virus, lactate dehydrogenase-elevating virus and simian hemorrhagic fever virus based on similar morphology, genomic organization, replication strategy and protein composition. In addition, they share a very narrow host tropism and a marked tropism for cells of the monocyte-macrophage lineage (Plagemann and Moennig, 1992). More specifically, in vivo PRRSV infects subpopulations of well-differentiated macrophages, with alveolar macrophages being the primary target cells, although in infected boars also testicular germ cells have been shown to allow PRRSV replication (Sur et al., 1997). In vitro, PRRSV replicates in primary cultures of alveolar macrophages and peripheral blood monocytes (PBMC), although PBMCs need treatments to improve infection (Delputte et al., 2007). Furthermore, African green monkey kidney cells and derivates thereof (Marc-145 and CL2621) have been shown to sustain PRRSV infection, although they are not from porcine origin and do not belong to the monocyte-macrophage lineage (Kim et al., 1993; Mengeling et al., 1995). Notwithstanding this very restricted cell tropism of PRRSV, the virus is able to replicate in several non-permissive cell-lines upon transfection of its viral RNA, indicating that cell tropism is determined by the presence or absence of specific receptors on the cell surface or other proteins involved in virus entry (Kreutz, 1998; Meulenberg et al., 1998).

[0004] So far, two PRRSV receptors were identified on macrophages, namely heparan sulphate (Delputte et al., 2002) and sialoadhesin (Vanderheijden et al., 2003; Wissink et al., 2003). In addition, Wissink et al. (2003) found a 150 kDa protein doublet to be involved in PRRSV infection of macrophages, however the identity of the N-glycosylated proteins is still unknown. In the current model for PRRSV infection of macrophages, PRRSV first binds to heparan sulphate most likely leading towards virus concentration. However, this first binding is rather unstable and is followed by binding to sialoadhesin and subsequent internalization (Delputte et al., 2005). Upon internalization, the virus is transported towards endosomes were a drop in pH is required for proper virus replication (Kreutz and Ackermann, 1996; Nauwynck et al., 1999). Despite this elegant research, the model is still incomplete. Transient expression of sialoadhesin in non-permissive PK-15 cells results in binding and internalization of the virus, but fusion and uncoating of the virus particles was not observed (Vanderheijden et al., 2003), indicating that other proteins are needed for virus disassembly, essential for virus replication.

[0005] PRRSV infection of Marc-145 cells makes use of a heparin-like molecule on the surface of Marc-145 cells (Jusa et al., 1997), resembling the initial step of PRRSV infection of macrophages. However, since sialoadhesin is absent from Marc-145 cells, virus entry will differ between the two cell-types. In Marc-145 cells, the intermediate filament vimentin has been described to bind to the PRRSV nucleocapsid protein and it has been suggested to interact with other cytoskeletal filaments to mediate transport of the virus in the cytosol (Kim et al., 2006). Recently, CD151 was found to interact specifically with PRRSV 3' untranslated region (UTR) RNA (Shanmukhappa et al., 2007). CD151 was proposed to be possibly involved in fusion between the viral envelope and the endosome or to relocalize the ribonucleoprotein complexes to promote viral replication. Still, further research is needed to elucidate their precise molecular modes of action during PRRSV infection.

[0006] Recently, the scavenger receptor CD163 has been described to play a role in PRRSV infection of Marc-145 cells and to make some non-permissive cells somewhat susceptible to PRRSV upon expression (Calvert et al., 2007), where others remain unproductive upon infection, despite expression of CD163 (Calvert et al., 2007). Although the CD163 gene was originally isolated from macrophages, thus far no role for CD163 in PRRSV infection of its primary target cells has been shown. Also, the mechanism by which CD163 confers partial susceptibility of selected cell types to PRRSV infection was not elucidated.

DISCLOSURE

[0007] We demonstrated that both sialoadhesin and CD163 are involved in PRRSV infection of macrophages. In addition, expression of recombinant forms of both CD163 and sialoadhesin in non-permissive cells renders all of them susceptible to PRRSV infection resulting in the production and release of infectious progeny virus. In contrast, when only CD163 is present, infection is clearly less efficient, and even absent in some cell types. In addition, viral adaptation that leads to antigenic differences in viral strains grown in cells only expressing CD163 when compared to the wild-type viruses, has been reported.

[0008] Based on detailed analysis of the kinetics of PRRSV infection, both in primary macrophages and in cells expressing sialoadhesin and CD 163, a role for CD 163 in virus fusion and uncoating is proposed. Compared to the above mentioned systems, i.e., cells solely expressing CD163 or sialoadhesin, it has been found that the combination of CD163 and sialoadhesin expression in one cell provides permissive cells that are highly efficient to sustain viral replication, and which closely mimic the entry of the virus in the natural host, i.e., the known subpopulations of well-differentiated macrophages, in particular alveolar macrophages being the primary target cells of the virus. Such mimicry of the entry of the natural target cells will certainly reduce or avoid virus adaptation in cell culture and the associated genetic and antigenic changes that might result in viruses with altered epitopes. Such modified epitopes can have tremendous effects on the antigenicity of vaccine viruses produced on given cells, resulting in loss of induction of important neutralizing antibodies. Clearly, avoiding changes in epitopes associated with adaptation during cell culture will be beneficial for production of vaccine virus.

[0009] The results presented show that Sn and CD163 work synergistically, since co-expression of both molecules results in higher virus production compared to expression of either of the two receptors alone, and this in all cell types tested. In addition, the molecular basis of this synergistic effect was elucidated, being the receptors acting at different steps during virus entry. Sn is expressed on the surface of target cells and very efficiently captures the virus and internalizes it into the cell in endosomes. CD163 on the other does not interact with the virus on the cell surface and does not internalize the virus, but co-localizes with the virus in early endosomes, where it mediates virus uncoating, followed by release of the RNA genome in the cytoplasm. Once the genome is released in the cytoplasm, genome translation, transcription and virus replication can proceed.

[0010] The finding that CD163, which is also expressed on the cell surface, does not act on the cell surface during infection, but rather interacts with the virus in endosomes inside the cell, is quite surprising. Generally, cellular receptors act during virus attachment or internalization, or direct fusion at the cell surface. This model, in which the CD163 receptor is not active on the cell surface but acts on the virus in endosomes is surprising and explains the unanticipated and cooperative action of both Sn and CD163 during virus infection, resulting in very efficient virus infection and production of high titers of virus.

[0011] Thus, these results provide new means to generate a PRRSV permissive cell that allow for efficient viral replication, with less adaptation and accordingly solves the problems recognized in the art.

[0012] This disclosure is based upon the characterization that both sialoadhesin and CD163 are not only involved in the permissivity of macrophages, the primary target cells, for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular for PRRSV, but that these molecules also act at different steps of virus infection, thus allowing a cooperative effect during infection, resulting in enhanced virus production.

[0013] It has been found that non-permissive cells can be rendered permissive, or the permissivity of partially susceptible cells can be increased by directing the cells to express both sialoadhesin and CD163.

[0014] Provided are methods to identify the permissiveness of cells for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular for PRRSV; the method comprising determining CD163 and sialoadhesin expression in the cells; wherein cells having a both CD163 and sialoadhesin expression, are identified as permissive cells for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae.

[0015] Provided is a method to generate a cell(s) permissive for, or to increase the permissiveness of a cell(s) for a virus of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular for PRRSV, the method comprising treating the cells to yield an expression of both CD163 and sialoadhesin.

[0016] Further provided is a method for preparing a culture of a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, the method comprising providing a cell line identified or obtained utilzing any one of the aforementioned methods, infecting the cell line with virus and harvesting the virus from the cell culture.

[0017] Once the virus has been grown to high titres, it can be processed according to the intended use, for example in diagnosis or vaccine production, by means known in the art. For example, but not limited to, inactivating the harvested viruses with formalin, BPI, BEA or gamma-irradiation, for use in vaccines. In the alternative, the viral strain used in the infection, may be an attenuated strain for use in the production of live, attenuated vaccines.

[0018] Hence, also provided is a vaccine comprising a viral strain/serotype obtained utilzing the aforementioned method. As already mentioned hereinbefore, due to the synergetic effect of CD163 and sialoadhesin, there will be a reduction in viral adaptation and loss of altered epitopes. This taken together with the increased viral production has a tremendous effect on the antigenicity of vaccine viruses produced utilzing the methods of the disclosure. As is known to a person skilled in the art, the latter is also beneficial in isolating further viral strains from in vivo samples when diagnosing PRRSV infection in a subject.

[0019] Provided are cell lines identified or obtained utilizing any one of the aforementioned methods. Cell lines identified utilzing the methods of the disclosure include primary cell cultures and continuous cell lines obtainable thereof, but for the natural host cells, i.e., the known subpopulations of well-differentiated macrophages, in particular the alveolar macrophages that are the primary target cells of a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular of a PRRSV infection. In one embodiment, the cells consist of non-permissive PRRSV cells, such as for example PK-15, CHO, BHK-21 and Hek293t cells, expressing both Sn and CD163; within a particular embodiment, the CHO cells stably expressing sialoadhesin and CD163 deposited on May 14, 2008 at the Belgian Coordinated Collections of Microorganisms as CHO-Sn/CD163 IC5; CHO-Sn/CD163 ID9 and CHO-Sn/CD163 IF3 with the respective accession numbers LMBP 6677CB, LMBP 6678CB, and LMBP 66779 CB, respectively.

[0020] The cell lines identified or obtained utilzing any one of the aforementioned methods, can also be used in a method of diagnosing a viral infection of a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular of a PRRSV infection in a subject. Further provided is a method for diagnosing a viral infection of a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular of a PRRSV infection in a subject, the method comprising contacting a cell line identified or obtained utilzing any one of the methods of the disclosure with a sample taken from the subject and determine whether viral replication occurs.

[0021] Alternatively, the viral infection is determined by assessing the presence of virus-specific antibodies in the sample taken from the subject. In this embodiment, the cell line identified or obtained utilzing any one of the methods of the disclosure is infected with a virus of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular with PRRSV, and the reaction of the antibodies in a sample taken from the subject is done by means well known to the person skilled in the art.

[0022] In these diagnostic methods, the sample taken from the subject, is typically a biological fluid; such as for example serum, colostrums, bronchoalveolar lavage fluids, saliva, urine or feces; tissue or a tissue extract. The tissue or tissue extract to be analyzed includes those which are known, or suspected, to be permissive for the virus such as, for example PBMC (peripheral blood mononuclear cells), alveolar macrophages, lymphoid tissues such as lymph nodes, spleen, tonsils and thymus and non-lymphoid tissues such as lungs and liver.

[0023] The cell lines identified or obtained utilzing any one of the aforementioned methods can be used in a method to identify anti-viral compounds, i.e., anti-viral compounds for a virus of the family Arteriviridae or Coronaviridae or Asfarviridae as defined herein, in particular for PRRSV. Accordingly, provided is a method to identify anti-viral compounds, the method comprising contacting a cell line infected with a virus of the Arteriviridae or Coronaviridae or Asfarviridae, with the compound to be tested; and determine the capability of the test compound to modulate the viral replication in the cell line.

[0024] The capability of a compound to modulate the viral replication can be determined by utilzing amongst others, the presence of infectious viral particles in the media. The latter can be determined utilzing any one of the available protein measurement techniques and is typically determined utilzing late viral specific antibodies, in particular, utilzing (virus) specific antibodies as provided hereinafter.

[0025] In the immunoassays related thereto, the amount of viral protein produced can be quantified by any standard assay such as, for example, utilzing a luminescence assay, a chemiluminescence assay, an enzyme-multiplied immunoassay technology (EMIT) assay, a fluorescence resonance excitation transfer immunoassay (FRET) assay, an enzyme channeling immunoassay (ECIA) assay, a substrate-labeled fluorescent immunoassay (SLFIA) assay, a fluorescence polarization assay, a fluorescence protection assay, an antigen-labeled fluorescence protection assay (ALFPIA), or scintillation proximity assay (SPA).

[0026] Alternatively, the effect of the compound on viral replication is determined by assessing the virus titers in the media, by quantifying numbers of infected cells by immunocytochemistry or by utilzing a MTS cytotoxicity assay to determine the cytotoxic concentration of the viral particles in the media.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1: Expression of sialoadhesin and CD163 on primary alveolar macrophages. Flow cytometric analysis of macrophages stained with mAb 41D3 for porcine sialoadhesin (black curve) or mAb 2A10 for porcine CD163 (black curve). In both experiments, the isotype-matched (IgG1) antibody 13D12 (white curve) was used as control.

[0028] FIG. 2: Effect of sialoadhesin and CD163 specific antibodies on PRRSV infection of macrophages. Panel A Macrophages were treated with different concentrations of sialoadhesin and CD163 recognizing antibodies at 37.degree. C. and inoculated with Marc-grown Lelystad virus. The relative percentage of infected macrophages was calculated, with untreated cells (RPMI) as reference. Each value represents the means.+-.standard deviation of three experiments. Panel B Macrophages were treated with 3.3 .mu.g/100 .mu.l of sialoadhesin and CD163 specific antibodies and inoculated with different PRRSV strains. The relative percentage of infected macrophages was calculated, with untreated cells (RPMI) as reference. Each value represents the means.+-.standard deviation of three experiments.

[0029] FIG. 3: PRRSV infection of non-permissive cells expressing sialoadhesin (Sn), CD163 or the combination of both. Transfected PK-15, CHO-K1 and BHK-21 cells were inoculated with either Lelystad virus or VR-2332. Twenty-four hours post-inoculation, supernatant was collected and infectious extracellular virus (black bars) was determined via titration, with 0.8 tissue culture infectious doses TCID50/ml (log.sub.10) being the detection limit. Background virus still remaining after removal of the inoculum (grey bars) was also determined. Each value represents the means.+-.standard deviation of three experiments.

[0030] FIG. 4: Kinetics of PRRSV infection in PK-15 cells expressing sialoadhesin and CD163. PK-15 cells expressing sialoadhesin in combination with CD163 were inoculated with PRRSV at a moi of 0.1 (dashed line) or a moi of 1 (full line). At different time points after inoculation, extra- and intracellular virus was collected and titrated with 0.8 TCID.sub.50/ml (log.sub.10) being the detection limit. Each value represents the means.+-.standard deviation of three experiments.

[0031] FIG. 5: Confocal microscopical analysis of PRRSV during infection of transfected PK-15 cells expressing PRRSV receptors sialoadhesin and/or CD163. The relative number of PK-15 cells with internalized virus particles was calculated with 1 hour post-inoculation as reference point. Data are shown for PK-15 cells expressing sialoadhesin (black bars) and the combination of sialoadhesin and CD163 (grey bars), but not for CD163-expressing PK-15 since no internalized virus particles were observed.

[0032] FIG. 6: Effect of sialoadhesin- and CD163-specific antibodies on PRRSV attachment to macrophages. Macrophages were treated with different concentrations of sialoadhesin- and CD163-specific antibodies at 4.degree. C. and inoculated with Lelystad virus at 4.degree. C. Unbound virus was then washed away and infection was allowed by shifting the cells to 37.degree. C. for 10 hours. The relative percentage of infected macrophages was calculated, with untreated cells as reference. Each value represents the means.+-.standard deviation of three experiments.

[0033] FIG. 7A: Sensitivity of CHO.sup.Sn-CD163 cells to PRRSV infection. Three different densities of cells (100,000, 200,000 and 300,000 cells/ml were infected at 1, 2 or 3 days post-seeding with LV marc-grown cells. After 48 hours, cells were stained with P3/27 primary antibodies and three microscope fields (500 cells per field) were counted, and represented as the absolute amounts of infected cells for the microscopic fields.

[0034] FIG. 7B: The same as FIG. 7A, but the cells were now pretreated with neuraminidase and subsequently infected with LV macrophage grown virus.

DESCRIPTION OF THE INVENTION

[0035] The instant disclosure is based upon the observation that both sialoadhesin and CD 163 are involved in the permissivity of macrophages, the primary target cells, for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular for PRRSV. In addition, and surprisingly, it was shown that CD163 does not act at the cell surface of susceptible cells during attachment and internalization, but rather acts during virus uncoating and genome release inside the cell in endosomes. This unexpected finding explains why CD163 acts synergistically with Sn during virus infection, since the latter interacts with the virus at the cell surface to allow virus attachment and internalization.

[0036] Provided are methods to identify the permissiveness of cells for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular, for PRRSV, the method comprising: determining CD163 and sialoadhesin expression in the cells, wherein cells having a both CD163 and sialoadhesin expression are identified as permissive cells for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae.

[0037] Asfarviridae is a family of icosohedral enveloped viruses whose genome consists of a single molecule of linear double-stranded DNA of about 150,000-190,000 nucleotides long. The name of the family is derived from African Swine Fever and Related Viruses. African Swine Fever Virus (ASFV) is the type species of the Asfivirus genus and is the sole member of the family. Recently, porcine CD163 polypeptide has been surmised by implication to be the cellular receptor for ASFV (Sanchez-Torres et al., 2003).

[0038] The Arteriviridae family is grouped with the Coronaviridae and Roniviridae to form the order Nidovirales. All members of the order have enveloped particles containing a single species of single-stranded RNA that encodes for a number of proteins by means of a series of nested (Latin Nido=nest) subgenomic RNAs. The family Arteriviridae contains those members with spherical virions 45-60 nm in diameter (those of the family Coronaviridae are more than 100 nm) and which infect mammals. Their genome consists of single-stranded RNA of size 12-16 kb and with a 3'-polyA tail. Two large, overlapping ORFs at the 5'-end of the genome encode the major non-structural proteins and are expressed as a fusion protein by ribosomal frameshift. Downstream are up to nine other genes, mostly or entirely encoding structural proteins, and these are expressed from a 3'-coterminal nested set of subgenomic RNAs.

[0039] Viruses of the family of Arteriviridae includes equine arteritis virus (EAV), lactate dehydrogenase-elevating virus (LDV) and simian hemorrhagic fever virus (SHFV). The Arterivirus having the greatest economic importance is PRRSV.

[0040] Thus, the methods of the disclosure are used to identify and/or modulate the permissivity of cells for a virus selected from the group consisting of ASFV, equine arteritis virus (EAV), lactate dehydrogenase-elevating virus (LDV), simian hemorrhagic fever virus (SHFV) or PRRSV, as well as variants thereof including orthologs and paralogs; in particular human orthologs. In a particular embodiment, the methods of the disclosure are used to identify and/or modulate the permissivity of cells for PRRSV.

[0041] As used herein, the terms "permissiveness of a cell(s)," "permissivity of cell(s)" and "permissive cell(s)" refers to the ability in which a particular virus, i.e., a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, can complete its replication cycle in a given cell. This in contrast to "non-permissive" cells that do not support complete replication of a virus.

[0042] "CD163" is a member of the scavenger receptor cysteine-rich (SRCR) family of transmembrane glycoproteins, and is thought to be expressed exclusively on monocytes and macrophages. One identified role of CD 163 is to inhibit oxidative tissue damage following hemolysis by consuming hemoglobin:haptoglobin complexes by endocytosis. The subsequent release of interleukin-10 and synthesis of hemeoxygenase-1 results in anti-inflammatory and cytoprotective effects. The human CD163 gene spans 35 kb on chromosome 12, and consists of 17 exons and 16 introns.

[0043] A number of isoforms of the CD163 polypeptide, including membrane bound, cytoplasmic and secreted types, are known to be generated by alternative splicing (Ritter et al., 1999). cDNA sequences that encodes a porcine CD 163 polypeptide (Genbank accession number AJ311716), a murine CD 163 polypeptide (Genbank access number AF274883), as well as multiple human variants, exemplified by Genbank access numbers AAH51281 and CAA80543, have been reported.

[0044] As used herein, the "CD163 polypeptide" is meant to be a protein encoded by a mammalian CD 163 gene, including allelic variants as well as biologically active fragments thereof containing conservative or non-conservative changes as well as artificial proteins that are substantially identical, i.e., 70%, 75%, 80%, 85%, 87%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the aforementioned CD 163 polypeptides. In a particular embodiment, the CD 163 polypeptide is 70%, 75%, 80%, 85%, 87%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the porcine CD 163 (encoded by Genbank Accession No. AJ311716 or bankit927381 EU016226).

[0045] By analogy, the "CD163 polynucleotide" is meant to include allelic variants as well as biologically active fragments thereof containing conservative or non-conservative changes as well as any nucleic acid molecule that is substantially identical, i.e., 70%, 75%, 80%, 85%, 87%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the aforementioned CD163 encoding polynucleotides. In a particular embodiment, the sialoadhesin polynucleotide is 70%, 75%, 80%, 85%, 87%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the nucleic acid molecule encoding for porcine CD163 (Genbank Accession No. AJ311716 or bankit927381 EU016226).

[0046] Biologically active fragments of CD163 are meant to include fragments that retain the activity of the full length protein, such as the isoform with SwissProt accession number Q2VL90-2, the soluble form of CD163 (sCD163), or fragments containing at least 1, 2, 3, 4, 5, 6, 7, 8 or 9 of the SRCR domain(s).

[0047] "Sialoadhesin" is a lectin-like adhesion shown to bind glycoconjugate ligands in a sialic acid-dependent manner and characterized in having conserved sialic acid binding sites. It is a transmembrane glycoprotein involved in cell-cell interactions and expressed only by a subpopulation of tissue macrophages.

[0048] cDNA sequences that encodes a porcine sialoadhesin polypeptide (Genbank accession number NM.sub.--214346), a murine sialoadhesin polypeptide (Genbank access number NM.sub.--011426), as well as a human variant (Genbank access number NM.sub.--023068), have been reported.

[0049] As used herein the "sialoadhesin" polypeptide is meant to be a protein encoded by a mammalian sialoadhesin gene, including allelic variants as well as biologically active fragments thereof containing conservative or non-conservative changes as well as artificial proteins that are substantially identical, i.e., 70%, 75%, 80%, 85%, 87%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the aforementioned sialoadhesin polypeptides. In a particular embodiment, the sialoadhesin polypeptide is 70%, 75%, 80%, 85%, 87%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the porcine sialoadhesin (encoded by Genbank Accession No. NM.sub.--214346).

[0050] By analogy, the "sialoadhesin" polynucleotide is meant to include allelic variants as well as biologically active fragments thereof containing conservative or non-conservative changes as well as any nucleic acid molecule that is substantially identical, i.e., 70%, 75%, 80%, 85%, 87%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of the aforementioned sialoadhesin encoding polynucleotides. In a particular embodiment, the sialoadhesin polynucleotide is 70%, 75%, 80%, 85%, 87%, 89%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the nucleic acid molecule encoding for porcine sialoadhesin (Genbank Accession No. NM.sub.--214346).

[0051] Biologically active fragments of sialoadhesin are meant to include fragments that retain the activity of the full length protein, i.e., that retain the capability of binding a virus of the family of Arteriviridae includes equine arteritis virus (EAV), lactate dehydrogenase-elevating virus (LDV) and simian hemorrhagic fever virus (SHFV), in particular of binding PRRSV. Biologically active fragments include, for example, the known soluble form of sialoadhesin, fragments containing at least 1, 2, 3 or 4 of the Ig-like domain(s); in particular the N-terminal domains; more in particular consisting of the N-terminal, variable, sialic acid-binding Ig-like domain.

[0052] As used herein, the terms "polynucleotide" and "nucleic acid" are used interchangeably to refer polynucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs (e.g., inosine, 7-deazaguanosine, etc.) thereof "Oligonucleotides" refer to polynucleotides of less than 100 nucleotides in length, preferably less than 50 nucleotides in length, and most preferably about 10 to 30 nucleotides in length. Polynucleotides can have any three-dimensional structure and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers. A polynucleotide can include modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. The term also refers to both double- and single-stranded molecules. Unless otherwise specified or required, any embodiment of this invention that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form.

[0053] "Polypeptide" refers to any peptide or protein comprising amino acids joined to each other by peptide bonds or modified peptide bonds. "Polypeptide" refers to both short chains, commonly referred to as peptides, oligopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.

[0054] "Polypeptides" include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.

[0055] Modifications may occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and/or the amino or carboxyl termini. It will be appreciated that the same type of modification may be present to the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications (see, for instance, Proteins-Structure and Molecular Properties, 2nd Ed., T. E. Creighton, W.H. Freeman and Company, New York, 1993; F. Wold, "Post-translational Protein Modifications: Perspectives and Prospects," pgs. 1-12 in Post-translational Covalent Modification of Proteins, B. C. Johnson, Ed., Academic Press, New York, 1983; Seifter et al., "Analysis for protein modifications and nonprotein cofactors," Meth. Enzymol. (1990) 182:626-646; and Rattan et al., "Protein Synthesis: Post-translational Modifications and Aging," Ann. N.Y. Acad. Sci. (1992) 663:4842).

Sequence Identity

[0056] The percentage identity of nucleic acid and polypeptide sequences can be calculated utilzing commercially available algorithms which compare a reference sequence with a query sequence. The following programs (provided by the National Center for Biotechnology Information) may be used to determine homologies/identities: BLAST, gapped BLAST, BLASTN and PSI-BLAST, which may be used with default parameters.

[0057] The algorithm GAP (Genetics Computer Group, Madison, Wis.) uses the Needleman and Wunsch algorithm to align two complete sequences that maximizes the number of matches and minimizes the number of gaps. Generally, the default parameters are used, with a gap creation penalty=12 and gap extension penalty=4.

[0058] Another method for determining the best overall match between a nucleic acid sequence or a portion thereof, and a query sequence is the use of the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci., 6:237-245 (1990)). The program provides a global sequence alignment. The result of the global sequence alignment is in percent identity. Suitable parameters used in a FASTDB search of a DNA sequence to calculate percent identity are: Matrix=Unitary, k-tuple=4, Mismatch penalty=1, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty=0.05, and Window Size=500 or query sequence length in nucleotide bases, whichever is shorter. Suitable parameters to calculate percent identity and similarity of an amino acid alignment are: Matrix=PAM 150, k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty=0.05, and Window Size=500 or query sequence length in nucleotide bases, whichever is shorter.

CD163 and Sialoadhesin Expression

[0059] The "expression" generally refers to the process by which polynucleotides are transcribed into mRNA and/or the process by which the mRNA is subsequently translated into peptides, polypeptides or proteins. Hence the "expression" of a gene product, in the disclosure of CD163 and sialoadhesin, can be determined either at the nucleic acid level or the protein level.

[0060] Detection can be by any appropriate method, including, e.g., detecting the quantity of mRNA transcribed from the gene or the quantity of nucleic acids derived from the mRNA transcripts. Examples of nucleic acids derived from an mRNA include a cDNA produced from the reverse transcription of the mRNA, an RNA transcribed from the cDNA, a DNA amplified from the cDNA, an RNA transcribed from the amplified cDNA, and the like. In order to detect the level of mRNA expression, the amount of the derived nucleic acid should be proportional to the amount of the mRNA transcript from which it is derived. The mRNA expression level of a gene can be detected by any method, including hybridization (e.g., nucleic acid arrays, Northern blot analysis, etc.) and/or amplification procedures according to methods widely known in the art. For example, the RNA in or from a sample can be detected directly or after amplification. Any suitable method of amplification may be used. In one embodiment, cDNA is reversed transcribed from RNA, and then optionally amplified, for example, by PCR. After amplification, the resulting DNA fragments can for example, be detected by agarose gel electrophoresis followed by visualization with ethidium bromide staining and ultraviolet illumination. A specific amplification of differentially expressed genes of interest can be verified by demonstrating that the amplified DNA fragment has the predicted size, exhibits the predicated restriction digestion pattern and/or hybridizes to the correct cloned DNA sequence.

[0061] In hybridization methods, a probe, i.e., nucleic acid molecules having at least ten nucleotides and exhibiting sequence complementarity or homology to the nucleic acid molecule to be determined, are used. It is known in the art that a "perfectly matched" probe is not needed for a specific hybridization. A probe useful for detecting mRNA is at least about 80%, 85%, 90%, 95%, 97% or 99% identical to the homologous region in the nucleic acid molecule to be determined. In one aspect, a probe is about 50 to about 75, nucleotides or, alternatively, about 50 to about 100 nucleotides in length. These probes can be designed from the sequence of full length genes. In certain embodiments, it will be advantageous to employ nucleic acid sequences as described herein in combination with an appropriate label for detecting hybridization and/or complementary sequences. A wide variety of appropriate labels, markers and/or reporters are known in the art, including fluorescent, radioactive, enzymatic or other ligands, such as avidin/biotin, which are capable of giving a detectable signal. One can employ a fluorescent label or an enzyme tag, such as urease, alkaline phosphatase or peroxidase, instead of radioactive or other environmental undesirable reagents. In the case of enzyme tags, colorimetric indicator substrates are known that can be employed to provide a signal that is visible to the human eye or spectrophotometrically, to identify specific hybridization with complementary nucleic acid-containing samples.

[0062] Detection of the level of gene expression can also include detecting the quantity of the polypeptide or protein encoded by the gene. A variety of techniques are available in the art for protein analysis. They include but are not limited to radioimmunoassay (RIA), ELISA (enzyme linked immunoradiometric assays), "sandwich" immunoassays, immunoradiometric assays, in situ immunoassays (using e.g., colloidal gold, enzyme or radioisotope labels), western blot analysis, immunoprecipitation assays, immunofluorescent assays and PAGE-SDS. One method to determine protein level involves (a) providing a biological sample containing polypeptides; and (b) measuring the amount of any immunospecific binding that occurs between an antibody reactive to the expression product of a gene of interest and a component in the sample, in which the amount of immunospecific binding indicates the level of the expressed proteins. Antibodies that specifically recognize and bind to the protein products of these genes are required for these immunoassays. These may be purchased from commercial vendors or generated and screened utilzing methods well known in the art. See, e.g., Sambrook, Fritsch and Maniatis, Molecular Cloning: A Laboratory Manual, 2nd edition (1989); Current Protocols In Molecular Biology (F. M. Ausubel et al. eds., (1987)); the series Methods In Enzymology(Academic Press, Inc.): PCR 2: A Practical Approach (M. J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995)); Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual and Animal Cell Culture (R. I. Freshney, ed. (1987)).

[0063] Provided is a method to generate a cell (or cells) permissive for, or to increase the permissiveness of a cell(s) for a virus of the family Asfarviridae or Arteriviridae, in particular for PRRSV, the method comprising treating the cells to yield an expression of both CD163 and sialoadhesin.

[0064] CD 163 and sialoadhesin expression may be facilitated or increased by methods that involve the introduction of exogenous nucleic acid into the cell. Such a cell may comprise a polynucleotide or vector in a manner that permits expression of an encoded CD 163 or sialoadhesin polypeptide.

[0065] Polynucleotides that encode CD 163 or sialoadhesin may be introduced into the host cell as part of a circular plasmid, or as linear DNA comprising an isolated protein-coding region, or in a viral vector. Methods for introducing exogenous nucleic acid into the host cell well known and routinely practiced in the art include transformation, transfection, electroporation, nuclear injection, or fusion with carriers such as liposomes, micelles, ghost cells, and protoplasts. Host cell systems hereof include plant, invertebrate and vertebrate cells systems. Hosts may include, but are not limited to, the following: insect cells, porcine kidney (PK) cells, feline kidney (FK) cells, swine testicular (ST) cells, African green monkey kidney cells (MA-104, MARC-145, VERO, and COS cells), Chinese hamster ovary (CHO) cells, baby hamster kidney cells, human 293 cells, and murine 3T3 fibroblasts. Insect host cell culture systems may also be used for the expression of the polypeptides hereof. In another embodiment, the polypeptides are expressed utilzing a drosophila expression system. Alternatively the polypeptides are expressed utilzing plant-based production platforms such as for example described in R. M. Twyman et al., Molecular farming in plants: host systems and expression technology, Trends Biotechnol. 21:570-578.

[0066] The choice of a suitable expression vector for expression of the polypeptides hereof depends upon the specific host cell to be used, and is within the skill of the ordinary artisan. Examples of suitable expression vectors include pSport and pcDNA3 (Invitrogen), pCMV-Script (Stratagene), and pSVL (Pharmacia Biotech). Expression vectors for use in mammalian host cells may include transcriptional and translational control sequences derived from viral genomes. Commonly used promoter sequences and modifier sequences which may be used in the disclosure include, but are not limited to, those derived from human cytomegalovirus (CMV), Rous sarcoma virus (RSV), Adenovirus 2, Polyoma virus, and Simian virus 40 (SV40). Methods for the construction of mammalian expression vectors are disclosed, for example, in Okayama and Berg (Mol. Cell. Biol. 3:280 (1983)); Cosman et al. (Mol. Immunol. 23:935 (1986)); Cosman et al. (Nature 312:768 (1984)); EP-A-0367566; and WO 91/18982.

[0067] Because CD163 sequences are known to exist in cells from various species, the endogenous gene may be modified to permit, or increase, expression of the CD 163 polypeptide. Cells can be modified (e.g., by homologous recombination) to provide increased expression by replacing, in whole or in part, the naturally occurring CD163 promoter with all or part of a heterologous promoter, so that the cells express CD 163 polypeptide at higher levels. The heterologous promoter is inserted in such a manner that it is operatively linked to endogenous CD163 encoding sequences. (See, for example, PCT International Publication No. WO 94/12650, PCT International Publication No. WO 92/20808, and PCT International Publication No. WO 91/09955.) It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional cad gene, which encodes for carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA. If linked to the CD 163 coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the CD163 coding sequences in the cells.

[0068] CD163 expression may also be induced by chemical treatment. Phorbol esters, especially phorbol myristyl acetate (PMA), activate one or more isozymes of the ubiquitous membrane receptor, protein kinase C (PKC) and are particularly preferred means of increasing CD163 expression. Other methods of intracellular calcium mobilization are also contemplated.

[0069] Sialoadhesin expression may also be induced by chemical treatment. It has been reported that IFN-.alpha. does increase and is even capable to induce sialoadhesin expression in the monocyte-macrophage lineage of cells. Thus, IFN-.alpha. treatment is an alternative means of increasing/inducing sialoadhesin expression in a cell.

Cell Lines

[0070] The cell lines identified or obtained utilzing the methods of the disclosure are part of the disclosure. In one embodiment, these cell lines consist of primary cell cultures of cells identified as being permissive for a virus of the family Asfarviridae or Arteriviridae, in particular for PRRSV, provided the cells are not the natural host cells, i.e., the known subpopulations of well-differentiated macrophages, in particular the alveolar macrophages that are the primary target cells of a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular of a PRRSV infection.

[0071] Cells that are cultured directly from an animal or person are known as "primary cells." With the exception of some derived from tumors, most primary cell cultures have limited lifespan. After a certain number of population doublings cells undergo the process of senescence and stop dividing, while generally retaining viability. Methods for growing suspension and adhesion cultures of primary cells are known to the person skilled in the art, such as for example described in General Techniques of Cell Culture, Maureen A. Harrison and Ian F. Rae, Cambridge University Press 2007.

[0072] As used in the methods of the disclosure, the "primary cells" are derived from; cells that support the replication of the viruses, in particular of PRRSV. In one embodiment, the cells consist of the known subpopulations of differentiated cells of the monocyte/macrophage lineage, in particular the alveolar macrophages that are the primary target cells of a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular of a PRRSV infection. In particular embodiments of the disclosure, the "primary cells" are derived from the alveolar macrophages that are the primary target cells

[0073] This in contrast to "continuous cells" also known as "an established" or "immortalized" cell line that has acquired the ability to proliferate indefinitely either through random mutation or deliberate modification, such as artificial expression of the telomerase gene. There are numerous well established cell lines representative of particular cell types.

[0074] In the context of the disclosure, the continuous cells are either derived by immortalization from the primary cell cultures mentioned herein before or obtained from a well established continuous cell line treated, in particular by transfection with a nucleic acid sequence encoding CD163 and/or sialoadhesin, to yield a stable expression of both CD163 and sialoadhesin. In an alternative embodiment, the CD163 expression may also be induced by chemical treatment in continuous cell lines stably expressing Sn. Phorbol esters, especially phorbol myristyl acetate (PMA), activate one or more isozymes of the ubiquitous membrane receptor, protein kinase C (PKC) and are particularly preferred means of increasing CD163 expression. Other methods of intracellular calcium mobilization are also contemplated. In analogy, continuous cells stably expressing CD163 may also be induced to express Sn by chemical treatment, utilzing for example IFN-.alpha..

[0075] Examples of continuous cell lines derived from the monocyte/macrophage lineage and useful in the context of the disclosure are THP-1, MM-1, J774, SU-DHL, RAW264, 3D4, and others.

[0076] Several established methods exist for immortalizing mammalian cells in culture. Viral genes, including Epstein-Barr virus (EBV), Simian virus 40 (SV40) T antigen, adenovirus E1A and E1B, and human papillomavirus (HPV) E6 and E7 can induce immortalization by a process known as viral transformation. Although the process is reliable and relatively simple, these cells may become genetically unstable (aneuploid) and lose the properties of primary cells. For the most part, these viral genes achieve immortalization by inactivating the tumor suppressor genes that put cells into a replicative senescent state. The preferred method to immortalize cells is through expression of the telomerase reverse transcriptase protein (TERT), particularly those cells most affected by telomere length (e.g., human). This protein is inactive in most somatic cells, but when hTERT is exogenously expressed the cells are able to maintain telomere lengths sufficient to avoid replicative senescence. Analysis of several telomerase-immortalized cell lines has verified that the cells maintain a stable genotype and retain critical phenotypic markers.

[0077] The well established continuous cells used herein are typically selected from the group consisting of cells with leukocyte characteristics or non-leukocyte cells such as for example swine testicle cells, swine kidney cells (e.g., PK15 (CCL-33), SK-RST (CRL-2842)), epithelial cell cultures, skin keratinocytes (e.g., HEK001 (CRL-2404), CCD1102 (CRL-2310)), Vero cells (CCL-81), human fetal lung fibroblasts (e.g., HFL1 (CCL-153)), human embryonic lung cells (e.g., HEL299 (CCL-137)), Chinese Hamster Ovary cells (CHO) or human embryonic kidney cells (HEK).

[0078] Hence, in a further embodiment, the cell lines consist of continuous cells expressing both CD163 and sialoadhesin.

Virus Culture and Vaccines

[0079] Provided is a method for preparing a culture of a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, the method comprising providing a cell line identified or obtained utilzing any one of the aforementioned methods, infecting the cell line with virus and harvesting the virus from the cell culture.

[0080] Once the virus has been grown to high titers, it can be processed according to the intended use, for example in diagnosis or vaccine production, by means known in the art.

[0081] For example, in case of vaccine production, the harvested viruses may be inactivated for example with formalin, BPI, BEA or gamma-irradiation, for use in vaccines. In the alternative, the viral strain used in the infection, may be an attenuated strain for use in the production of live, attenuated vaccines.

[0082] Hence, the disclosure also provides a vaccine comprising a viral strain/serotype obtained utilzing the aforementioned method.

[0083] Killed (inactivated) or live vaccines can be produced. To make a live vaccine, a viral isolate, or an attenuated or mutated variant thereof, is grown in cell culture. The virus is harvested according to methods well known in the art. The virus may then be concentrated, frozen, and stored at -70.degree. C., or freeze-dried and stored at 4.degree. C. Prior to vaccination the virus is mixed at an appropriate dosage, (which is from about 10 to 10.sup.8 tissue culture infectious doses per ml), with a pharmaceutically acceptable carrier such as a saline solution, and optionally an adjuvant.

[0084] The vaccine produced may also comprise an inactivated vaccine comprising a PRRSV strain obtained by the methods hereof. The inactivated vaccine is made by methods well known in the art. For example, once the virus is propagated to high titers, the virus antigenic mass could be obtained by methods well known in the art. For example, the virus antigenic mass may be obtained by dilution, concentration, or extraction. All of these methods have been employed to obtain appropriate viral antigenic mass to produce vaccines. The virus is then inactivated by treatment with formalin, betapropriolactone (BPL), binary ethyleneimine (BEI), or other methods known to those skilled in the art. The inactivated virus is then mixed with a pharmaceutically acceptable carrier such as a saline solution, and optionally an adjuvant. Examples of adjuvants include, but not limited to, aluminum hydroxide, oil-in-water and water-in-oil emulsions, AMPHIGEN, saponins such as QuilA, and polypeptide adjuvants including interleukins, interferons, and other cytokines.

[0085] Inactivation by formalin is performed by mixing the viral suspension with 37% formaldehyde to a final formaldehyde concentration of 0.05%. The virus-formaldehyde mixture is mixed by constant stirring for approximately 24 hours at room temperature. The inactivated virus mixture is then tested for residual live virus by assaying for growth on a suitable cell line.

[0086] Inactivation by BEI is performed by mixing the viral suspension of the disclosure with 0.1 M BEI (2-bromo-ethylamine in 0.175 N NaOH) to a final BEI concentration of 1 mM. The virus-BEI mixture is mixed by constant stirring for approximately 48 hours at room temperature, followed by the addition of 1.0 M sodium thiosulfate to a final concentration of 0.1 mM. Mixing is continued for an additional two hours. The inactivated virus mixture is tested for residual live virus by assaying for growth on a suitable cell line.

[0087] Also provided is the use of a virus, of an inactivated virus or of a vaccine of the disclosure for preparing a medicament which is employed for the prophylactic and/or therapeutic treatment of PRRSV infection in animals, in particular in swine and piglets.

[0088] The vaccine used herein advantageously is provided in a suitable formulation. Preferred are such formulations with a pharmaceutically acceptable carrier. This comprises, e.g., auxiliary substances, buffers, salts, preservatives.

Diagnosis

[0089] In the diagnostic methods, the permissive cells of the disclosure are contacted with a sample taken from an infected subject; the cells cultured to allow replication of the virus; the virus harvested from the cell culture and identified utilzing art known procedures, such as for example utilzing specific antibodies for a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular for PRRSV.

[0090] The (virus-) specific antibody is in particular a monoclonal antibody or a derivative thereof, the latter preferably selected from the group of antibody fragments, conjugates or homologues, but also complexes and absorbates known to the skilled artisan. In a particular embodiment, the (virus-) specific antibodies are selected from the group consisting of PRRSV nucleocapsid-specific antibodies such as P3/27 and SDOW17 and WBE1, 4, 5 and 6.

[0091] In the alternative, the disclosure provides the use of the viruses harvested from the above mentioned cell cultures in methods to determine a viral infection or a previous viral infection in a subject, by assessing the presence of virus-specific antibodies in the sample taken from the subject, i.e., detecting the binding of the virus-specific antibodies to the viruses harvested from the cell culture or the binding of the virus-specific antibodies to the viral protein-expressing infected cells.

[0092] A variety of techniques are available in the art to determine binding of the virus-specific antibodies to the virus. They include but are not limited to radioimmunoassay (RIA), ELISA (enzyme linked immunoradiometric assays), "sandwich" immunoassays, "competition" immunoassays, immunoradiometric assays, in situ immunoassays (using, e.g., colloidal gold, enzyme or radioisotope labels), western blot analysis, immunoprecipitation assays, immunofluorescent assays and PAGE-SDS.

[0093] In one embodiment, the presence of virus-specific antibodies will be determined utilzing a typical competition or sandwich assay. For example, in a sandwich assay the binding of the virus-specific antibodies is done utilzing a secondary labeled antibody, which is reactive for the primary virus-specific antibody and preferably has the ability to react with multiple sites on the primary antibody. In a competition assay a standard amount of a labeled virus-specific antibody will compete with the antibodies present in the sample for binding to the virus.

[0094] Known labels are of the radioactive or fluorometric type, which are detected by instrumentation, and colorimetric labels, typically enzyme labels which cause the conversion of a corresponding substrate to colored form.

[0095] Enzymes have often been used as labels in immunoassay. In conventional enzyme immunoassay (EIA), an enzyme is covalently conjugated with one component of a specifically binding antigen-antibody pair, and the resulting enzyme conjugate is reacted with a substrate to produce a signal which is detected and measured. The signal may be a color change, detected with the naked eye or by a spectrophotometric technique, or may be conversion of the substrate to a product detected by fluorescence.

[0096] Also provided is a method to determine a viral infection or a previous viral infection in a subject, the method comprising: [0097] harvesting a virus that is a member of the family Arteriviridae or Coronaviridae or Asfarviridae, in particular for PRRSV, from a cell culture obtainable utilzing any one of the methods of the disclosure; [0098] contacting the virus with a sample taken from the subject; and [0099] determine the presence of virus-specific antibodies in the sample taken from the subject.

[0100] In any one of the diagnostic methods, mentioned hereinbefore, the sample is typically a biological fluid; such as for example serum, colostrums, bronchoalveolar lavage fluids, saliva, urine or feces; tissue or a tissue extract. The tissue or tissue extract to be analyzed includes those which are known, or suspected, to be permissive for the virus such as, for example PBMC (peripheral blood mononuclear cells), alveolar macrophages, lymphoid tissues such as lymph nodes, spleen, tonsils and thymus and non-lymphoid tissues such as lungs and liver.

[0101] The disclosure will be better understood by reference to the following Experimental Details, but those skilled in the art will readily appreciate that these are only illustrative. Additionally, throughout this application, various patents and publications are cited. The disclosure of these is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. The following examples illustrate the invention. Other embodiments will occur to the person skilled in the art in light of these examples.

EXAMPLES

Methods

Cell Culture and Transfection

[0102] Primary alveolar macrophages were obtained from 4- to 6-week old conventional Belgian Landrace pigs from a PRRSV-negative herd as described by Wensvoort et al. (Wensvoort et al., 1991), and cultivated in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 1% nonessential amino acids and 1 mM sodium pyruvate. Marc-145 cells were cultivated in Minimum Essential Medium with Earle's salts (MEM) supplemented with 5% FBS. PK-15 cells were grown in MEM supplemented with 10% FBS. BHK-21 cells were cultivated in MEM supplemented with 10% FBS, 1% nonessential amino acids and 1 mM sodium pyruvate. CHO-K1 cells were cultivated in F-12 medium supplemented with 10% FBS and 1 mM sodium pyruvate. All cells were grown in their specific medium supplemented with 2 mM L-glutamine and a mixture of antibiotics in a humified 5% CO.sub.2 atmosphere at 37.degree. C. PK-15, BHK-21 and CHO-K1 cells were transfected respectively with lipofectamine (Invitrogen), lipofectamine 2000 (Invitrogen) and FuGENE 6 (Roche) according to the manufacturers' instructions.

Viruses

[0103] A thirteenth passage on macrophages of the European prototype PRRSV strain, Lelystad virus (LV) (kindly provided by G. Wensvoort), was used (Wensvoort et al., 1991). The European PRRSV strain was first passaged on macrophages and subsequently cultivated on Marc-145 cells for four passages, while for the American prototype PRRSV strain, VR-2332, a fourth passage on Marc-145 cells was used which was never passaged on macrophages (Collins et al., 1992). From the Belgian isolate 94v360 a fifth passage on Marc-145 cells was used (Duan et al., 1997a).

Antibodies

[0104] CD163 was detected via mouse monoclonal anti-porcine CD163 antibody (mAb) 2A10 (Ab-Direct) (Bullido et al., 1997; Sanchez et al., 1999) or goat polyclonal anti-human CD163 antibody (pAb) (R&D Systems). For porcine sialoadhesin recognition, mAb 41D3 has been used (Duan et al., 1998b; Vanderheijden et al., 2003). Isotype-matched irrelevant mAb 13D12 directed against gD of pseudorabies virus (Nauwynck and Pensaert, 1995) and purified goat antibodies were used as negative controls. PRRSV was visualized via the nucleocapsid-recognizing mAb P3/27 (Wieczorek-Krohmer et al., 1996) or a polyclonal swine serum obtained from PRRSV infected pigs.

Constructs

[0105] CD163 variants differing in their cytoplasmic tail have been described (Nielsen et al., 2006). Since these variations do not appear to determine PRRSV receptor function (Calvert et al., 2007), only one variant, the short one, has been cloned. Therefore, total cellular RNA was isolated from porcine macrophages via the RNeasy Mini Kit (Qiagen) and subsequently converted into cDNA via oligo dT primers (Invitrogen) and SuperScript II reverse transcriptase (Invitrogen) followed by an RNase H (Gibco) treatment. The obtained single stranded cDNA served on its turn as template for PCR amplification of the CD163 sequence via the Platinum Pfx polymerase (Invitrogen) and following primers: forward primer 5'CAC CAT GGA CAA ACT CAG AAT GGT GCT ACA TGA AAA CTC T3' (SEQ ID NO:15) and reverse primer 5'TCA TTG TAC TTC AGA GTG GTC TCC TGA GGG ATT 3' (SEQ ID NO:16) (Invitrogen). The PCR fragment was then finally cloned in the pcDNA3.1D/V5-His-TOPO vector (Invitrogen).

[0106] Sialoadhesin was cloned into the same vector as was described by Vanderheijden et al. (2003). All sequences were verified via restriction digestion and sequencing.

Stable Cell Lines

[0107] To construct a cell line co-expressing Sn and CD163, CHO-K1 cells were transfected with a plasmid containing the Sn cDNA and a geneticine resistance gene. After selection for geneticine resistance, cells were transfected with a plasmid containing the CD163 cDNA and a zeocin resistance gene, which allowed selection of cells expressing both Sn and CD163. Finally, 16 clones that co-expressed Sn and CD163 (CHO.sup.Sn-CD163) were isolated. Ten clones in which 100% of the cells stably expressed Sn and CD163 were isolated, while the other six clones lost either Sn or CD 163 receptor expression. After a first screening for susceptibility to PRRSV infection, three CHO.sup.Sn-CD163 clones, i.e., IC5, ID9 & IF3 were selected for further research and deposited at the Belgian Coordinated Collections of Microorganisms as CHO-Sn/CD163 IC5; CHO-Sn/CD163 ID9 and CHO-Sn/CD163 IF3 with the respective accession numbers LMBP 6677CB; LMBP 6678CB; and LMBP 66779 CB respectively.

Viral Inactivation

[0108] Inactivation with ultraviolet (UV) radiation was performed with a UV cross-linker (UVP, Inc). Purified virus (10.sup.7 TCID50/ml) was radiated with UV light of different doses (0-100-1000-2000-3000 or 4000 mJ/cm.sup.2) (Darnell et al., 2004). Inactivation with binary ethyleneimine (BEI) was done by incubating purified virus (10.sup.7 TCID50/ml) with 1 mM BEI (Aldrich) for several (0-6-12-24-48 or 72 hours) at 37.degree. C. The reaction was stopped with 0.1 mM sodium thiosulfate (Sigma) (Mondal et al. 2005).

Flow Cytometry

[0109] Twenty-four hours after seeding, macrophages were lifted from the cell culture plate by incubation with ice-cold PBS for 30 minutes at 4.degree. C. immediately prior to immunostaining and flow-cytometric analysis. Cells were first fixed with 3% paraformaldehyde followed by washing and incubation with primary mAb 41D3, 2A10 or isotype-matched control antibodies at 4.degree. C. Afterwards, cells were washed three times and subsequently incubated with FITC-labeled goat-anti-mouse Ab (Molecular Probes). Finally, cells were washed three times, resuspended in phosphate buffered saline (PBS) and analyzed with a Becton-Dickinson (San Jose, Calif.) FACScalibur. Twenty thousand cells were analyzed for each sample and three parameters were stored for further analysis: forward light scatter, sideward light scatter and green fluorescence.

Virus Titration

[0110] To determine the titer of extracellular virus, supernatant was collected and centrifuged to remove cell debris. To determine the titer of intracellular virus, cells were washed, collected and lysed by three cycles of freeze-thawing. For titration on Marc-145 cells, cells were planted three days before inoculation. Then, they were inoculated with a ten-fold dilution series of the samples and incubated for seven days at 37.degree. C. followed by evaluation of the cytopathic effect (CPE). For titration on macrophages, cells were planted one day before inoculation followed by inoculation with a ten-fold dilution series of the samples, incubation for three days at 37.degree. C. and finally evaluation. CPE was studied and furthermore infected cells were visualized via an immunoperoxidase monolayer assay (IPMA) (Wensvoort et al., 1991).

Immunofluorescence Staining and Microscopy

[0111] Transfected and/or infected cells were fixed with ice-cold methanol, unless pictures or colocalization studies were demanded. In those cases 3% paraformaldehyde was used and if needed, those cells were permeabilized with 0.1% Triton X-100. Fixation and permeabilization reagentia were removed via three times washing with PBS. Fixed cells were incubated with primary antibodies for at least 1 hour at 37.degree. C., washed three times with PBS and further incubated with secondary antibodies for at least 1 hour at 37.degree. C. Finally, cells were washed three times, embedded in glycerine-DABCO, mounted and analyzed via fluorescence microscopy.

Colocalization

[0112] To quantitate colocalization between sialoadhesin and CD163 on the surface of macrophages, confocal images were taken and analyzed via the program CoLocalizer Pro. Prior to merging the two images, weak fluorescent background was substracted. Based on the overlay, different colocalization parameters were calculated according to the manual.

Treatment of Macrophages with Sialoadhesin and CD163 Specific Antibodies

[0113] Macrophages were seeded in 96-well plates 24 hours before the experiment was performed. A three-fold dilution series was prepared for different antibodies (2A10, CD163-pAb, 41D3, 13D12, purified goat antibodies) and the HbHp complex (Hb A.sub.oH0267, Hp type2-2 H9762 from Sigma-Aldrich), which was made by 15 minutes incubation of both components at room temperature. Macrophages were then incubated for one hour at 37.degree. C. with the concentration gradient of antibodies/proteins followed by inoculation with PRRSV in the presence of antibodies/proteins for one hour at 37.degree. C. After the treatment, cells were washed, further incubated for 9 hours at 37.degree. C. and fixed with methanol. Infected cells were visualized via an immunoperoxidase staining with mAb P3/27 or the polyclonal swine serum as primary antibodies and respectively goat-anti-mouse HRP or rabbit-anti-swine HRP (Dako) as secondary antibodies. In control reactions, no difference in the percentage of infected cells was observed for the two different PRRSV-recognizing antibodies. After counting the percentage of infected cells, relative percentages of infection were calculated with cells without any antibody/protein treatment as reference value represented by the RPMI data.

Infection Experiments on Non-Target Cells and on Macrophages

[0114] For different infection experiments, a similar protocol was used as will be described here. Twenty-four hours post-transfection of PRRSV non-target cells or 24 hours post-seeding of the macrophages, cells were washed once with RPMI followed by inoculation with PRRSV viral supernatant which was cleared from cell debris via centrifugation. Inoculated cells were incubated for 1 hour at 37.degree. C. in the presence of the virus. After virus removal, macrophages were directly covered with medium unlike non-target cells, which were washed five times with RPMI before incubation in medium. The final wash solution was collected and titrated to determine the amount of background virus still present after removal of the inoculum. At different time points after inoculation, cells were fixed with ice-cold methanol or paraformaldehyde and intra- and extracellular virus was collected as described in virus titration.

Infection Experiments on CHO.sup.Sn-CD163 Cells

[0115] For different infection experiments, a similar protocol was used as will be described here. Three different CHO.sup.Sn-CD163 cell clones (IC5, ID9 and IF3) seeded at different densities (100,000, 200,000 or 300,000 cells/ml) are infected at different days post-seeding (1, 2 or 3 days post-seeding) with LV marc grown (moi 1) or with LV macrophage grown (moi 10). After 48 hours post-inoculation the cells are fixed with methanol and stained with primary antibody P3/27 and secondary antibody goat-anti-mouse HRP. Afterwards AEC substrate is added. With a microscope infected cells of three fields with a 40.times. lens (500 cells per field) are counted. To enhance virus interaction with the sialoadhesin receptor that depends on interaction of virus-linked sialic acids with the N-terminal, sialic acid binding domain of Sn, and subsequent infection, the cells were treated with neuramimidae (50 mU/ml of Vibirio cholerae neuraminidase) to remove cis-acting cellular sialic acids prior to infection with the PRRSV macrophage grown viruses.

Results

1. Expression of PRRSV Receptors Sialoadhesin and CD163 on Macrophages, the In Vivo Target Cells of PRRSV

[0116] Both PRRSV receptors sialoadhesin and CD163 are described to be restricted to monocytes-macrophages (Duan et al., 1998b; Sanchez et al., 1999). To further investigate their role in PRRSV infection, we first wanted to confirm their presence and analyze their expression pattern in a population of macrophages. Therefore, macrophages were cultivated for 24 hours, lifted from the cell culture plate, immunostained and analyzed via flow cytometry or they were cultivated for 24 hours, fixed, immunostained and analyzed via confocal microscopy. Similar to previous reports, the flow cytometry data (FIG. 1A) shows that nearly 100% of the macrophages are positive for both PRRSV receptors. Thus, macrophages represent a homogenous population with respect to the expression of sialoadhesin and CD163. Immunofluorescence staining followed by confocal analysis (FIG. 1B) reveals an almost exclusive expression of sialoadhesin on the cell membrane. This is in contrast to CD163, which is clearly present on the cell membrane and also intracellularly.

2. Effect of Sialoadhesin and CD163 Specific Antibodies on PRRSV Infection of Macrophages

[0117] To examine the role of CD163 in PRRSV infection of primary macrophages, the effect of a CD163-specific mAb and a pAb on PRRSV infection of macrophages was evaluated. Therefore, macrophages were pre-incubated with different concentrations of antibodies followed by inoculation of the macrophages with PRRSV in the presence of the antibodies for 1 hour, washing, further incubation for 9 hours at 37.degree. C., methanol-fixation and finally staining with PRRSV-specific antibodies. Relative percentages of infected macrophages are represented in FIG. 2A showing that mAb 41D3, directed against porcine sialoadhesin, strongly reduces PRRSV infection in a dose dependent manner, as has been described before (Duan et al., 1998a). Interestingly, also the CD163-specific polyclonal antibody clearly reduces PRRSV infection up to 75% in a dose dependent fashion, suggesting a role for CD163 in PRRSV infection of macrophages. However, the CD163-specific monoclonal antibody had no effect on PRRSV infection (data not shown). Also the best-characterized ligand of CD163, the hemoglobin-haptoglobin complex, did not influence PRRSV infection (data not shown). Ultimately, when 41D3 and the CD163-specific polyclonal antibody were combined, PRRSV infection was completely blocked. None of the negative controls, being irrelevant isotype-matched control antibodies, had an effect on PRRSV infection. These results clearly demonstrate that CD163 and sialoadhesin are involved in PRRSV infection of macrophages.

[0118] PRRSV displays remarkable genetic, antigenic, and clinical variability resulting in distinct groups of isolates within the same viral family (Goldberg et al., 2003), urging the need to investigate whether sialoadhesin and CD163 are involved in infection of different PRRSV strains (FIG. 2, Panels B and C). Therefore, different isolates were tested for their infectivity on macrophages in the presence of PRRSV-receptor-recognizing antibodies as described above. The European prototype PRRSV strain Lelystad virus (LV), the American prototype strain VR-2332 and the Belgian isolate 94v360 all show a clear reduction in the presence of 41D3 and the CD163-specific polyclonal antibody and an even greater reduction when both antibodies are combined. All three isolates used were adapted to grow on Marc-145 cells. Interestingly, the LV strain grown on macrophages without any adaptation to a cell-line shows the same trend, suggesting that the genetic diversity or the producer cells of PRRSV do not influence the need of different PRRSV strains for sialoadhesin and CD163 to infect macrophages.

3. PRRSV Non-Target Cells Expressing Both Sialoadhesin and CD163 Support Productive PRRSV Infection and are More Efficient Compared to CD163 Alone

[0119] Since the experiment with antibodies showed that both sialoadhesin and CD163 are involved in PRRSV infection of macrophages, we investigated their potential role in productive PRRSV infection in different non-susceptible cell-lines, either expressed separately or combined. PK-15, CHO-K1 and BHK-21 cells were transfected with sialoadhesin, CD163 or a combination of both and 24 hours post-transfection, cells were inoculated with the European prototype Lelystad virus or the American prototype VR-2332 virus. At 24 hours post-inoculation, supernatant was collected and cells were fixed. The supernatant was titrated on Marc-145 cells to determine the amount of infectious virus produced in the transiently transfected cells (FIG. 3). The fixed cells were analyzed via immunofluorescence microscopy for the presence of PRRSV.

[0120] In addition to PK-15, CHO-K1 and BHK-21 cells, HEK293t cells were tested for their susceptibility to PRRSV infection. Similar to the three other cell lines, HEK293t cells expressing sialoadhesin did not support productive PRRSV infection. HEK293t cells expressing CD163 alone supported productive PRRSV infection and 10 to 100 times more infected cells were observed in cells expressing both sialoadhesin and CD163 (data not shown).

[0121] Bottom line, cells only expressing sialoadhesin never showed infection, as was already noted by Vanderhijden et al. (2003). Infected cells were only observed when CD163 was present, alone or in combination with sialoadhesin (data not shown), but where CD163 alone is able to sustain PRRSV infection, 10 to 100 times more infected cells were observed in cells expressing both sialoadhesin and CD 163.

[0122] In agreement with the results obtained via immunofluorescence microscopy, no extracellular virus was detected for cells only expressing sialoadhesin. Except for PK-15 cells, were some extracellular virus is present, however without showing infected cells. When only CD163 is expressed, all three cell-lines produce new infectious virus, but the virus titers are rather low probably because of low infection efficiency. When both sialoadhesin and CD163 are present, all three cell-lines produce new infectious virus with virus titers remarkably higher compared to cells with only CD163, especially for PK-15 and CHO-K1 cells. Comparison between the European and the American prototype PRRSV strain shows higher virus titers for the VR-2332 strain in PK-15 and CHO-K1 cells but not in BHK-21 cells. Furthermore, for one repetition of the experiment the titration was performed not only on Marc-145 cells but also on macrophages revealing the same virus titers. Thus, PRRSV non-target cells expressing CD163 or CD163 combined with sialoadhesin produce new virus that is infectious on both Marc-145 cells and on macrophages. Further support, to the fact that non-permissive PRRSV cells can be rendered permissive with high virus titers when expression both CD163 and Sialoadhesin, was given in assessing the infectivity of the European prototype PRRSV strain Lelystad, the American prototype PRRSV strain VR-2332, and the Belgian PRRSV isolate 94V360 on the PK-15, CHO-K1, BHK-21 and HEK293t cells. For all four cell lines, similar results were observed as described for the two prototype strains. 94V360 was not able to infect cells only expressing sialoadhesin. Cells expressing CD163 were able to sustain PRRSV infection, however 10 to 100 times more infected cells were observed in cells expressing both sialoadhesin and CD163.

4. Kinetics of PRRSV Infection in PK-15 Cells Expressing Both Sialoadhesin and CD163

[0123] Because the combination of sialoadhesin and CD163 efficiently supports PRRSV infection in non-permissive cells, we wanted to study the kinetics of PRRSV infection in those non-target cells. Therefore, swine kidney PK-15 cells were transfected with a combination of sialoadhesin and CD 163 and 24 hours post-transfection, cells were inoculated with Lelystad virus at a moi of 0.1 or 1. At different time points after infection, intra- and extracellular virus was collected to be titrated on Marc-145 cells, as shown in FIG. 4. Starting from 12 hpi, an increase in the extracellular virus titer can be seen, which reaches its maximum around 48 hpi. Afterwards the titer drops which can possibly be explained by the limited number of sialoadhesin and CD163 expressing cells and/or the virus that becomes inactivated by the temperature. The amount of internalized virus particles is clearly dependent upon the titer in the inoculum. In the first six hours, the amount of internalized virus stays the same or shows a little drop. Afterwards it increases to reach a maximum around 24 hpi, which on its turn, is followed by a decrease of the intracellular virus.

5. Specific Function for Sialoadhesin and CD163 During PRRSV Infection of PK-15 Cells

[0124] Since PRRSV infection of macrophages and non-target cells is clearly dependent upon sialoadhesin and CD163, their specific molecular contributions to PRRSV infection need to be investigated. Results previously obtained in the lab indicate that sialoadhesin is important for the internalization of the virus (Vanderheijden et al., 2003). We want to confirm these results and study the role of CD163 during PRRSV infection. Therefore PK-15 cells were transfected with sialoadhesin, CD163 or a combination of both, which was followed by inoculation with Lelystad virus. At different time points after infection cells were fixed and PRRSV was visualized via immunofluorescence staining with the mAb P3/27 recognizing the PRRSV nucleocapsid protein represented in FIG. 5. Sialoadhesin expressing cells clearly internalize PRRSV virus particles, however virus disassembly does not occur at any time point and the cells do not become productively infected. Only at 24 hpi there is a small decrease in the number of cells with internalized virus particles. In CD163 expressing cells, internalized virus particles could not be observed. Surprisingly, those cells become infected and produce new infectious virus particles. PK-15 cells expressing both sialoadhesin and CD163 internalize virus particles similar to sialoadhesin expressing PK-15 cells. However, due to the presence of CD163 a clear reduction in the number of cells showing internalized virus particles is observed at 6 hpi resulting in infection at 12 hpi and even more at 24 hpi. Thus, infection of cells expressing both sialoadhesin and CD163 is much more efficient than cells only expressing CD163, as has been shown before (FIG. 3). Those results confirm the role of sialoadhesin as internalization receptor and unexpectedly show a role for CD 163 in fusion.

6. Treatment of Macrophages with Sialoadhesin- and CD163-Specific Antibodies at 4.degree. C.

[0125] In addition to sialoadhesin, CD163 is shown to be involved during PRRSV entry in macrophages. Sialoadhesin is known as PRRSV attachment and internalization receptor. Our data suggest a role for CD163 during PRRSV uncoating, however, further research is needed to unravel its exact functioning. Therefore, we wanted to investigate whether CD 163 is involved during PRRSV attachment.

[0126] Macrophages were seeded in 96-well plates 24 hours before the experiment was performed. A three-fold dilution series was prepared for different antibodies (pAb CD163, 41D3, 13D12, purified control goat antibodies). For treatment at 4.degree. C., macrophages were preincubated for 30 minutes at 4.degree. C. prior to incubation for 1 hour at 4.degree. C. with the ligands followed by inoculation with PRRSV in the presence of a new dilution series of ligands for 1 hour at 4.degree. C. After the inoculation, cells were washed, incubated for 10 hours at 37.degree. C. and fixed with methanol. Infected cells were visualized via an immunoperoxidase staining with mAb P3/27 or the polyclonal swine serum as primary antibodies and respectively HRP-labeled goat-anti-mouse or rabbit-anti-swine (Dako) as secondary antibodies. No difference in the percentage of infected cells was observed for the two different PRRSV-recognizing antibodies. Cells without ligand treatment are represented as control. For these untreated cells the average percentage of infected cells was calculated from six replicates. This average percentage was used as reference value in the calculation of the relative percentages of infection.

[0127] Monoclonal antibody 41D3 reduced PRRSV infection, contrasting with the pAb directed against CD163, which did not reduce PRRSV infection when administered at 4.degree. C. (FIG. 6). These data confirm the role of sialoadhesin as PRRSV attachment receptor and suggest that CD163 is not involved in PRRSV attachment to macrophages.

7. PRRSV Entry in Macrophages: Colocalization Between CD163 and PRRSV

[0128] CD163 is shown to be involved in PRRSV entry of macrophages, however not during attachment. Furthermore, CD163 enables PRRSV to disassemble and productively infect non-target cells, suggesting that CD163 acts during PRRSV entry. To test this hypothesis, we investigated the entry of PRRSV in macrophages via confocal analysis of immunofluorescence experiments showing PRRSV and CD163 at different time points after inoculation.

[0129] Twenty-four hours after seeding, macrophages were washed and incubated with PRRSV for 5, 10 or maximum 15 minutes at 37.degree. C. Fifteen minutes post-inoculation, the virus was replaced by medium and cells were further incubated at 37.degree. C. At different time point post-inoculation, cells were washed, fixed with paraformaldehyde, permeablized with TX-100 and stained. Cells were first incubated with a mAb directed against GP5 (isotype IgG2a), followed by incubation with the secondary antibody goat-anti-mouse Texas Red. Cells were then again incubated with the GP5 recognizing antibody. Finally, CD163 was visualized via mAb 2A10, which was directly labeled with Alexa 488 via the mouse IgG1 specific zenon labelings kit (Invitrogen). Stainings were analyzed via confocal microscopy.

[0130] PRRSV attaches to macrophages from 5 minutes post-inoculation and first internalized virions were observed starting from 10 minutes post-inoculation (data not shown). PRRSV bound to the surface of the macrophages did not colocalize with CD163. However, internalized virus particles ended up in CD163 positive endosomes. Starting from 45 minutes after inoculation, endosomes disappeared and PRRSV and CD163 started to separate.

[0131] The surprising observation that PRRSV and CD163 colocalize in endosomes, this in contrast to Sn which colocalizes with PRRSV on the cell surface, further shows that CD163 is not involved in PRRSV attachment to macrophages, but rather has a role in virus fusion and uncoating inside the cell in endosomes.

8. Binding, Internalization, Fusion and Infection of PRRSV in CHO Cells Stably Expressing Sn and CD163.

[0132] From Day 2 onward, there is little difference in the degree of infectivity of the stable CHO.sup.Sn-CD163 cells irrespective of the fact whether the PRRSV was grown on Marc-145 cells (FIG. 7A) or macrophages (FIG. 7B). Pretreatment of the cells with neuraminidase enhanced the infection of the cells with macrophage grown PRRS virus. True permissivity of the stable CHO.sup.Sn-CD163 cells was confirmed by immunostaining in the cells.

[0133] Three different CHO.sup.Sn-CD163 cell clones (IC5, ID9 and IF3) were seeded at 200 000 cells/ml in a 24-well plate with insert. After two days, the cells were inoculated with LV grown on marc cells or with inactivated LV grown on marc cells. The cells were fixed with methanol after 1 hour at 4.degree. C. (binding, at 4.degree. C. virus is not able to internalize), 1 hour at 37.degree. C. (internalization), 5 hours at 37.degree. C. (fusion, this means that virus particles are dismantled, as a consequence virus staining disappears), 12 hours at 37.degree. C. (infection) and 24 hours at 37.degree. C. (infection). The virus was stained with a primary antibody P3/27 and a secondary antibody goat-anti-mouse FITC. The virus particles were counted with a confocal microscope.

TABLE-US-00001 TABLE 1 Binding, internalization, fusion and infection of LV (control) and inactivated LV in three different CHO.sup.Sn-CD163 cell lines (IC5, ID9 and IF3) Control BEI UV IC5 ID9 IF3 IC5 ID9 IF3 IC5 ID9 IF3 Binding 14 12 7 18 9 10 5 6 5 (particles) Internalization 41 31 31 38 34 25 35 23 24 (particles) Fusion 3 2 2 1 1 2 0 0 0 (particles) Infection 0 0 0 0 0 0 0 0 0 12 hpi (%) Infection 5 2 2 0 0 0 0 0 0 24 hpi (%)

[0134] As shown in the aforementioned table, LV marc grown virus can perform a complete virus cycle in the three CHO.sup.Sn-CD163 cell lines. First, the virus particles bind to the cells, then virus particles enter the cells, after which the particles are dismantled to release the genome. Finally infection occurs. Clearly, this shows that the infection route of PRRSV in these cells mimics the infection observed in the in vivo target cells, the macrophages. LV inactivated with BEI and UV show binding, internalization and fusion identical to the non-inactivated LV, but there is no infection, so these methods are good candidates for vaccine development. These results clearly demonstrate the use of the stable CHO.sup.Sn-CD163 cell lines, in studying and optimizing viral inactivation processes as part of vaccine production, and accordingly provide an interesting alternative for the less accessible natural host cells.

9. Intracellular and Extracellular Virus Production on Cells Infected Two Days Post-Seeding.

[0135] Further evidence for the permissivity of the stable CHO.sup.Sn-CD163 cells was shown when analyzing the intracellular and extracellular virus production in the cells by titrating the produced virus not only on the CHO.sup.Sn-CD163 cells, but also on the natural host (alveolar macrophages) and the Marc-145 cells known to sustain PRRSV infection. CHO.sup.Sn-CD163 clone IC5 was infected two days post-seeding with LV grown on marc cells, VR grown on marc cells, 94V360 grown on macrophages, similar to the infection procedures described hereinbefore. Pretreatment of the cells with neuraminidase was also included for infection with PRRSV 94V360 grown on macrophages. Titration of extracellular (extra) and intracellular (intra) was done at three days (Table 2) and five days (Table 3) post-inoculation, respectively, and expressed as log.sub.10 units of the TCID.sub.50/ml.

TABLE-US-00002 TABLE 2 Titration on different cells types (Marc-145, macrophages and CHO.sup.Sn-CD163 clone IC5) of intra - and extra-cellular virus production 3 days post-inoculation. 94V360 LV VR 94V360 macrophage + marc marc macrophage neuraminidase Extra on marc cells 4.3 4.8 / 3.8 Extra on macrophages 4.3 5.3 4.8 5.3 Extra on CHO.sup.Sn-CD163 3.3 4.8 2.8 4.3 Intra on marc cells 4.8 5.8 2.1 3.3 Intra on macrophages 4.3 5.3 3.8 4.8 Intra on CHO.sup.Sn-CD163 3.8 5.3 / 3.8

TABLE-US-00003 TABLE 3 Titration on different cells types (Marc-145, macrophages and CHO.sup.Sn-CD163 clone IC5) of intra- and extra-cellular virus production five days post-inoculation. 94V360 LV VR 94V360 macrophage + marc marc macrophage neuraminidase Extra on marc cells 4.3 5.3 / 3.8 Extra on macrophages 5.55 5.3 4.8 5.3 Extra on CHO.sup.Sn-CD163 2.1 4.8 3.3 4.8 Intra on marc cells 3.1 4.0 2.1 2.8 Intra on macrophages 3.8 4.3 4.3 3.6 Intra on CHO.sup.Sn-CD163 2.8 4.3 3.3 3.3

[0136] Together, these results clearly show that virus is produced on CHO.sup.Sn-CD163 cells and that this virus can infect not only CHO.sup.Sn-CD163 cells, but also Marc-145 cells and primary macrophages, showing that no virus adaptation had occurred during infection of CHO.sup.Sn-CD163 cells. In particular, it is interesting that for all the viruses produced in CHO.sup.Sn-CD163 cells, highest levels were always detected by titration on macrophages, again showing that no adaptation during in vitro culture had occurred that would modify virus epitopes involved in infection of macrophages and induction of neutralizing antibodies.

[0137] In conclusion these results show that the CHO.sup.Sn-CD163 cells can be used for virus production for use in vaccines or diagnosis.

REFERENCES

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Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 16 <210> SEQ ID NO 1 <211> LENGTH: 3400 <212> TYPE: DNA <213> ORGANISM: Sus scrofa <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AJ311716 <309> DATABASE ENTRY DATE: 2005-04-15 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(3400) <400> SEQUENCE: 1 atggtgctac ttgaagactc tggatctgca gactttagaa gatgttctgc ccatttaagt 60 tccttcactt ttgctgtagt cgctgttctc agtgcctgct tggtcactag ttctcttgga 120 ggaaaagaca aggagctgag gctaacgggt ggtgaaaaca agtgctctgg aagagtggag 180 gtgaaagtgc aggaggagtg gggaactgtg tgtaataatg gctgggacat ggatgtggtc 240 tctgttgttt gtaggcagct gggatgtcca actgctatca aagccactgg atgggctaat 300 tttagtgcag gttctggacg catttggatg gatcatgttt cttgtcgagg gaatgagtca 360 gctctctggg actgcaaaca tgatggatgg ggaaagcata actgtactca ccaacaggat 420 gctggagtaa cctgctcaga tggatctgat ttagagatga ggctggtgaa tggaggaaac 480 cggtgcttag gaagaataga agtcaaattt caagagcggt ggggaacagt gtgtgatgat 540 aacttcaaca taaatcatgc ttctgtggtt tgtaaacaac ttgaatgtgg aagtgctgtc 600 agtttctctg gttcagctaa ttttggagaa ggttctggac caatctggtt tgatgatctt 660 gtatgcaatg gaaatgagtc agctctctgg aactgcaaac atgaaggatg gggaaagcac 720 aattgcgatc atgctgagga tgctggagtg atttgcttaa atggagcaga cctgaaactg 780 agagtggtag atggactcac tgaatgttca ggaagattgg aagtgaaatt ccaaggagaa 840 tggggaacaa tctgtgatga tggctgggat agtgatgatg ccgctgtggc atgtaagcaa 900 ctgggatgtc caactgctgt cactgccatt ggtcgagtta acgccagtga gggaactgga 960 cacatttggc ttgacagtgt ttcttgccat ggacacgagt ctgctctctg gcagtgtaga 1020 caccatgaat ggggaaagca ttattgcaat cataatgaag atgctggtgt gacatgttct 1080 gatggatcag atctggaact gagacttaaa ggtggaggca gccactgtgc tgggacagtg 1140 gaggtggaaa ttcagaaact ggtaggaaaa gtgtgtgata gaagctgggg actgaaagaa 1200 gctgatgtgg tttgcaggca gctgggatgt ggatctgcac tcaaaacatc atatcaagtt 1260 tattccaaaa ccaaggcaac aaacacatgg ctgtttgtaa gcagctgtaa tggaaatgaa 1320 acttctcttt gggactgcaa gaattggcag tggggtggac ttagttgtga tcactatgac 1380 gaagccaaaa ttacctgctc agcccacagg aaacccaggc tggttggagg ggacattccc 1440 tgctctggtc gtgttgaagt acaacatgga gacacgtggg gcaccgtctg tgattctgac 1500 ttctctctgg aggcggccag cgtgctgtgc agggaactac agtgcggcac tgtggtttcc 1560 ctcctggggg gagctcactt tggagaagga agtggacaga tctgggctga agaattccag 1620 tgtgaggggc acgagtccca cctttcactc tgcccagtag caccccgccc tgacgggaca 1680 tgtagccaca gcagggacgt cggcgtagtc tgctcaagat acacacaaat ccgcttggtg 1740 aatggcaaga ccccatgtga aggaagagtg gagctcaaca ttcttgggtc ctgggggtcc 1800 ctctgcaact ctcactggga catggaagat gcccatgttt tatgccagca gcttaaatgt 1860 ggagttgccc tttctatccc gggaggagca ccttttggga aaggaagtga gcaggtctgg 1920 aggcacatgt ttcactgcac tgggactgag aagcacatgg gagattgttc cgtcactgct 1980 ctgggcgcat cactctgttc ttcagggcaa gtggcctctg taatctgctc agggaaccag 2040 agtcagacac tatccccgtg caattcatca tcctcggacc catcaagctc tattatttca 2100 gaagaaagtg gtgttgcctg catagggagt ggtcaacttc gcctggtcga tggaggtggt 2160 cgttgtgctg ggagagtaga ggtctatcct ggggcatcct ggggcaccat ctgtgatgac 2220 agctgggacc tgaatgatgc ccatgtggtg tgcaaacagc tgagctgtgg atgggccatt 2280 aatgccactg gttctgctca ttttggggaa ggaacagggc ccatttggct ggatgagata 2340 aactgtaatg gaaaagaatc tcatatttgg caatgccact cacatggttg ggggcggcac 2400 aattgcaggc ataaggagga tgcaggagtc atctgctcag agttcatgtc tctgagactg 2460 atcagtgaaa acagcagaga gacctgtgca gggcgcctgg aagtttttta caacggagct 2520 tggggcagcg ttggcaggaa tagcatgtct ccagccacag tgggggtggt atgcaggcag 2580 ctgggctgtg cagacagagg ggacatcagc cctgcatctt cagacaagac agtgtccagg 2640 cacatgtggg tggacaatgt tcagtgtcct aaaggacctg acacactatg gcagtgcccc 2700 tcatctccat ggaagaagag actggccagc ccctcagagg agacatggat cacatgtgcc 2760 aacaaaataa gacttcaaga aggaaacact aattgttctg gacgtgtgga gatctggtac 2820 ggaggttcct ggggcactgt gtgtgacgac tcctgggacc ttgaagatgc tcaggtggtg 2880 tgccgacagc tgggctgtgg ctcagctttg gaggcaggaa aagagcccgc atttggccag 2940 gggactgggc ccatatggct caatgaagtg aagtgcaagg ggaatgaacc ctccttgtgg 3000 gattgtcctg ccagatcctg gggccacagt gactgtggac acaaggagga tgctgctgtg 3060 acgtgctcag aaattgcaaa gagccgagaa tccctacatg ccacaggtcg ctcatctttt 3120 gttgcacttg caatctttgg ggtcattctg ttggcctgtc tcatcgcatt cctcatttgg 3180 actcagaagc gaagacagag gcagcggctc tcagttttct caggaggaga gaattctgtc 3240 catcaaattc aataccggga gatgaattct tgcctgaaag cagatgaaac ggatatgcta 3300 aatccctcag gagaccactc tgaagtacaa tgaaaaggaa aatgggaatt ataacctggt 3360 gagttcagcc tttaagatac cttgatgaag acctggacta 3400 <210> SEQ ID NO 2 <211> LENGTH: 1115 <212> TYPE: PRT <213> ORGANISM: Sus scrofa <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/CAC84397 <309> DATABASE ENTRY DATE: 2005-04-15 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1115) <400> SEQUENCE: 2 Met Asp Lys Leu Arg Met Val Leu His Glu Asn Ser Gly Ser Ala Asp 1 5 10 15 Phe Arg Arg Cys Ser Ala His Leu Ser Ser Phe Thr Phe Ala Val Val 20 25 30 Ala Val Leu Ser Ala Cys Leu Val Thr Ser Ser Leu Gly Gly Lys Asp 35 40 45 Lys Glu Leu Arg Leu Thr Gly Gly Glu Asn Lys Cys Ser Gly Arg Val 50 55 60 Glu Val Lys Val Gln Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp 65 70 75 80 Asp Met Asp Val Val Ser Val Val Cys Arg Gln Leu Gly Cys Pro Thr 85 90 95 Ala Ile Lys Ala Thr Gly Trp Ala Asn Phe Ser Ala Gly Ser Gly Arg 100 105 110 Ile Trp Met Asp His Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp 115 120 125 Asp Cys Lys His Asp Gly Trp Gly Lys His Asn Cys Thr His Gln Gln 130 135 140 Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asp Leu Glu Met Gly Leu 145 150 155 160 Val Asn Gly Gly Asn Arg Cys Leu Gly Arg Ile Glu Val Lys Phe Gln 165 170 175 Gly Arg Trp Gly Thr Val Cys Asp Asp Asn Phe Asn Ile Asn His Ala 180 185 190 Ser Val Val Cys Lys Gln Leu Glu Cys Gly Ser Ala Val Ser Phe Ser 195 200 205 Gly Ser Ala Asn Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp Asp 210 215 220 Leu Val Cys Asn Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His Glu 225 230 235 240 Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Ala Gly Val Ile 245 250 255 Cys Leu Asn Gly Ala Asp Leu Lys Leu Arg Val Val Asp Gly Val Thr 260 265 270 Glu Cys Ser Gly Arg Leu Glu Val Lys Phe Gln Gly Glu Trp Gly Thr 275 280 285 Ile Cys Asp Asp Gly Trp Asp Ser Asp Asp Ala Ala Val Ala Cys Lys 290 295 300 Gln Leu Gly Cys Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn Ala 305 310 315 320 Ser Glu Gly Thr Gly His Ile Trp Leu Asp Ser Val Ser Cys His Gly 325 330 335 His Glu Ser Ala Leu Trp Gln Cys Arg His His Glu Trp Gly Lys His 340 345 350 Tyr Cys Asn His Asp Glu Asp Ala Gly Val Thr Cys Ser Asp Gly Ser 355 360 365 Asp Leu Glu Leu Arg Leu Lys Gly Gly Gly Ser His Cys Ala Gly Thr 370 375 380 Val Glu Val Glu Ile Gln Lys Leu Val Gly Lys Val Cys Asp Arg Ser 385 390 395 400 Trp Gly Leu Lys Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys Gly 405 410 415 Ser Ala Leu Lys Thr Ser Tyr Gln Val Tyr Ser Lys Thr Lys Ala Thr 420 425 430 Asn Thr Trp Leu Phe Val Ser Ser Cys Asn Gly Asn Glu Thr Ser Leu 435 440 445 Trp Asp Cys Lys Asn Trp Gln Trp Gly Gly Leu Ser Cys Asp His Tyr 450 455 460 Asp Glu Ala Lys Ile Thr Cys Ser Ala His Arg Lys Pro Arg Leu Val 465 470 475 480 Gly Gly Asp Ile Pro Cys Ser Gly Arg Val Glu Val Gln His Gly Asp 485 490 495 Thr Trp Gly Thr Val Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala Ser 500 505 510 Val Leu Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Leu Leu Gly 515 520 525 Gly Ala His Phe Gly Glu Gly Ser Gly Gln Ile Trp Ala Glu Glu Phe 530 535 540 Gln Cys Glu Gly His Glu Ser His Leu Ser Leu Cys Pro Val Ala Pro 545 550 555 560 Arg Pro Asp Gly Thr Cys Ser His Ser Arg Asp Val Gly Val Val Cys 565 570 575 Ser Arg Tyr Thr Gln Ile Arg Leu Val Asn Gly Lys Thr Pro Cys Glu 580 585 590 Gly Arg Val Glu Leu Asn Ile Leu Gly Ser Trp Gly Ser Leu Cys Asn 595 600 605 Ser His Trp Asp Met Glu Asp Ala His Val Leu Cys Gln Gln Leu Lys 610 615 620 Cys Gly Val Ala Leu Ser Ile Pro Gly Gly Ala Pro Phe Gly Lys Gly 625 630 635 640 Ser Glu Gln Val Trp Arg His Met Phe His Cys Thr Gly Thr Glu Lys 645 650 655 His Met Gly Asp Cys Ser Val Thr Ala Leu Gly Ala Ser Leu Cys Ser 660 665 670 Ser Gly Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln Thr 675 680 685 Leu Ser Pro Cys Asn Ser Ser Ser Ser Asp Pro Ser Ser Ser Ile Ile 690 695 700 Ser Glu Glu Asn Gly Val Ala Cys Ile Gly Ser Gly Gln Leu Arg Leu 705 710 715 720 Val Asp Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Val Tyr His Glu 725 730 735 Gly Ser Trp Gly Thr Ile Cys Asp Asp Ser Trp Asp Leu Asn Asp Ala 740 745 750 His Val Val Cys Lys Gln Leu Ser Cys Gly Trp Ala Ile Asn Ala Thr 755 760 765 Gly Ser Ala His Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu Asp Glu 770 775 780 Ile Asn Cys Asn Gly Lys Glu Ser His Ile Trp Gln Cys His Ser His 785 790 795 800 Gly Trp Gly Arg His Asn Cys Arg His Lys Glu Asp Ala Gly Val Ile 805 810 815 Cys Ser Glu Phe Met Ser Leu Arg Leu Ile Ser Glu Asn Ser Arg Glu 820 825 830 Thr Cys Ala Gly Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp Gly Ser 835 840 845 Val Gly Arg Asn Ser Met Ser Pro Ala Thr Val Gly Val Val Cys Arg 850 855 860 Gln Leu Gly Cys Ala Asp Arg Gly Asp Ile Ser Pro Ala Ser Ser Asp 865 870 875 880 Lys Thr Val Ser Arg His Met Trp Val Asp Asn Val Gln Cys Pro Lys 885 890 895 Gly Pro Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Lys Lys Arg 900 905 910 Leu Ala Ser Pro Ser Glu Glu Thr Trp Ile Thr Cys Ala Asn Lys Ile 915 920 925 Arg Leu Gln Glu Gly Asn Thr Asn Cys Ser Gly Arg Val Glu Ile Trp 930 935 940 Tyr Gly Gly Ser Trp Gly Thr Val Cys Asp Asp Ser Trp Asp Leu Glu 945 950 955 960 Asp Ala Gln Val Val Cys Arg Gln Leu Gly Cys Gly Ser Ala Leu Glu 965 970 975 Ala Gly Lys Glu Ala Ala Phe Gly Gln Gly Thr Gly Pro Ile Trp Leu 980 985 990 Asn Glu Val Lys Cys Lys Gly Asn Glu Thr Ser Leu Trp Asp Cys Pro 995 1000 1005 Ala Arg Ser Trp Gly His Ser Asp Cys Gly His Lys Glu Asp Ala 1010 1015 1020 Ala Val Thr Cys Ser Glu Ile Ala Lys Ser Arg Glu Ser Leu His 1025 1030 1035 Ala Thr Gly Arg Ser Ser Phe Val Ala Leu Ala Ile Phe Gly Val 1040 1045 1050 Ile Leu Leu Ala Cys Leu Ile Ala Phe Leu Ile Trp Thr Gln Lys 1055 1060 1065 Arg Arg Gln Arg Gln Arg Leu Ser Val Phe Ser Gly Gly Glu Asn 1070 1075 1080 Ser Val His Gln Ile Gln Tyr Arg Glu Met Asn Ser Cys Leu Lys 1085 1090 1095 Ala Asp Glu Thr Asp Met Leu Asn Pro Ser Gly Asp His Ser Glu 1100 1105 1110 Val Gln 1115 <210> SEQ ID NO 3 <211> LENGTH: 4405 <212> TYPE: DNA <213> ORGANISM: mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AF274883 <309> DATABASE ENTRY DATE: 2001-05-10 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(4405) <400> SEQUENCE: 3 gtggtcatcc actttctaca gagaacacgt ctatgaaata gtatcaggag acacacggag 60 ccatcaaaat catcaagctt tggaatgggt ggacacagaa tggttcttct tggaggtgct 120 ggatctcctg gttgtaaaag gtttgtccat ctaggtttct ttgttgtggc tgtgagctca 180 cttctcagtg cctctgctgt cactaacgct cctggagaaa tgaagaagga actgagactg 240 gcgggtggtg aaaacaactg tagtgggaga gtggaactta agatccatga caagtggggc 300 acagtgtgca gtaacggctg gagcatgaat gaagtgtccg tggtttgcca gcagctggga 360 tgcccaactt ctattaaagc ccttggatgg gctaactcca gcgccggctc tggatatatc 420 tggatggaca aagtttcttg tacagggaat gagtcagctc tttgggactg caaacatgat 480 gggtggggaa agcataactg tacccatgaa aaagatgctg gagtgacctg ctcagatgga 540 tctaatttgg agatgagact ggtgaacagt gcgggccacc gatgcttagg aagagtagaa 600 ataaagttcc agggaaagtg ggggacggtg tgtgacgaca acttcagcaa agatcacgct 660 tctgtgattt gtaaacagct tggatgtgga agtgccatta gtttctctgg ctcagctaaa 720 ttgggagctg gttctggacc aatctggctc gatgacctgg catgcaatgg aaatgagtca 780 gctctctggg actgcaaaca ccggggatgg ggcaagcata actgtgacca tgctgaggat 840 gtcggtgtga tttgcttaga gggagcagat ctgagcctga gactagtgga tggagtgtcc 900 agatgttcag gaagattgga agtgagattc caaggagaat gggggaccgt gtgtgatgat 960 aactgggatc tccgggatgc ttctgtggtg tgcaagcaac tgggatgtcc aactgccatc 1020 agtgccattg gtcgagttaa tgccagtgag ggatctggac agatttggct tgacaacatt 1080 tcatgcgaag gacatgaggc aactctttgg gagtgtaaac accaagagtg gggaaagcat 1140 tactgtcatc atagagaaga cgctggtgtg acatgttctg atggagcaga tctggaactt 1200 agacttgtag gtggaggcag tcgctgtgct ggcattgtgg aggtggagat tcagaagctg 1260 actgggaaga tgtgtagccg aggctggaca ctggcagatg cggatgtggt ttgcagacag 1320 cttggatgtg gatctgcgct tcaaacccag gctaagatct actctaaaac tggggcaaca 1380 aatacgtggc tctttcctgg atcttgtaat ggaaatgaaa ctactttttg gcaatgcaaa 1440 aactggcagt ggggcggcct ttcctgtgat aatttcgaag aagccaaagt tacctgctca 1500 ggccacaggg aacccagact ggttggagga gaaatcccat gctctggtcg tgtggaagtg 1560 aaacacggag acgtgtgggg ctccgtctgt gattttgact tgtctctgga agctgccagt 1620 gtggtgtgca gggaattaca atgtggaaca gtcgtctcta tcctaggggg agcacatttt 1680 ggagaaggaa gtggacagat ctggggtgaa gaattccagt gtagtgggga tgagtcccat 1740 ctttcactat gctcagtggc gcccccgcta gacagaactt gtacccacag cagggatgtc 1800 agcgtagtct gctcacgata catagatatt cgtctggcag gcggcgagtc ctcctgtgag 1860 ggaagagtgg agctcaagac actcggagcc tggggtcccc tctgcagttc tcattgggac 1920 atggaagatg ctcatgtctt atgtcagcag ctgaagtgtg gggttgccca atctattcca 1980 gaaggagcac attttgggaa aggagctggt caggtctgga gtcacatgtt ccactgcact 2040 ggaactgagg aacatatagg agattgcctc atgactgctc tgggtgcgcc gacgtgttcc 2100 gaaggacagg tggcctctgt catctgctca ggaaaccaat cccagacact attgccatgt 2160 agttcattgt ctccagtcca aacaacaagc tctacaattc caaaggagag tgaagttccc 2220 tgcatagcaa gtggccagct tcgcttggta ggtggaggtg gtcgctgcgc tggaagagtg 2280 gaggtctgcc acgagggctc ttggggcacc gtctgtgatg acaattggga tatgactgat 2340 gccaatgtgg tgtgcaagca gctggactgt ggcgtggcaa ttaacgccac tggctctgct 2400 tacttcgggg aaggagcagg agctatctgg ctagacgaag tcatctgcac tgggaaagag 2460 tctcatattt ggcagtgcca ttcacatggc tggggacgcc ataactgcag gcacaaagaa 2520 gatgcaggtg ttatctgctc cgagttcatg tctctgaggc tgaccaacga agcccacaaa 2580 gaaaactgca caggtcgcct tgaagtgttt tacaatggta catggggcag tattggcagt 2640 agcaatatgt ctccaaccac tgtgggggtg gtgtgccgtc agctgggctg tgcagacaac 2700 gggactgtga aacccatacc ttcagacaag acaccatcca ggcccatgtg ggtagatcgt 2760 gtgcagtgtc caaaaggagt tgacactttg tggcagtgcc cctcgtcacc ttggaaacag 2820 agacaggcca gcccctcctc ccaggagtcc tggatcatct gtgacaacaa aataagactc 2880 caggaagggc atacagactg ttctggacgt gtggagatct ggcacaaagg ttcctgggga 2940 acagtgtgtg atgactcctg ggatcttaat gatgctaagg ttgtatgtaa gcagttgggc 3000 tgtggccaag ctgtgaaggc actaaaagaa gcagcatttg gtccaggaac tgggcccata 3060 tggctcaatg aaattaagtg tagagggaat gagtcttccc tgtgggattg tcctgccaaa 3120 ccgtggagtc acagcgactg tgggcacaaa gaagatgctt ccatccagtg cctcccaaaa 3180 atgacttcag aatcacatca tggcacaggt caccccaccc tcacggcact cttggtttgt 3240 ggagccattc tattggtcct cctcattgtc ttcctcctgt ggactctgaa gcgacgacgg 3300 attcagcgac ttacagtttc ctcaagagga gaggtcttga tacatcaagt tcagtaccaa 3360 gagatggatt caaaggcgga tgatctggac ttgctgaaat cctcgggggt cattcagagg 3420 cacactgaga aggaaaatga taatttataa tccactgagg ttggagttta agaagccttg 3480 acaggacagc cagctaaatg gaacaagagc ccaggcaacg cacggatgac cacagctgca 3540 tcttcatgca gtcctttgtt tcctggaact ctgctgaacc tgcaaaaacc atatttgtga 3600 atgtgaccac ttaatagaga tgggagactt ttgagggaat taaacaatat tgctattggt 3660 ttgcttgttc gcaatagggt ctcattatgt atagccctgg agatggcgat agagagcagg 3720 caagcctaga attcacagag atctgcttgt ctctgcttcc caaatgctgg gatcaaatat 3780 gtggaccacc acatgtggtt taacaattgt gtcttgattt tataaatttc tggttggttt 3840 ttctgacgtt tttagggttt cgtgaatata aaataatgtc ttttcggttg gcatgctaat 3900 ttttaaatat tatacacttc cttgtagtga gtttaagaat aatttcttat aaccaagtca 3960 attcattttc actttgaatt atttaataaa ggaatatggt cattgtgacc acacacacag 4020 cagttgtgac cgcctgtatg aggccttcaa aaaatatttt aaaaatagag ggctggagaa 4080 atggctcaga ggtcctgagt tcaattccta gcaaccacat ggtggctcac aaccatctgt 4140 aatgggaatc cgatgccctc ttccagtgta tctgaagata gtgacactgt cctcattaac 4200 ataaaataaa taaataaatc tttaaaaaaa gaaaagacaa tagaggaggg gaggggcgtg 4260 agcgtaggag tgaggactga ttgagaagaa ggttggagga agtgggggga ggtgaaaagc 4320 tagttgggaa cttatgtgat cacagtgcat catgtccaaa tatgacatgt ccaaaaatgt 4380 tattaataaa gaaacggaaa tcaaa 4405 <210> SEQ ID NO 4 <211> LENGTH: 1121 <212> TYPE: PRT <213> ORGANISM: Mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/AAK16065 <309> DATABASE ENTRY DATE: 2001-05-10 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1121) <400> SEQUENCE: 4 Met Gly Gly His Arg Met Val Leu Leu Gly Gly Ala Gly Ser Pro Gly 1 5 10 15 Cys Lys Arg Phe Val His Leu Gly Phe Phe Val Val Ala Val Ser Ser 20 25 30 Leu Leu Ser Ala Ser Ala Val Thr Asn Ala Pro Gly Glu Met Lys Lys 35 40 45 Glu Leu Arg Leu Ala Gly Gly Glu Asn Asn Cys Ser Gly Arg Val Glu 50 55 60 Leu Lys Ile His Asp Lys Trp Gly Thr Val Cys Ser Asn Gly Trp Ser 65 70 75 80 Met Asn Glu Val Ser Val Val Cys Gln Gln Leu Gly Cys Pro Thr Ser 85 90 95 Ile Lys Ala Leu Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Tyr Ile 100 105 110 Trp Met Asp Lys Val Ser Cys Thr Gly Asn Glu Ser Ala Leu Trp Asp 115 120 125 Cys Lys His Asp Gly Trp Gly Lys His Asn Cys Thr His Glu Lys Asp 130 135 140 Ala Gly Val Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg Leu Val 145 150 155 160 Asn Ser Ala Gly His Arg Cys Leu Gly Arg Val Glu Ile Lys Phe Gln 165 170 175 Gly Lys Trp Gly Thr Val Cys Asp Asp Asn Phe Ser Lys Asp His Ala 180 185 190 Ser Val Ile Cys Lys Gln Leu Gly Cys Gly Ser Ala Ile Ser Phe Ser 195 200 205 Gly Ser Ala Lys Leu Gly Ala Gly Ser Gly Pro Ile Trp Leu Asp Asp 210 215 220 Leu Ala Cys Asn Gly Asn Glu Ser Ala Leu Trp Asp Cys Lys His Arg 225 230 235 240 Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Val Gly Val Ile 245 250 255 Cys Leu Glu Gly Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val Ser 260 265 270 Arg Cys Ser Gly Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly Thr 275 280 285 Val Cys Asp Asp Asn Trp Asp Leu Arg Asp Ala Ser Val Val Cys Lys 290 295 300 Gln Leu Gly Cys Pro Thr Ala Ile Ser Ala Ile Gly Arg Val Asn Ala 305 310 315 320 Ser Glu Gly Ser Gly Gln Ile Trp Leu Asp Asn Ile Ser Cys Glu Gly 325 330 335 His Glu Ala Thr Leu Trp Glu Cys Lys His Gln Glu Trp Gly Lys His 340 345 350 Tyr Cys His His Arg Glu Asp Ala Gly Val Thr Cys Ser Asp Gly Ala 355 360 365 Asp Leu Glu Leu Arg Leu Val Gly Gly Gly Ser Arg Cys Ala Gly Ile 370 375 380 Val Glu Val Glu Ile Gln Lys Leu Thr Gly Lys Met Cys Ser Arg Gly 385 390 395 400 Trp Thr Leu Ala Asp Ala Asp Val Val Cys Arg Gln Leu Gly Cys Gly 405 410 415 Ser Ala Leu Gln Thr Gln Ala Lys Ile Tyr Ser Lys Thr Gly Ala Thr 420 425 430 Asn Thr Trp Leu Phe Pro Gly Ser Cys Asn Gly Asn Glu Thr Thr Phe 435 440 445 Trp Gln Cys Lys Asn Trp Gln Trp Gly Gly Leu Ser Cys Asp Asn Phe 450 455 460 Glu Glu Ala Lys Val Thr Cys Ser Gly His Arg Glu Pro Arg Leu Val 465 470 475 480 Gly Gly Glu Ile Pro Cys Ser Gly Arg Val Glu Val Lys His Gly Asp 485 490 495 Val Trp Gly Ser Val Cys Asp Phe Asp Leu Ser Leu Glu Ala Ala Ser 500 505 510 Val Val Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu Gly 515 520 525 Gly Ala His Phe Gly Glu Gly Ser Gly Gln Ile Trp Gly Glu Glu Phe 530 535 540 Gln Cys Ser Gly Asp Glu Ser His Leu Ser Leu Cys Ser Val Ala Pro 545 550 555 560 Pro Leu Asp Arg Thr Cys Thr His Ser Arg Asp Val Ser Val Val Cys 565 570 575 Ser Arg Tyr Ile Asp Ile Arg Leu Ala Gly Gly Glu Ser Ser Cys Glu 580 585 590 Gly Arg Val Glu Leu Lys Thr Leu Gly Ala Trp Gly Pro Leu Cys Ser 595 600 605 Ser His Trp Asp Met Glu Asp Ala His Val Leu Cys Gln Gln Leu Lys 610 615 620 Cys Gly Val Ala Gln Ser Ile Pro Glu Gly Ala His Phe Gly Lys Gly 625 630 635 640 Ala Gly Gln Val Trp Ser His Met Phe His Cys Thr Gly Thr Glu Glu 645 650 655 His Ile Gly Asp Cys Leu Met Thr Ala Leu Gly Ala Pro Thr Cys Ser 660 665 670 Glu Gly Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln Thr 675 680 685 Leu Leu Pro Cys Ser Ser Leu Ser Pro Val Gln Thr Thr Ser Ser Thr 690 695 700 Ile Pro Lys Glu Ser Glu Val Pro Cys Ile Ala Ser Gly Gln Leu Arg 705 710 715 720 Leu Val Gly Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Val Tyr His 725 730 735 Glu Gly Ser Trp Gly Thr Val Cys Asp Asp Asn Trp Asp Met Thr Asp 740 745 750 Ala Asn Val Val Cys Lys Gln Leu Asp Cys Gly Val Ala Ile Asn Ala 755 760 765 Thr Gly Ser Ala Tyr Phe Gly Glu Gly Ala Gly Ala Ile Trp Leu Asp 770 775 780 Glu Val Ile Cys Thr Gly Lys Glu Ser His Ile Trp Gln Cys His Ser 785 790 795 800 His Gly Trp Gly Arg His Asn Cys Arg His Lys Glu Asp Ala Gly Val 805 810 815 Ile Cys Ser Glu Phe Met Ser Leu Arg Leu Thr Asn Glu Ala His Lys 820 825 830 Glu Ser Cys Thr Gly Arg Leu Glu Val Phe Tyr Asn Gly Thr Trp Gly 835 840 845 Ser Ile Gly Ser Ser Asn Met Ser Pro Thr Thr Val Gly Val Val Cys 850 855 860 Arg Gln Leu Gly Cys Ala Asp Asn Gly Thr Val Lys Pro Ile Pro Ser 865 870 875 880 Asp Lys Thr Pro Ser Arg Pro Met Trp Val Asp Arg Val Gln Cys Pro 885 890 895 Lys Gly Val Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Lys Gln 900 905 910 Arg Gln Ala Ser Pro Ser Ser Gln Glu Ser Trp Ile Ile Cys Asp Asn 915 920 925 Lys Ile Arg Leu Gln Glu Gly His Thr Asp Cys Ser Gly Arg Val Glu 930 935 940 Ile Trp His Lys Gly Phe Trp Gly Thr Val Cys Asp Asp Ser Trp Asp 945 950 955 960 Leu Asn Asp Ala Lys Val Val Cys Lys Gln Leu Gly Cys Gly Gln Ala 965 970 975 Val Lys Ala Leu Lys Glu Ala Ala Phe Gly Pro Gly Thr Gly Pro Ile 980 985 990 Trp Leu Asn Glu Ile Lys Cys Arg Gly Asn Glu Ser Ser Leu Trp Asp 995 1000 1005 Cys Pro Ala Lys Pro Trp Ser His Ser Asp Cys Gly His Lys Glu 1010 1015 1020 Asp Ala Ser Ile Gln Cys Leu Pro Lys Met Thr Ser Glu Ser His 1025 1030 1035 His Gly Thr Gly His Pro Thr Leu Thr Ala Leu Leu Val Cys Gly 1040 1045 1050 Ala Ile Leu Leu Val Leu Leu Ile Val Phe Leu Leu Trp Thr Leu 1055 1060 1065 Lys Arg Arg Gln Ile Gln Arg Leu Thr Val Ser Ser Arg Gly Glu 1070 1075 1080 Val Leu Ile His Gln Val Gln Tyr Gln Glu Met Asp Ser Lys Ala 1085 1090 1095 Asp Asp Leu Asp Leu Leu Lys Ser Ser Gly Val Ile Gln Arg His 1100 1105 1110 Thr Glu Lys Glu Asn Asp Asn Leu 1115 1120 <210> SEQ ID NO 5 <211> LENGTH: 3780 <212> TYPE: DNA <213> ORGANISM: homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/BC051281 <309> DATABASE ENTRY DATE: 2006-07-15 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(3780) <400> SEQUENCE: 5 aacatttcta gggaataata caagaagatt taggaatcat tgaagttata aatctttgga 60 atgagcaaac tcagaatggt gctacttgaa gactctggat ctgctgactt cagaagacat 120 tttgtcaact tgagtccctt caccattact gtggtcttac ttctcagtgc ctgttttgtc 180 accagttctc ttggaggaac agacaaggag ctgaggctag tggatggtga aaacaagtgt 240 agcgggagag tggaagtgaa agtccaggag gagtggggaa cggtgtgtaa taatggctgg 300 agcatggaag cggtctctgt gatttgtaac cagctgggat gtccaactgc tatcaaagcc 360 cctggatggg ctaattccag tgcaggttct ggacgcattt ggatggatca tgtttcttgt 420 cgtgggaatg agtcagctct ttgggattgc aaacatgatg gatggggaaa gcatagtaac 480 tgtactcacc aacaagatgc tggagtgacc tgctcagatg gatccaattt ggaaatgagg 540 ctgacgcgtg gagggaatat gtgttctgga agaatagaga tcaaattcca aggacggtgg 600 ggaacagtgt gtgatgataa cttcaacata gatcatgcat ctgtcatttg tagacaactt 660 gaatgtggaa gtgctgtcag tttctctggt tcatctaatt ttggagaagg ctctggacca 720 atctggtttg atgatcttat atgcaacgga aatgagtcag ctctctggaa ctgcaaacat 780 caaggatggg gaaagcataa ctgtgatcat gctgaggatg ctggagtgat ttgctcaaag 840 ggagcagatc tgagcctgag actggtagat ggagtcactg aatgttcagg aagattagaa 900 gtgagattcc aaggagaatg ggggacaata tgtgatgacg gctgggacag ttacgatgct 960 gctgtggcat gcaagcaact gggatgtcca actgccgtca cagccattgg tcgagttaac 1020 gccagtaagg gatttggaca catctggctt gacagcgttt cttgccaggg acatgaacct 1080 gctgtctggc aatgtaaaca ccatgaatgg ggaaagcatt attgcaatca caatgaagat 1140 gctggcgtga catgttctga tggatcagat ctggagctaa gacttagagg tggaggcagc 1200 cgctgtgctg ggacagttga ggtggagatt cagagactgt tagggaaggt gtgtgacaga 1260 ggctggggac tgaaagaagc tgatgtggtt tgcaggcagc tgggatgtgg atctgcactc 1320 aaaacatctt atcaagtgta ctccaaaatc caggcaacaa acacatggct gtttctaagt 1380 agctgtaacg gaaatgaaac ttctctttgg gactgcaaga actggcaatg gggtggactt 1440 acctgtgatc actatgaaga agccaaaatt acctgctcag cccacaggga acccagactg 1500 gttggagggg acattccctg ttctggacgt gttgaagtga agcatggtga cacgtggggc 1560 tccatctgtg attcggactt ctctctggaa gctgccagcg ttctatgcag ggaattacag 1620 tgtggcacag ttgtctctat cctgggggga gctcactttg gagagggaaa tggacagatc 1680 tgggctgaag aattccagtg tgagggacat gagtcccatc tttcactctg cccagtagca 1740 ccccgcccag aaggaacttg tagccacagc agggatgttg gagtagtctg ctcaagatac 1800 acagaaattc gcttggtgaa tggcaagacc ccgtgtgagg gcagagtgga gctcaaaacg 1860 cttggtgcct ggggatccct ctgtaactct cactgggaca tagaagatgc ccatgttctt 1920 tgccagcagc ttaaatgtgg agttgccctt tctaccccag gaggagcacg ttttggaaaa 1980 ggaaatggtc agatctggag gcatatgttt cactgcactg ggactgagca gcacatggga 2040 gattgtcctg taactgctct aggtgcttca ttatgtcctt cagagcaagt ggcctctgta 2100 atctgctcag gaaaccagtc ccaaacactg tcctcgtgca attcatcgtc tttgggccca 2160 acaaggccta ccattccaga agaaagtgct gtggcctgca tagagagtgg tcaacttcgc 2220 ctggtaaatg gaggaggtcg ctgtgctggg agagtagaga tctatcatga gggctcctgg 2280 ggcaccatct gtgatgacag ctgggacctg agtgatgccc acgtggtttg cagacagctg 2340 ggctgtggag aggccattaa tgccactggt tctgctcatt ttggggaagg aacagggccc 2400 atctggctgg atgagatgaa atgcaatgga aaagaatccc gcatttggca gtgccattca 2460 cacggctggg ggcagcaaaa ttgcaggcac aaggaggatg cgggagttat ctgctcagaa 2520 ttcatgtctc tgagactgac cagtgaagcc agcagagagg cctgtgcagg gcgtctggaa 2580 gttttttaca atggagcttg gggcactgtt ggcaagagta gcatgtctga aaccactgtg 2640 ggtgtggtgt gcaggcagct gggctgtgca gacaaaggga aaatcaaccc tgcatcttta 2700 gacaaggcca tgtccattcc catgtgggtg gacaatgttc agtgtccaaa aggacctgac 2760 acgctgtggc agtgcccatc atctccatgg gagaagagac tggccagccc ctcggaggag 2820 acctggatca catgtgacaa caagataaga cttcaggaag gacccacttc ctgttctgga 2880 cgtgtggaga tctggcatgg aggttcctgg gggacagtgt gtgatgactc ttgggacttg 2940 gacgatgctc aggtggtgtg tcaacaactt ggctgtggtc cagctttgaa agcattcaaa 3000 gaagcagagt ttggtcaggg gactggaccg atatggctca atgaagtgaa gtgcaaaggg 3060 aatgagtctt ccttgtggga ttgtcctgcc agacgctggg gccatagtga gtgtgggcac 3120 aaggaagacg ctgcagtgaa ttgcacagat atttcagtgc agaaaacccc acaaaaagcc 3180 acaacaggtc gctcatcccg tcagtcatcc tttattgcag tcgggatcct tggggttgtt 3240 ctgttggcca ttttcgtcgc attattcttc ttgactaaaa agcgaagaca gagacagcgg 3300 cttgcagttt cctcaagagg agagaactta gtccaccaaa ttcaataccg ggagatgaat 3360 tcttgcctga atgcagatga tctggaccta atgaattcct cagaaaattc ccatgagtca 3420 gctgatttca gtgctgctga actaatttct gtgtctaaat ttcttcctat ttctggaatg 3480 gaaaaggagg ccattctgag ccacactgaa aaggaaaatg ggaatttata acccagtgag 3540 ttcagccttt aagatacctt gatgaagacc tggactattg aatggagcag aaattcacct 3600 ctctcactga ctattacagt tgcattttta tggagttctt cttctcctag gattcctaag 3660 actgctgctg aatttataaa aattaagttt gtgaatgtga ctacttagtg gtgtatatga 3720 gactttcaag ggaattaaat aaataaataa gaatgttatt gaaaaaaaaa aaaaaaaaaa 3780 <210> SEQ ID NO 6 <211> LENGTH: 1156 <212> TYPE: PRT <213> ORGANISM: HOMO SAPIENS <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/AAH51281 <309> DATABASE ENTRY DATE: 2006-07-15 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1156) <400> SEQUENCE: 6 Met Ser Lys Leu Arg Met Val Leu Leu Glu Asp Ser Gly Ser Ala Asp 1 5 10 15 Phe Arg Arg His Phe Val Asn Leu Ser Pro Phe Thr Ile Thr Val Val 20 25 30 Leu Leu Leu Ser Ala Cys Phe Val Thr Ser Ser Leu Gly Gly Thr Asp 35 40 45 Lys Glu Leu Arg Leu Val Asp Gly Glu Asn Lys Cys Ser Gly Arg Val 50 55 60 Glu Val Lys Val Gln Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp 65 70 75 80 Ser Met Glu Ala Val Ser Val Ile Cys Asn Gln Leu Gly Cys Pro Thr 85 90 95 Ala Ile Lys Ala Pro Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Arg 100 105 110 Ile Trp Met Asp His Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp 115 120 125 Asp Cys Lys His Asp Gly Trp Gly Lys His Ser Asn Cys Thr His Gln 130 135 140 Gln Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg 145 150 155 160 Leu Thr Arg Gly Gly Asn Met Cys Ser Gly Arg Ile Glu Ile Lys Phe 165 170 175 Gln Gly Arg Trp Gly Thr Val Cys Asp Asp Asn Phe Asn Ile Asp His 180 185 190 Ala Ser Val Ile Cys Arg Gln Leu Glu Cys Gly Ser Ala Val Ser Phe 195 200 205 Ser Gly Ser Ser Asn Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp 210 215 220 Asp Leu Ile Cys Asn Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His 225 230 235 240 Gln Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Ala Gly Val 245 250 255 Ile Cys Ser Lys Gly Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val 260 265 270 Thr Glu Cys Ser Gly Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly 275 280 285 Thr Ile Cys Asp Asp Gly Trp Asp Ser Tyr Asp Ala Ala Val Ala Cys 290 295 300 Lys Gln Leu Gly Cys Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn 305 310 315 320 Ala Ser Lys Gly Phe Gly His Ile Trp Leu Asp Ser Val Ser Cys Gln 325 330 335 Gly His Glu Pro Ala Val Trp Gln Cys Lys His His Glu Trp Gly Lys 340 345 350 His Tyr Cys Asn His Asn Glu Asp Ala Gly Val Thr Cys Ser Asp Gly 355 360 365 Ser Asp Leu Glu Leu Arg Leu Arg Gly Gly Gly Ser Arg Cys Ala Gly 370 375 380 Thr Val Glu Val Glu Ile Gln Arg Leu Leu Gly Lys Val Cys Asp Arg 385 390 395 400 Gly Trp Gly Leu Lys Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys 405 410 415 Gly Ser Ala Leu Lys Thr Ser Tyr Gln Val Tyr Ser Lys Ile Gln Ala 420 425 430 Thr Asn Thr Trp Leu Phe Leu Ser Ser Cys Asn Gly Asn Glu Thr Ser 435 440 445 Leu Trp Asp Cys Lys Asn Trp Gln Trp Gly Gly Leu Thr Cys Asp His 450 455 460 Tyr Glu Glu Ala Lys Ile Thr Cys Ser Ala His Arg Glu Pro Arg Leu 465 470 475 480 Val Gly Gly Asp Ile Pro Cys Ser Gly Arg Val Glu Val Lys His Gly 485 490 495 Asp Thr Trp Gly Ser Ile Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala 500 505 510 Ser Val Leu Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu 515 520 525 Gly Gly Ala His Phe Gly Glu Gly Asn Gly Gln Ile Trp Ala Glu Glu 530 535 540 Phe Gln Cys Glu Gly His Glu Ser His Leu Ser Leu Cys Pro Val Ala 545 550 555 560 Pro Arg Pro Glu Gly Thr Cys Ser His Ser Arg Asp Val Gly Val Val 565 570 575 Cys Ser Arg Tyr Thr Glu Ile Arg Leu Val Asn Gly Lys Thr Pro Cys 580 585 590 Glu Gly Arg Val Glu Leu Lys Thr Leu Gly Ala Trp Gly Ser Leu Cys 595 600 605 Asn Ser His Trp Asp Ile Glu Asp Ala His Val Leu Cys Gln Gln Leu 610 615 620 Lys Cys Gly Val Ala Leu Ser Thr Pro Gly Gly Ala Arg Phe Gly Lys 625 630 635 640 Gly Asn Gly Gln Ile Trp Arg His Met Phe His Cys Thr Gly Thr Glu 645 650 655 Gln His Met Gly Asp Cys Pro Val Thr Ala Leu Gly Ala Ser Leu Cys 660 665 670 Pro Ser Glu Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln 675 680 685 Thr Leu Ser Ser Cys Asn Ser Ser Ser Leu Gly Pro Thr Arg Pro Thr 690 695 700 Ile Pro Glu Glu Ser Ala Val Ala Cys Ile Glu Ser Gly Gln Leu Arg 705 710 715 720 Leu Val Asn Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Ile Tyr His 725 730 735 Glu Gly Ser Trp Gly Thr Ile Cys Asp Asp Ser Trp Asp Leu Ser Asp 740 745 750 Ala His Val Val Cys Arg Gln Leu Gly Cys Gly Glu Ala Ile Asn Ala 755 760 765 Thr Gly Ser Ala His Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu Asp 770 775 780 Glu Met Lys Cys Asn Gly Lys Glu Ser Arg Ile Trp Gln Cys His Ser 785 790 795 800 His Gly Trp Gly Gln Gln Asn Cys Arg His Lys Glu Asp Ala Gly Val 805 810 815 Ile Cys Ser Glu Phe Met Ser Leu Arg Leu Thr Ser Glu Ala Ser Arg 820 825 830 Glu Ala Cys Ala Gly Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp Gly 835 840 845 Thr Val Gly Lys Ser Ser Met Ser Glu Thr Thr Val Gly Val Val Cys 850 855 860 Arg Gln Leu Gly Cys Ala Asp Lys Gly Lys Ile Asn Pro Ala Ser Leu 865 870 875 880 Asp Lys Ala Met Ser Ile Pro Met Trp Val Asp Asn Val Gln Cys Pro 885 890 895 Lys Gly Pro Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Glu Lys 900 905 910 Arg Leu Ala Ser Pro Ser Glu Glu Thr Trp Ile Thr Cys Asp Asn Lys 915 920 925 Ile Arg Leu Gln Glu Gly Pro Thr Ser Cys Ser Gly Arg Val Glu Ile 930 935 940 Trp His Gly Gly Ser Trp Gly Thr Val Cys Asp Asp Ser Trp Asp Leu 945 950 955 960 Asp Asp Ala Gln Val Val Cys Gln Gln Leu Gly Cys Gly Pro Ala Leu 965 970 975 Lys Ala Phe Lys Glu Ala Glu Phe Gly Gln Gly Thr Gly Pro Ile Trp 980 985 990 Leu Asn Glu Val Lys Cys Lys Gly Asn Glu Ser Ser Leu Trp Asp Cys 995 1000 1005 Pro Ala Arg Arg Trp Gly His Ser Glu Cys Gly His Lys Glu Asp 1010 1015 1020 Ala Ala Val Asn Cys Thr Asp Ile Ser Val Gln Lys Thr Pro Gln 1025 1030 1035 Lys Ala Thr Thr Gly Arg Ser Ser Arg Gln Ser Ser Phe Ile Ala 1040 1045 1050 Val Gly Ile Leu Gly Val Val Leu Leu Ala Ile Phe Val Ala Leu 1055 1060 1065 Phe Phe Leu Thr Lys Lys Arg Arg Gln Arg Gln Arg Leu Ala Val 1070 1075 1080 Ser Ser Arg Gly Glu Asn Leu Val His Gln Ile Gln Tyr Arg Glu 1085 1090 1095 Met Asn Ser Cys Leu Asn Ala Asp Asp Leu Asp Leu Met Asn Ser 1100 1105 1110 Ser Glu Asn Ser His Glu Ser Ala Asp Phe Ser Ala Ala Glu Leu 1115 1120 1125 Ile Ser Val Ser Lys Phe Leu Pro Ile Ser Gly Met Glu Lys Glu 1130 1135 1140 Ala Ile Leu Ser His Thr Glu Lys Glu Asn Gly Asn Leu 1145 1150 1155 <210> SEQ ID NO 7 <211> LENGTH: 4950 <212> TYPE: DNA <213> ORGANISM: homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/Z22970 <309> DATABASE ENTRY DATE: 2005-04-18 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(4950) <400> SEQUENCE: 7 gaattcttag ttgttttctt tagaagaaca tttctaggga ataatacaag aagatttagg 60 aatcattgaa gttataaatc tttggaatga gcaaactcag aatggtgcta cttgaagact 120 ctggatctgc tgacttcaga agacattttg tcaacctgag tcccttcacc attactgtgg 180 tcttacttct cagtgcctgt tttgtcacca gttctcttgg aggaacagac aaggagctga 240 ggctagtgga tggtgaaaac aagtgtagcg ggagagtgga agtgaaagtc caggaggagt 300 ggggaacggt gtgtaataat ggctggagca tggaagcggt ctctgtgatt tgtaaccagc 360 tgggatgtcc aactgctatc aaagcccctg gatgggctaa ttccagtgca ggttctggac 420 gcatttggat ggatcatgtt tcttgtcgtg ggaatgagtc agctctttgg gattgcaaac 480 atgatggatg gggaaagcat agtaactgta ctcaccaaca agatgctgga gtgacctgct 540 cagatggatc caatttggaa atgaggctga cgcgtggagg gaatatgtgt tctggaagaa 600 tagagatcaa attccaagga cggtggggaa cagtgtgtga tgataacttc aacatagatc 660 atgcatctgt catttgtaga caacttgaat gtggaagtgc tgtcagtttc tctggttcat 720 ctaattttgg agaaggctct ggaccaatct ggtttgatga tcttatatgc aacggaaatg 780 agtcagctct ctggaactgc aaacatcaag gatggggaaa gcataactgt gatcatgctg 840 aggatgctgg agtgatttgc tcaaagggag cagatctgag cctgagactg gtagatggag 900 tcactgaatg ttcaggaaga ttagaagtga gattccaagg agaatggggg acaatatgtg 960 atgacggctg ggacagttac gatgctgctg tggcatgcaa gcaactggga tgtccaactg 1020 ccgtcacagc cattggtcga gttaacgcca gtaagggatt tggacacatc tggcttgaca 1080 gcgtttcttg ccagggacat gaacctgctg tctggcaatg taaacaccat gaatggggaa 1140 agcattattg caatcacaat gaagatgctg gcgtgacatg ttctgatgga tcagatctgg 1200 agctaagact tagaggtgga ggcagccgct gtgctgggac agttgaggtg gagattcaga 1260 gactgttagg gaaggtgtgt gacagaggct ggggactgaa agaagctgat gtggtttgca 1320 ggcagctggg atgtggatct gcactcaaaa catcttatca agtgtactcc aaaatccagg 1380 caacaaacac atggctgttt ctaagtagct gtaacggaaa tgaaacttct ctttgggact 1440 gcaagaactg gcaatggggt ggacttacct gtgatcacta tgaagaagcc aaaattacct 1500 gctcagccca cagggaaccc agactggttg gaggggacat tccctgttct ggacgtgttg 1560 aagtgaagca tggtgacacg tggggctcca tctgtgattc ggacttctct ctggaagctg 1620 ccagcgttct atgcagggaa ttacagtgtg gcacagttgt ctctatcctg gggggagctc 1680 actttggaga gggaaatgga cagatctggg ctgaagaatt ccagtgtgag ggacatgagt 1740 cccatctttc actctgccca gtagcacccc gcccagaagg aacttgtagc cacagcaggg 1800 atgttggagt agtctgctca agatacacag aaattcgctt ggtgaatggc aagaccccgt 1860 gtgagggcag agtggagctc aaaacgcttg gtgcctgggg atccctctgt aactctcact 1920 gggacataga agatgcccat gttctttgcc agcagcttaa atgtggagtt gccctttcta 1980 ccccaggagg agcacgtttt ggaaaaggaa atggtcagat ctggaggcat atgtttcact 2040 gcactgggac tgagcagcac atgggagatt gtcctgtaac tgctctaggt gcttcattat 2100 gtccttcaga gcaagtggcc tctgtaatct gctcaggaaa ccagtcccaa acactgtcct 2160 cgtgcaattc atcgtctttg ggcccaacaa ggcctaccat tccagaagaa agtgctgtgg 2220 cctgcataga gagtggtcaa cttcgcctgg taaatggagg aggtcgctgt gctgggagag 2280 tagagatcta tcatgagggc tcctggggca ccatctgtga tgacagctgg gacctgagtg 2340 atgcccacgt ggtttgcaga cagctgggct gtggagaggc cattaatgcc actggttctg 2400 ctcattttgg ggaaggaaca gggcccatct ggctggatga gatgaaatgc aatggaaaag 2460 aatcccgcat ttggcagtgc cattcacacg gctgggggca gcaaaattgc aggcacaagg 2520 aggatgcggg agttatctgc tcagaattca tgtctctgag actgaccagt gaagccagca 2580 gagaggcctg tgcagggcgt ctggaagttt tttacaatgg agcttggggc actgttggca 2640 agagtagcat gtctgaaacc actgtgggtg tggtgtgcag gcagctgggc tgtgcagaca 2700 aagggaaaat caaccctgca tctttagaca aggccatgtc cattcccatg tgggtggaca 2760 atgttcagtg tccaaaagga cctgacacgc tgtggcagtg cccatcatct ccatgggaga 2820 agagactggc cagcccctcg gaggagacct ggatcacatg tgacaacaag ataagacttc 2880 aggaaggacc cacttcctgt tctggacgtg tggagatctg gcatggaggt tcctggggga 2940 cagtgtgtga tgactcttgg gacttggacg atgctcaggt ggtgtgtcaa caacttggct 3000 gtggtccagc tttgaaagca ttcaaagaag cagagtttgg tcaggggact ggaccgatat 3060 ggctcaatga agtgaagtgc aaagggaatg agtcttcctt gtgggattgt cctgccagac 3120 gctggggcca tagtgagtgt gggcacaagg aagacgctgc agtgaattgc acagatattt 3180 cagtgcagaa aaccccacaa aaagccacaa caggtcgctc atcccgtcag tcatccttta 3240 ttgcagtcgg gatccttggg gttgttctgt tggccatttt cgtcgcatta ttcttcttga 3300 ctaaaaagcg aagacagaga cagcggcttg cagtttcctc aagaggagag aacttagtcc 3360 accaaattca ataccgggag atgaattctt gcctgaatgc agatgatctg gacctaatga 3420 attcctcagg tctgtgggtt cttggagggt ctattgccca ggggttcaga tcagtggctg 3480 cagttgaggc acagacattc tactttgata aacagttaaa aaagtctaaa aatgtaatag 3540 gaagcttaga tgcatataat ggacaagaat gactgaaaat tattcttgga gaatatcaaa 3600 attgcaatca tagggaggcc tttagcttaa gaggcctgtg attattcctg atagaggtat 3660 ggaaagaacc atgcagagga atattatgac ttggacctca ttttattaaa acagaaatta 3720 atcttacaaa agattgtcat aagtgacagt ttaacttttt tctttaaatt ttgttgtgta 3780 tatttaaggt atacaacatg attttatggg atgtatatag atagtaaaaa gcttactaaa 3840 gcaaagcaaa tgaacacacc catcatctga catagttacc cttttttgtg ttgttcttgt 3900 ggcaagagca gctaaaacct actcacttag catgaatcct acatacagca caatgttatt 3960 acctataatc ctcatgttgt acattagacc tctagactgg ttcattctac gtatctgcta 4020 ctttgtatcc tctgacctac atacgtcttt cacagtttct tccattccca tttcctgtca 4080 ttttttttct ctagcttgat atttattata tttttcccta aaagtctaaa accttaaact 4140 ttcaatatct ttattgcatg agaagccata caaatccaca gaactagcct tatttctcat 4200 cacatcatgc tgttttatcc ttgaacttct atttagcacc agtgcactaa ttctgcatct 4260 gggcaggatg actttactgg gttggaagaa atatcccaaa acccattgtc tttactccat 4320 gaagggtccc tgaccttctg agaggggcct gcctcacttc ttccatccaa agaattatgc 4380 atctgctact gtgtcaggga acatatttaa ggaacatgta ctgttactgt gtcaggaaac 4440 atatttaaga aataggaaag actttctctg ccccttaaat cacacatgct tttcttccta 4500 gttatgggtg gtgtttttag ttgctcaaag agcctcacag ttacgtgaga agaggtctgg 4560 tttatttccc agtaattatt ttcttccttt cagaaaattc ccatgagtca gctgatttca 4620 gtgctgctga actaatttct gtgtctaaat ttcttcctat ttctggaatg gaaaaggagg 4680 ccattctgag ccacactgaa aaggaaaatg ggaatttata acccagtgag ttcagccttt 4740 aagatacctt gatgaagacc tggactattg aatggagcag aaattcacct ctctcactga 4800 ctattacagt tgcattttta tggagttctt cttctcctag gattcctaag actgctgctg 4860 aatttataaa aattaagttt gtgaatgtga ctacttagtg gtgtatatga gactttcaag 4920 ggaattaaat aaataaataa gaatgttaaa 4950 <210> SEQ ID NO 8 <211> LENGTH: 1156 <212> TYPE: PRT <213> ORGANISM: HOMO SAPIENS <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/CAA80543 <309> DATABASE ENTRY DATE: 2005-04-18 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1156) <400> SEQUENCE: 8 Met Val Leu Leu Glu Asp Ser Gly Ser Ala Asp Phe Arg Arg His Phe 1 5 10 15 Val Asn Leu Ser Pro Phe Thr Ile Thr Val Val Leu Leu Leu Ser Ala 20 25 30 Cys Phe Val Thr Ser Ser Leu Gly Gly Thr Asp Lys Glu Leu Arg Leu 35 40 45 Val Asp Gly Glu Asn Lys Cys Ser Gly Arg Val Glu Val Lys Val Gln 50 55 60 Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp Ser Met Glu Ala Val 65 70 75 80 Ser Val Ile Cys Asn Gln Leu Gly Cys Pro Thr Ala Ile Lys Ala Pro 85 90 95 Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Arg Ile Trp Met Asp His 100 105 110 Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp Asp Cys Lys His Asp 115 120 125 Gly Trp Gly Lys His Ser Asn Cys Thr His Gln Gln Asp Ala Gly Val 130 135 140 Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg Leu Thr Arg Gly Gly 145 150 155 160 Asn Met Cys Ser Gly Arg Ile Glu Ile Lys Phe Gln Gly Arg Trp Gly 165 170 175 Thr Val Cys Asp Asp Asn Phe Asn Ile Asp His Ala Ser Val Ile Cys 180 185 190 Arg Gln Leu Glu Cys Gly Ser Ala Val Ser Phe Ser Gly Ser Ser Asn 195 200 205 Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp Asp Leu Ile Cys Asn 210 215 220 Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His Gln Gly Trp Gly Lys 225 230 235 240 His Asn Cys Asp His Ala Glu Asp Ala Gly Val Ile Cys Ser Lys Gly 245 250 255 Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val Thr Glu Cys Ser Gly 260 265 270 Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly Thr Ile Cys Asp Asp 275 280 285 Gly Trp Asp Ser Tyr Asp Ala Ala Val Ala Cys Lys Gln Leu Gly Cys 290 295 300 Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn Ala Ser Lys Gly Phe 305 310 315 320 Gly His Ile Trp Leu Asp Ser Val Ser Cys Gln Gly His Glu Pro Ala 325 330 335 Val Trp Gln Cys Lys His His Glu Trp Gly Lys His Tyr Cys Asn His 340 345 350 Asn Glu Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asp Leu Glu Leu 355 360 365 Arg Leu Arg Gly Gly Gly Ser Arg Cys Ala Gly Thr Val Glu Val Glu 370 375 380 Ile Gln Arg Leu Leu Gly Lys Val Cys Asp Arg Gly Trp Gly Leu Lys 385 390 395 400 Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys Gly Ser Ala Leu Lys 405 410 415 Thr Ser Tyr Gln Val Tyr Ser Lys Ile Gln Ala Thr Asn Thr Trp Leu 420 425 430 Phe Leu Ser Ser Cys Asn Gly Asn Glu Thr Ser Leu Trp Asp Cys Lys 435 440 445 Asn Trp Gln Trp Gly Gly Leu Thr Cys Asp His Tyr Glu Glu Ala Lys 450 455 460 Ile Thr Cys Ser Ala His Arg Glu Pro Arg Leu Val Gly Gly Asp Ile 465 470 475 480 Pro Cys Ser Gly Arg Val Glu Val Lys His Gly Asp Thr Trp Gly Ser 485 490 495 Ile Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala Ser Val Leu Cys Arg 500 505 510 Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu Gly Gly Ala His Phe 515 520 525 Gly Glu Gly Asn Gly Gln Ile Trp Ala Glu Glu Phe Gln Cys Glu Gly 530 535 540 His Glu Ser His Leu Ser Leu Cys Pro Val Ala Pro Arg Pro Glu Gly 545 550 555 560 Thr Cys Ser His Ser Arg Asp Val Gly Val Val Cys Ser Arg Tyr Thr 565 570 575 Glu Ile Arg Leu Val Asn Gly Lys Thr Pro Cys Glu Gly Arg Val Glu 580 585 590 Leu Lys Thr Leu Gly Ala Trp Gly Ser Leu Cys Asn Ser His Trp Asp 595 600 605 Ile Glu Asp Ala His Val Leu Cys Gln Gln Leu Lys Cys Gly Val Ala 610 615 620 Leu Ser Thr Pro Gly Gly Ala Arg Phe Gly Lys Gly Asn Gly Gln Ile 625 630 635 640 Trp Arg His Met Phe His Cys Thr Gly Thr Glu Gln His Met Gly Asp 645 650 655 Cys Pro Val Thr Ala Leu Gly Ala Ser Leu Cys Pro Ser Glu Gln Val 660 665 670 Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln Thr Leu Ser Ser Cys 675 680 685 Asn Ser Ser Ser Leu Gly Pro Thr Arg Pro Thr Ile Pro Glu Glu Ser 690 695 700 Ala Val Ala Cys Ile Glu Ser Gly Gln Leu Arg Leu Val Asn Gly Gly 705 710 715 720 Gly Arg Cys Ala Gly Arg Val Glu Ile Tyr His Glu Gly Ser Trp Gly 725 730 735 Thr Ile Cys Asp Asp Ser Trp Asp Leu Ser Asp Ala His Val Val Cys 740 745 750 Arg Gln Leu Gly Cys Gly Glu Ala Ile Asn Ala Thr Gly Ser Ala His 755 760 765 Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu Asp Glu Met Lys Cys Asn 770 775 780 Gly Lys Glu Ser Arg Ile Trp Gln Cys His Ser His Gly Trp Gly Gln 785 790 795 800 Gln Asn Cys Arg His Lys Glu Asp Ala Gly Val Ile Cys Ser Glu Phe 805 810 815 Met Ser Leu Arg Leu Thr Ser Glu Ala Ser Arg Glu Ala Cys Ala Gly 820 825 830 Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp Gly Thr Val Gly Lys Ser 835 840 845 Ser Met Ser Glu Thr Thr Val Gly Val Val Cys Arg Gln Leu Gly Cys 850 855 860 Ala Asp Lys Gly Lys Ile Asn Pro Ala Ser Leu Asp Lys Ala Met Ser 865 870 875 880 Ile Pro Met Trp Val Asp Asn Val Gln Cys Pro Lys Gly Pro Asp Thr 885 890 895 Leu Trp Gln Cys Pro Ser Ser Pro Trp Glu Lys Arg Leu Ala Ser Pro 900 905 910 Ser Glu Glu Thr Trp Ile Thr Cys Asp Asn Lys Ile Arg Leu Gln Glu 915 920 925 Gly Pro Thr Ser Cys Ser Gly Arg Val Glu Ile Trp His Gly Gly Ser 930 935 940 Trp Gly Thr Val Cys Asp Asp Ser Trp Asp Leu Asp Asp Ala Gln Val 945 950 955 960 Val Cys Gln Gln Leu Gly Cys Gly Pro Ala Leu Lys Ala Phe Lys Glu 965 970 975 Ala Glu Phe Gly Gln Gly Thr Gly Pro Ile Trp Leu Asn Glu Val Lys 980 985 990 Cys Lys Gly Asn Glu Ser Ser Leu Trp Asp Cys Pro Ala Arg Arg Trp 995 1000 1005 Gly His Ser Glu Cys Gly His Lys Glu Asp Ala Ala Val Asn Cys 1010 1015 1020 Thr Asp Ile Ser Val Gln Lys Thr Pro Gln Lys Ala Thr Thr Gly 1025 1030 1035 Arg Ser Ser Arg Gln Ser Ser Phe Ile Ala Val Gly Ile Leu Gly 1040 1045 1050 Val Val Leu Leu Ala Ile Phe Val Ala Leu Phe Phe Leu Thr Lys 1055 1060 1065 Lys Arg Arg Gln Arg Gln Arg Leu Ala Val Ser Ser Arg Gly Glu 1070 1075 1080 Asn Leu Val His Gln Ile Gln Tyr Arg Glu Met Asn Ser Cys Leu 1085 1090 1095 Asn Ala Asp Asp Leu Asp Leu Met Asn Ser Ser Gly Leu Trp Val 1100 1105 1110 Leu Gly Gly Ser Ile Ala Gln Gly Phe Arg Ser Val Ala Ala Val 1115 1120 1125 Glu Ala Gln Thr Phe Tyr Phe Asp Lys Gln Leu Lys Lys Ser Lys 1130 1135 1140 Asn Val Ile Gly Ser Leu Asp Ala Tyr Asn Gly Gln Glu 1145 1150 1155 <210> SEQ ID NO 9 <211> LENGTH: 5193 <212> TYPE: DNA <213> ORGANISM: sus scrofa <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/NM_214346 <309> DATABASE ENTRY DATE: 2004-08-05 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(5193) <400> SEQUENCE: 9 atggacttcc tgctcctgct cctcctcctg gcttcatctg ctctagcagg cctggcctcg 60 tggacggttt ccagccccga gaccgtgcag ggcatcaagg gctcctgcct catcatcccc 120 tgcaccttcg gcttcccggc caacgtggag gtgccccatg gcatcacagc catctggtac 180 tatgactact caggcaagcg cctggtagtg agccactcca ggaacccaaa ggtggtggag 240 aaccacttcc aaggccgggc cctgctgttg gggcaggttg aacagaggac gtgcagcctg 300 ctgctgaagg acctgcagcc ccaggactcg ggctcctata acttccgctt tgagatcagc 360 gagggcaacc gctggtcaga tgtcaaaggc acagttgtca ccgtgacaga ggtgcccagc 420 gtgcccacca ttgccttgcc agccaagctg catgagggca tggaggtgga cttcaactgc 480 tccactccct atgtgtgccc gacggagccg gtcaacctac agtggcaagg ccaggatccc 540 acccgctccg tcacctccca cctccagaag cttgagccct cgggcaccag ccacatggag 600 accctgcaca tggccctgtc ctggcaggac catggccgga tcctgagctg ccaggtctca 660 gcagccgaac gcaggatgca gaaggagatt cacctccaag tgcagtatgc ccccaagggt 720 gtggagatcc ttttcagcca ctccggacgg aacgtccttc caggtgatct ggtcaccctc 780 agctgccagg tgaatagcag caaccctcag gtcagttccg tgcagtgggt caaggatggg 840 acgaagctca aagaccagaa acgtgtactg cagttgcgcc gggcagcctg ggctgatgct 900 ggcgtctaca cctgccaagc cgggaatgcc gtgggctctt cagtctcacc cccggtcagc 960 ctccacgtct tcatggctga ggtccaggta agccctgtgg gctccatcct ggagaaccag 1020 acggtgacgc tggcctgcaa tacacctaag gaagcgccca gcgagctgcg ctacagctgg 1080 tacaagaacc acgccctgct ggagggctct cacagccgca ccctccggct gcactcagtt 1140 accagggcgg attcgggctt ctacttctgc gaggtgcaga acgcccgggg cagagagcgc 1200 tctccccctg tcagcgtggt ggtcagccac ccacccctca ccccggacct aactgccttc 1260 ctggagacac aggcggggct ggtgggcatc ctccaatgct ctgtggtcag cgagccccca 1320 gctactctgg tgttgtcaca cgggggcctc atcttggcct ctacctccgg ggagggtgac 1380 cacagcccac gcttcagtgt cgcctctgcc cccaactccc tgcgcctgga gattcaagac 1440 ctggggccaa cagacagtgg ggaatacatg tgctcagcca gcagttctct tgggaatgcg 1500 tcctccaccc tggacttcca tgccaatgca gcccgcctcc tcatcagccc agcagcagag 1560 gtggtggaag ggcaggcggt gacactgagc tgcaggagca gcctgagcct gatgcctgac 1620 acccgttttt cctggtacct gaacggggcc ctgattctcg aggggcccag cagcagcctc 1680 ctgctcccag cagcctccag cacagatgcc ggctcatacc actgccgggc ccagaacagc 1740 cacagcacca gcgggccctc ctcacctgct gttctcaccg tgctctacgc cccacgccag 1800 cccgtgttca ctgcccagct ggaccctgat actgcaggag ctggggccgg acgccaaggc 1860 ctcctcttgt gccgtgtgga cagcgacccc ccagcccagc tgcagctgct ccacaggggc 1920 cgtgttgtgg cctcttctct gtcatggggg ggcggctgct gcacctgcgg aggctgtttc 1980 caccgcatga aggtcaccaa agcacccaac ctactgcgtg tagagatccg agacccggtg 2040 ctggaggatg agggtgtgta cctgtgcgag gccagcagcg ccctgggcaa cgcctccgcc 2100 tctgcaacct tggatgccca ggccactgtc ctggtcatca caccgtcaca cacgctgcag 2160 gaaggcattg aagccaacct gacttgcaac gtgagccgtg aagccagcgg ccctgccaac 2220 ttctcctggt tccgagatgg ggcgctatgg gcccagggcc ctctggacac cgtgacgctg 2280 ctacctgtgg ccagaactga tgctgccctc tatgcttgcc gcatcgtcac cgaggctggt 2340 gctggcctct ccacccctgt ggccctgaat gtgctctatc cccccgatcc tccaaagttg 2400 tcagccctcc tggacgtgga ccagggccac acggctgtgt tcgtctgtac tgtggacagt 2460 cgccctcttg cccagttggc cctgttccgt ggggaacacc tcctggccgc cagctcggca 2520 ctccggctcc cccctcgtgg ccgcctccag gccaaagcct cggccaactc cttgcagcta 2580 gaggtccgag acttgagcct tggggactct ggcagctacc actgtgaggc caccaacatc 2640 cttggatcag ccaacacttc tcttaccttc caggtccgag gagcctgggt ccgggtgtca 2700 ccgtcgcctg agctccagga gggccaggct gtggtcctga gctgccaggt acccataggg 2760 gtcctggagg ggacctcata tcgttggtat cgggatggcc agcccctcca ggagtccact 2820 tcggccacgc tccgttttgc agccataact ctgagccagg ctggagccta ccattgccaa 2880 gcccaagctc caggctcagc caccacggac ctggctgccc ctgtcagcct ccacgtgacc 2940 tacgcacctc gccaggccac actcaccacc ctgatggact caggcctcgg gcgactgggc 3000 ctccttctgt gccgtgtgaa cagtgaccct cctgcccagc tccgactgct ccatgggagc 3060 cgcctcgtgg cctctactct acaaggtgtg gaggagcttg caggcagctc tccccgccta 3120 caggtggcca cagcccccaa cacgctgcgc ctggagatcc acaacgcagt gctggaggat 3180 gaaggcgtct acacctgcga ggccaccaac accctgggtc agaccttggc ctccgccgcc 3240 ttcgatgccc aggctatgag agtgcaggtg tggcccaatg ccaccgtgca agaggggcag 3300 ctggtgaacc tgacctgcct tgtatggacc acgcacctgg cccagctcac ctacacgtgg 3360 taccgagacc agcagcagct cccaggtgct gcccactcca tcctcctgcc caatgtcact 3420 gtcacagatg ccgcctccta ccgctgtggc atattgatcc ctggccaggc actccgcctc 3480 tccagacctg tcgccctgga tgtcctctac gcaccccgca gactgcgcct gacccatctc 3540 ttggagagcc gtggtgggca gctggccgtg gtgctgtgca ctgtggacag tcgcccagct 3600 gcccagctga ccctcagcca tgctggccgc ctcctggcct cctcaaccgc agcctctgtc 3660 cccaacaccc tgcgcctgga gctgtgggag ccccggccca gtgatgaggg tctctacagc 3720 tgctcggccc gcagtcctct gggccaggcc aacacatccc tggagctgcg gctagagggc 3780 gtgcaggtgg cactggctcc atcggccact gtgccggagg gggcccctgt cacagtgacc 3840 tgtgaagacc ctgctgcccg cccacccact ctctatgtct ggtaccacaa cagccgttgg 3900 ctgcaggagg ggtcggctgc ctccctctcg tttccagcgg ctacacgggc tcacgcgggc 3960 gcctatacct gccaggtcca ggatgcccag ggcacacgca tctcccagcc cgcagcactg 4020 cacatcctct atgcccctcg ggatgctgtc ctttcctcct tctgggactc aagggccagc 4080 cctatggccg tggtacagtg cactgtggac agcgagccac ctgccgagat gaccctgtcc 4140 catgatggca aggtgctggc caccagccat ggggtccacg gcttagcagt ggggacaggc 4200 catgtccagg tggcccgcaa cgccctgcag ctgcgggtgc agaatgtgcc ctcacgtgac 4260 aaggacacct acgtctgcat ggaccgcaac tccttgggct cagtcagcac catggggcag 4320 ctgcagccag aaggtgtgca cgtggtagct gagccagggc tggatgtgcc tgaaggcaca 4380 gcgctgaacc tgagctgtcg cctccctagt ggccctgggc acataggcaa ctccaccttt 4440 gcttggttcc ggaacggtcg gcagctacac acagagtctg tgcccaccct taccttcacc 4500 catgtggccc gcgcccaagc tggcttgtac cactgccagg ctgagctccc cgccggggct 4560 gccacctctg ctccagtctt gctccgggtg ctctaccctc ccaagacgcc caccatgact 4620 gtttttgtgg agcccgaggg tggcatccag ggcattctgg actgccgagt ggacagtgag 4680 cccctagcca gcctgaccct ccacctgggc agtcggctgg tggcctccag ccagcctcag 4740 gctgcccctg ccaagccgca catccgcgtc tcagccagtc ccaatgcctt gcgagtggac 4800 atggaggagc tgaagcccag tgaccagggg gagtatgtgt gctcggcctc caatgccctg 4860 ggctctgcct ctgctgccac ctacttcgga accagagccc tgcatcgcct gcatctgttc 4920 cagcaccttc tctggttcct ggggctgctg gcgagcctcc tcttcctact gttgggcctg 4980 ggggtctggt acgcctggag acggggaaat ttttacaagc tgagaatggg cgaatattca 5040 gtagagatgg tatctcggaa ggaaaccacg cagatgtcca ctgaccagga agaagttact 5100 ggaatcggtg atgatgcggg ctctgtgaac caggcggcat ttgatcctgc ccacctctgt 5160 gaaaacacac agtctgtgaa aagcacagtc tga 5193 <210> SEQ ID NO 10 <211> LENGTH: 1730 <212> TYPE: PRT <213> ORGANISM: sus scrofa <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/NP_999511 <309> DATABASE ENTRY DATE: 2004-08-05 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1730) <400> SEQUENCE: 10 Met Asp Phe Leu Leu Leu Leu Leu Leu Leu Ala Ser Ser Ala Leu Ala 1 5 10 15 Gly Leu Ala Ser Trp Thr Val Ser Ser Pro Glu Thr Val Gln Gly Ile 20 25 30 Lys Gly Ser Cys Leu Ile Ile Pro Cys Thr Phe Gly Phe Pro Ala Asn 35 40 45 Val Glu Val Pro His Gly Ile Thr Ala Ile Trp Tyr Tyr Asp Tyr Ser 50 55 60 Gly Lys Arg Leu Val Val Ser His Ser Arg Asn Pro Lys Val Val Glu 65 70 75 80 Asn His Phe Gln Gly Arg Ala Leu Leu Leu Gly Gln Val Glu Gln Arg 85 90 95 Thr Cys Ser Leu Leu Leu Lys Asp Leu Gln Pro Gln Asp Ser Gly Ser 100 105 110 Tyr Asn Phe Arg Phe Glu Ile Ser Glu Gly Asn Arg Trp Ser Asp Val 115 120 125 Lys Gly Thr Val Val Thr Val Thr Glu Val Pro Ser Val Pro Thr Ile 130 135 140 Ala Leu Pro Ala Lys Leu His Glu Gly Met Glu Val Asp Phe Asn Cys 145 150 155 160 Ser Thr Pro Tyr Val Cys Pro Thr Glu Pro Val Asn Leu Gln Trp Gln 165 170 175 Gly Gln Asp Pro Thr Arg Ser Val Thr Ser His Leu Gln Lys Leu Glu 180 185 190 Pro Ser Gly Thr Ser His Met Glu Thr Leu His Met Ala Leu Ser Trp 195 200 205 Gln Asp His Gly Arg Ile Leu Ser Cys Gln Val Ser Ala Ala Glu Arg 210 215 220 Arg Met Gln Lys Glu Ile His Leu Gln Val Gln Tyr Ala Pro Lys Gly 225 230 235 240 Val Glu Ile Leu Phe Ser His Ser Gly Arg Asn Val Leu Pro Gly Asp 245 250 255 Leu Val Thr Leu Ser Cys Gln Val Asn Ser Ser Asn Pro Gln Val Ser 260 265 270 Ser Val Gln Trp Val Lys Asp Gly Thr Lys Leu Lys Asp Gln Lys Arg 275 280 285 Val Leu Gln Leu Arg Arg Ala Ala Trp Ala Asp Ala Gly Val Tyr Thr 290 295 300 Cys Gln Ala Gly Asn Ala Val Gly Ser Ser Val Ser Pro Pro Val Ser 305 310 315 320 Leu His Val Phe Met Ala Glu Val Gln Val Ser Pro Val Gly Ser Ile 325 330 335 Leu Glu Asn Gln Thr Val Thr Leu Ala Cys Asn Thr Pro Lys Glu Ala 340 345 350 Pro Ser Glu Leu Arg Tyr Ser Trp Tyr Lys Asn His Ala Leu Leu Glu 355 360 365 Gly Ser His Ser Arg Thr Leu Arg Leu His Ser Val Thr Arg Ala Asp 370 375 380 Ser Gly Phe Tyr Phe Cys Glu Val Gln Asn Ala Arg Gly Arg Glu Arg 385 390 395 400 Ser Pro Pro Val Ser Val Val Val Ser His Pro Pro Leu Thr Pro Asp 405 410 415 Leu Thr Ala Phe Leu Glu Thr Gln Ala Gly Leu Val Gly Ile Leu Gln 420 425 430 Cys Ser Val Val Ser Glu Pro Pro Ala Thr Leu Val Leu Ser His Gly 435 440 445 Gly Leu Ile Leu Ala Ser Thr Ser Gly Glu Gly Asp His Ser Pro Arg 450 455 460 Phe Ser Val Ala Ser Ala Pro Asn Ser Leu Arg Leu Glu Ile Gln Asp 465 470 475 480 Leu Gly Pro Thr Asp Ser Gly Glu Tyr Met Cys Ser Ala Ser Ser Ser 485 490 495 Leu Gly Asn Ala Ser Ser Thr Leu Asp Phe His Ala Asn Ala Ala Arg 500 505 510 Leu Leu Ile Ser Pro Ala Ala Glu Val Val Glu Gly Gln Ala Val Thr 515 520 525 Leu Ser Cys Arg Ser Ser Leu Ser Leu Met Pro Asp Thr Arg Phe Ser 530 535 540 Trp Tyr Leu Asn Gly Ala Leu Ile Leu Glu Gly Pro Ser Ser Ser Leu 545 550 555 560 Leu Leu Pro Ala Ala Ser Ser Thr Asp Ala Gly Ser Tyr His Cys Arg 565 570 575 Ala Gln Asn Ser His Ser Thr Ser Gly Pro Ser Ser Pro Ala Val Leu 580 585 590 Thr Val Leu Tyr Ala Pro Arg Gln Pro Val Phe Thr Ala Gln Leu Asp 595 600 605 Pro Asp Thr Ala Gly Ala Gly Ala Gly Arg Gln Gly Leu Leu Leu Cys 610 615 620 Arg Val Asp Ser Asp Pro Pro Ala Gln Leu Gln Leu Leu His Arg Gly 625 630 635 640 Arg Val Val Ala Ser Ser Leu Ser Trp Gly Gly Gly Cys Cys Thr Cys 645 650 655 Gly Gly Cys Phe His Arg Met Lys Val Thr Lys Ala Pro Asn Leu Leu 660 665 670 Arg Val Glu Ile Arg Asp Pro Val Leu Glu Asp Glu Gly Val Tyr Leu 675 680 685 Cys Glu Ala Ser Ser Ala Leu Gly Asn Ala Ser Ala Ser Ala Thr Leu 690 695 700 Asp Ala Gln Ala Thr Val Leu Val Ile Thr Pro Ser His Thr Leu Gln 705 710 715 720 Glu Gly Ile Glu Ala Asn Leu Thr Cys Asn Val Ser Arg Glu Ala Ser 725 730 735 Gly Pro Ala Asn Phe Ser Trp Phe Arg Asp Gly Ala Leu Trp Ala Gln 740 745 750 Gly Pro Leu Asp Thr Val Thr Leu Leu Pro Val Ala Arg Thr Asp Ala 755 760 765 Ala Leu Tyr Ala Cys Arg Ile Val Thr Glu Ala Gly Ala Gly Leu Ser 770 775 780 Thr Pro Val Ala Leu Asn Val Leu Tyr Pro Pro Asp Pro Pro Lys Leu 785 790 795 800 Ser Ala Leu Leu Asp Val Asp Gln Gly His Thr Ala Val Phe Val Cys 805 810 815 Thr Val Asp Ser Arg Pro Leu Ala Gln Leu Ala Leu Phe Arg Gly Glu 820 825 830 His Leu Leu Ala Ala Ser Ser Ala Leu Arg Leu Pro Pro Arg Gly Arg 835 840 845 Leu Gln Ala Lys Ala Ser Ala Asn Ser Leu Gln Leu Glu Val Arg Asp 850 855 860 Leu Ser Leu Gly Asp Ser Gly Ser Tyr His Cys Glu Ala Thr Asn Ile 865 870 875 880 Leu Gly Ser Ala Asn Thr Ser Leu Thr Phe Gln Val Arg Gly Ala Trp 885 890 895 Val Arg Val Ser Pro Ser Pro Glu Leu Gln Glu Gly Gln Ala Val Val 900 905 910 Leu Ser Cys Gln Val Pro Ile Gly Val Leu Glu Gly Thr Ser Tyr Arg 915 920 925 Trp Tyr Arg Asp Gly Gln Pro Leu Gln Glu Ser Thr Ser Ala Thr Leu 930 935 940 Arg Phe Ala Ala Ile Thr Leu Ser Gln Ala Gly Ala Tyr His Cys Gln 945 950 955 960 Ala Gln Ala Pro Gly Ser Ala Thr Thr Asp Leu Ala Ala Pro Val Ser 965 970 975 Leu His Val Thr Tyr Ala Pro Arg Gln Ala Thr Leu Thr Thr Leu Met 980 985 990 Asp Ser Gly Leu Gly Arg Leu Gly Leu Leu Leu Cys Arg Val Asn Ser 995 1000 1005 Asp Pro Pro Ala Gln Leu Arg Leu Leu His Gly Ser Arg Leu Val 1010 1015 1020 Ala Ser Thr Leu Gln Gly Val Glu Glu Leu Ala Gly Ser Ser Pro 1025 1030 1035 Arg Leu Gln Val Ala Thr Ala Pro Asn Thr Leu Arg Leu Glu Ile 1040 1045 1050 His Asn Ala Val Leu Glu Asp Glu Gly Val Tyr Thr Cys Glu Ala 1055 1060 1065 Thr Asn Thr Leu Gly Gln Thr Leu Ala Ser Ala Ala Phe Asp Ala 1070 1075 1080 Gln Ala Met Arg Val Gln Val Trp Pro Asn Ala Thr Val Gln Glu 1085 1090 1095 Gly Gln Leu Val Asn Leu Thr Cys Leu Val Trp Thr Thr His Leu 1100 1105 1110 Ala Gln Leu Thr Tyr Thr Trp Tyr Arg Asp Gln Gln Gln Leu Pro 1115 1120 1125 Gly Ala Ala His Ser Ile Leu Leu Pro Asn Val Thr Val Thr Asp 1130 1135 1140 Ala Ala Ser Tyr Arg Cys Gly Ile Leu Ile Pro Gly Gln Ala Leu 1145 1150 1155 Arg Leu Ser Arg Pro Val Ala Leu Asp Val Leu Tyr Ala Pro Arg 1160 1165 1170 Arg Leu Arg Leu Thr His Leu Leu Glu Ser Arg Gly Gly Gln Leu 1175 1180 1185 Ala Val Val Leu Cys Thr Val Asp Ser Arg Pro Ala Ala Gln Leu 1190 1195 1200 Thr Leu Ser His Ala Gly Arg Leu Leu Ala Ser Ser Thr Ala Ala 1205 1210 1215 Ser Val Pro Asn Thr Leu Arg Leu Glu Leu Trp Glu Pro Arg Pro 1220 1225 1230 Ser Asp Glu Gly Leu Tyr Ser Cys Ser Ala Arg Ser Pro Leu Gly 1235 1240 1245 Gln Ala Asn Thr Ser Leu Glu Leu Arg Leu Glu Gly Val Gln Val 1250 1255 1260 Ala Leu Ala Pro Ser Ala Thr Val Pro Glu Gly Ala Pro Val Thr 1265 1270 1275 Val Thr Cys Glu Asp Pro Ala Ala Arg Pro Pro Thr Leu Tyr Val 1280 1285 1290 Trp Tyr His Asn Ser Arg Trp Leu Gln Glu Gly Ser Ala Ala Ser 1295 1300 1305 Leu Ser Phe Pro Ala Ala Thr Arg Ala His Ala Gly Ala Tyr Thr 1310 1315 1320 Cys Gln Val Gln Asp Ala Gln Gly Thr Arg Ile Ser Gln Pro Ala 1325 1330 1335 Ala Leu His Ile Leu Tyr Ala Pro Arg Asp Ala Val Leu Ser Ser 1340 1345 1350 Phe Trp Asp Ser Arg Ala Ser Pro Met Ala Val Val Gln Cys Thr 1355 1360 1365 Val Asp Ser Glu Pro Pro Ala Glu Met Thr Leu Ser His Asp Gly 1370 1375 1380 Lys Val Leu Ala Thr Ser His Gly Val His Gly Leu Ala Val Gly 1385 1390 1395 Thr Gly His Val Gln Val Ala Arg Asn Ala Leu Gln Leu Arg Val 1400 1405 1410 Gln Asn Val Pro Ser Arg Asp Lys Asp Thr Tyr Val Cys Met Asp 1415 1420 1425 Arg Asn Ser Leu Gly Ser Val Ser Thr Met Gly Gln Leu Gln Pro 1430 1435 1440 Glu Gly Val His Val Val Ala Glu Pro Gly Leu Asp Val Pro Glu 1445 1450 1455 Gly Thr Ala Leu Asn Leu Ser Cys Arg Leu Pro Ser Gly Pro Gly 1460 1465 1470 His Ile Gly Asn Ser Thr Phe Ala Trp Phe Arg Asn Gly Arg Gln 1475 1480 1485 Leu His Thr Glu Ser Val Pro Thr Leu Thr Phe Thr His Val Ala 1490 1495 1500 Arg Ala Gln Ala Gly Leu Tyr His Cys Gln Ala Glu Leu Pro Ala 1505 1510 1515 Gly Ala Ala Thr Ser Ala Pro Val Leu Leu Arg Val Leu Tyr Pro 1520 1525 1530 Pro Lys Thr Pro Thr Met Thr Val Phe Val Glu Pro Glu Gly Gly 1535 1540 1545 Ile Gln Gly Ile Leu Asp Cys Arg Val Asp Ser Glu Pro Leu Ala 1550 1555 1560 Ser Leu Thr Leu His Leu Gly Ser Arg Leu Val Ala Ser Ser Gln 1565 1570 1575 Pro Gln Ala Ala Pro Ala Lys Pro His Ile Arg Val Ser Ala Ser 1580 1585 1590 Pro Asn Ala Leu Arg Val Asp Met Glu Glu Leu Lys Pro Ser Asp 1595 1600 1605 Gln Gly Glu Tyr Val Cys Ser Ala Ser Asn Ala Leu Gly Ser Ala 1610 1615 1620 Ser Ala Ala Thr Tyr Phe Gly Thr Arg Ala Leu His Arg Leu His 1625 1630 1635 Leu Phe Gln His Leu Leu Trp Phe Leu Gly Leu Leu Ala Ser Leu 1640 1645 1650 Leu Phe Leu Leu Leu Gly Leu Gly Val Trp Tyr Ala Trp Arg Arg 1655 1660 1665 Gly Asn Phe Tyr Lys Leu Arg Met Gly Glu Tyr Ser Val Glu Met 1670 1675 1680 Val Ser Arg Lys Glu Thr Thr Gln Met Ser Thr Asp Gln Glu Glu 1685 1690 1695 Val Thr Gly Ile Gly Asp Asp Ala Gly Ser Val Asn Gln Ala Ala 1700 1705 1710 Phe Asp Pro Ala His Leu Cys Glu Asn Thr Gln Ser Val Lys Ser 1715 1720 1725 Thr Val 1730 <210> SEQ ID NO 11 <211> LENGTH: 6387 <212> TYPE: DNA <213> ORGANISM: mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/NM_011426 <309> DATABASE ENTRY DATE: 2000-01-25 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(6387) <400> SEQUENCE: 11 agacaagatt aggcctagag taagtctatg aaacacagag aaaggggaca gcataggggt 60 taagaaatga ggtctttcaa aatctcaggg ggcaatgagg agttttttga gagaggaagg 120 actctttaaa ggaagttgaa ggaggattct gtgaacttga gaccaccctg agctgccaag 180 ttgagaactt tgtctacaaa caagccaggc agcctcagcg tgtgctcagt ccgacttgta 240 gctggagagg caggagacca atttccggtg cttacggtgc ttgctggatg ccctggagta 300 agtgacaggg tctcactgga ctccaggttc tgttggtttg agtaatagga ggcggcaggg 360 gagaagtgaa gagagacatg cactgctgat ctgccttgag gctgtgtcct taaggggtgg 420 agccaagggg cacagaagac tctctgggac atgccaccaa gtgagagcat ttccaatcac 480 tccctgagcc aggaacaggg gcttctggtt ccctgctggt ggctgccaca gcagtccttc 540 ctgttgggtt gaccaacaca gcaggtgaga taaaccctat agacttgggc cctggagtgc 600 tccaggcagt ctctgtgtgc ctacccaccc ggcttcccta ggcacctgaa tgcacctggg 660 cactgggatg tgtgtcctgt tctccctgct cctgctggcc tctgtcttct cactaggcca 720 gaccacatgg ggtgtctcca gtcccaagaa tgtgcagggc ttgtcgggat cctgcctgct 780 cattccctgc atcttcagct accctgccga tgtcccagtg tccaatggca tcacagccat 840 ctggtactat gactactcgg gcaagcggca ggtggtaatc cactcagggg accccaagct 900 ggtggacaag cgtttcaggg gtcgagctga actgatgggg aacatggacc acaaggtgtg 960 caacctgttg ctcaaagact tgaagcctga agactctggc acctacaact tccgctttga 1020 gatcagtgat agcaaccgct ggttagatgt caaaggcacc acggtcactg tgacaacgga 1080 tcccagcccc cccactatta ccattcctga ggagctgcgt gaaggcatgg agaggaactt 1140 caactgttcc acaccctacc tgtgcctgca ggagaagcaa gtcagcctgc agtggcgagg 1200 ccaggacccc acccactctg tcacctccag cttccagagc ctcgagccca ctggcgtcta 1260 tcaccagacg accctacata tggccctatc ctggcaggac cacggtcgga ccctgctctg 1320 ccagttctca ttgggcgcac acagtagtcg gaaagaggtt tacctgcaag tgccacatgc 1380 ccccaaaggt gtggagatcc tcctcagctc ctcagggagg aacatccttc ccggggatcc 1440 agtcacactc acctgcagag tgaacagcag ctatcctgct gtcagtgccg tgcagtgggc 1500 cagggacgga gtgaacctcg gagtcacggg acatgtgctt cggctgttct cagcagcctg 1560 gaatgattct ggggcctaca cctgccaagc aacaaatgat atgggctctc tggtgtcatc 1620 cccgctcagc ctccatgttt ttatggctga agtcaaaatg aaccccgcag ggcccgtctt 1680 ggaaaatgag acagtgactc tgctctgtag cacgccgaag gaggctcccc aggagctccg 1740 ctatagctgg tacaagaacc acattctcct ggaagatgcc catgcctcaa ccttgcacct 1800 gcctgcagtc accagggctg atactggctt ctacttctgt gaagtgcaga atgcccaggg 1860 cagtgagcgc tccagtccat tgagtgtggt ggtcagatat ccacccctta ctccagacct 1920 gaccaccttc ctggagacac aggccggact tgtgggcatc ttgcattgct ccgtggtcag 1980 tgagcccctg gctactgtgg tgctgtcaca cggaggcctc acgttggcct ccaactctgg 2040 agaaaatgac ttcaaccccc gattcaggat ctcctctgcc cccaactccc tgcgcctaga 2100 aatccgagac ttgcagccag cagacagcgg agagtacaca tgcttagctg tcaactccct 2160 tggaaactca acgtccagcc tagacttcta tgctaatgtg gcccgactcc tcatcaaccc 2220 ttcagcagag gttgtggaag ggcaggcggt gaccctgagc tgcaggagtg gcctgagccc 2280 agctcctgac actcgcttct cctggtacct gaacggagct ctacttctgg aaggatccag 2340 cagcagcctc ctgcttcctg cggcttccag cactgatgcg ggctcatact actgtaggac 2400 gcaggctggc cccaacacca gcggcccctc cctgcctact gtcctcactg tgttctatcc 2460 cccaagaaag cccacattca ctgccaggct ggatttggat acctctggag tcggggatgg 2520 acgacggggc atcctcttgt gccacgtaga cagcgatccc ccagcccagc tacggcttct 2580 ccacaaaggc catgttgtgg ccacttctct gccatcaagg tgtgggagct gttcccagcg 2640 cacaaaagtc agcagaacct ccaactcact gcacgtggag atccagaagc ctgtattaga 2700 ggatgagggc gtgtacctgt gtgaggctag caacacattg ggcaactcct cagccgcagc 2760 ctctttcaat gctaaggcca ctgtactggt catcacaccg tcaaatacac tgcgtgaagg 2820 cacagaggcc aacctaactt gcaacgtgaa ccaggaggtt gctgtcagcc ctgccaactt 2880 ctcctggttc cggaatggag tgctgtggac ccagggatca ctggagactg tgaggctgca 2940 gcctgtggcc agaactgatg ctgctgtcta tgcctgccgc ctcctcaccg aggatggggc 3000 tcagctctcg gctcctgtgg tcctaagtgt gctgtatgcc ccagaccctc caaagctgtc 3060 agccctccta gatgtgggtc agggccacat ggccgtgttc atctgcactg tggacagcta 3120 tcccctggct cacctgtctc tgttccgtgg ggaccatctc ctggccacca acttggaacc 3180 ccagcgtccc tcccatggca ggatccaggc caaggccaca gccaactccc tgcagctaga 3240 ggtccgagaa ctaggtcttg tggactctgg aaactaccac tgtgaagcca ccaatattct 3300 tgggtcagcc aacagttcac tcttcttcca ggtcagagga gcctgggtcc aggtttcacc 3360 atcacctgag ctccgggagg gccaggctgt ggtcctgagc tgccaggtgc ccacaggagt 3420 ctctgagggg acctcataca gctggtatca ggatggccgc cccctccagg agtcaacctc 3480 atctacactc cgcattgcag ccataagtct gaggcaagct ggtgcctacc attgccaagc 3540 tcaggcccca gacacagcta ttgccagcct ggctgcccct gtcagcctcc atgtgtccta 3600 taccccacgt catgttacac tcagtgccct gctgagcacg gaccctgagc gactaggcca 3660 cctggtgtgc agtgtacaaa gtgaccctcc agcgcagctg caactgtttc accggaatcg 3720 cctcgtggcc tctaccctac aaggcgcgga cgaattggca ggcagtaatc cccggctgca 3780 tgtgactgtg ctccccaatg agctgcgcct gcagatccac tttccagagc tggaggatga 3840 cgggacctat acatgcgaag ccagcaacac actgggccag gcctcggctg cagctgactt 3900 cgatgcccag gctgtgcgag tgactgtgtg gcccaatgcc actgtgcaag aggggcagca 3960 ggtgaacctg acctgcttgg tgtggagcac ccaccaggac tcactcagct acacatggta 4020 caagggcggg caacaactcc ttggtgccag atccatcacc ctgcccagtg ttaaggtttt 4080 ggatgctacc tcctaccgct gtggtgtggg gctccccggc cacgcacccc atctctccag 4140 acccgtgacc ctggatgtcc tccatgctcc ccgaaacctg cggctgacct acctcctaga 4200 gacccagggc aggcagctgg ccctggtact gtgtacggtg gatagtcgtc cacctgccca 4260 gctaactctc agccatggtg accagcttgt agcctcctca actgaagcct ctgtccccaa 4320 caccctgcgc ctagagcttc aggatccaag gcctagtaat gaggggctct atagctgctc 4380 tgcccacagc ccattgggca aggccaacac gtccctggaa cttctgctgg aaggtgtccg 4440 agtgaaaatg aatccctctg gtagtgtacc cgagggagag cctgtcacag tgacctgcga 4500 ggaccctgct gccctctcat ccgccctcta tgcctggttt cacaatggcc attggcttca 4560 ggagggaccg gcttcctcac tccagttcct ggtgactaca cgggctcacg ctggtgctta 4620 cttttgccag gtgcatgata cacaaggcac acggagctcc agacctgcca gcctgcaaat 4680 tctctatgcc ccccgggatg ctgtcctgtc ttcctttcga gactcaagga ccaggctcat 4740 ggtcgtgatt cagtgcaccg tggacagtga gccacctgct gagatggtcc tatcccacaa 4800 tggcaaggtg ctagctgcca gccacgagcg tcacagctca gcatcaggga taggccacat 4860 ccaggtagcc cgaaatgctc ttcgactaca agtgcaagat gtgactctgg gtgatggcaa 4920 cacctatgtt tgcacagccc agaatacact gggctccatc agtaccaccc agaggcttct 4980 gacggagact gatatacgtg tgacagctga gccaggcttg gatgtgccag agggcacagc 5040 tctgaactta agctgcctcc tccctggtgg ctctgggccc acgggcaact cttccttcac 5100 gtggttctgg aatcgccacc gactacattc agctcctgtg cccacactct ccttcacccc 5160 tgtggtccgg gctcaggctg ggctgtacca ctgcagggct gatctcccca ccggggccac 5220 tacctctgct ccagttatgc tccgtgtcct ctatcccccc aagacgccca ctctcatagt 5280 gtttgtggag cctcagggtg gccaccaggg catcctcgac tgtcgagtgg acagtgagcc 5340 cctggccatc ctcactcttc accggggcag tcaactagta gcctccaacc aacttcacga 5400 tgctcccacc aagccccaca tccgagtcac tgctcctccc aatgccttga gagtggacat 5460 agaggagctc ggccctagca atcaagggga gtatgtgtgc actgcctcca acactctggg 5520 ctctgcctca gcctctgcct actttgggac cagagctctg caccaactgc agctgttcca 5580 gaggctgctc tgggtcctgg gatttctggc aggcttcctg tgcctgctgc tgggtctggt 5640 ggcctatcac acctggagaa agaagagttc taccaagctg aatgaggatg agaattcagc 5700 agagatggcc actaagaaaa atactatcca ggaggaagtg gttgctgctc tctgacaact 5760 caggtgctgt gaacaagatc ctgcctacct ctgtataagc agtacagaga catctggctt 5820 tcctgacctg cccgacttgc cttccaagcc tcttgatcct aagaaaaatg gacgaaggga 5880 ggtttggggt tggaggtcaa cctgccgcct ccagggctct gagacggact cagccatgtt 5940 gcccacgtct ctctgtgtgg ttttcctctg tatccctttg cctttctctt caaagctcac 6000 cttggacttt cttggtgggt tagagcaaca tccagtttct cacagacttt ctaagacggt 6060 ctgtaccagc caggatatca gtcaggttgc tctaacagag actcaataca gtgaccacag 6120 catgacaggg tcttagtttt ccctcctggc ctggttatgt tgttgtggta tcagaatcct 6180 tcttgcttga ttttctccat tccccaagtg ttgcctttga ttatgaagct caggtaactg 6240 cagtgcccat ggaccctaca gggagaagga agagtgaagg gaagacatac ccatccccat 6300 ggtccatgga ctgtgtgtgc aattgcaccc cacccaactt ctcatccgct agaaactggt 6360 cacataaaca taccatgctg aaaggga 6387 <210> SEQ ID NO 12 <211> LENGTH: 1695 <212> TYPE: PRT <213> ORGANISM: mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept <309> DATABASE ENTRY DATE: 2000-01-25 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1695) <400> SEQUENCE: 12 Met Cys Val Leu Phe Ser Leu Leu Leu Leu Ala Ser Val Phe Ser Leu 1 5 10 15 Gly Gln Thr Thr Trp Gly Val Ser Ser Pro Lys Asn Val Gln Gly Leu 20 25 30 Ser Gly Ser Cys Leu Leu Ile Pro Cys Ile Phe Ser Tyr Pro Ala Asp 35 40 45 Val Pro Val Ser Asn Gly Ile Thr Ala Ile Trp Tyr Tyr Asp Tyr Ser 50 55 60 Gly Lys Arg Gln Val Val Ile His Ser Gly Asp Pro Lys Leu Val Asp 65 70 75 80 Lys Arg Phe Arg Gly Arg Ala Glu Leu Met Gly Asn Met Asp His Lys 85 90 95 Val Cys Asn Leu Leu Leu Lys Asp Leu Lys Pro Glu Asp Ser Gly Thr 100 105 110 Tyr Asn Phe Arg Phe Glu Ile Ser Asp Ser Asn Arg Trp Leu Asp Val 115 120 125 Lys Gly Thr Thr Val Thr Val Thr Thr Asp Pro Ser Pro Pro Thr Ile 130 135 140 Thr Ile Pro Glu Glu Leu Arg Glu Gly Met Glu Arg Asn Phe Asn Cys 145 150 155 160 Ser Thr Pro Tyr Leu Cys Leu Gln Glu Lys Gln Val Ser Leu Gln Trp 165 170 175 Arg Gly Gln Asp Pro Thr His Ser Val Thr Ser Ser Phe Gln Ser Leu 180 185 190 Glu Pro Thr Gly Val Tyr His Gln Thr Thr Leu His Met Ala Leu Ser 195 200 205 Trp Gln Asp His Gly Arg Thr Leu Leu Cys Gln Phe Ser Leu Gly Ala 210 215 220 His Ser Ser Arg Lys Glu Val Tyr Leu Gln Val Pro His Ala Pro Lys 225 230 235 240 Gly Val Glu Ile Leu Leu Ser Ser Ser Gly Arg Asn Ile Leu Pro Gly 245 250 255 Asp Pro Val Thr Leu Thr Cys Arg Val Asn Ser Ser Tyr Pro Ala Val 260 265 270 Ser Ala Val Gln Trp Ala Arg Asp Gly Val Asn Leu Gly Val Thr Gly 275 280 285 His Val Leu Arg Leu Phe Ser Ala Ala Trp Asn Asp Ser Gly Ala Tyr 290 295 300 Thr Cys Gln Ala Thr Asn Asp Met Gly Ser Leu Val Ser Ser Pro Leu 305 310 315 320 Ser Leu His Val Phe Met Ala Glu Val Lys Met Asn Pro Ala Gly Pro 325 330 335 Val Leu Glu Asn Glu Thr Val Thr Leu Leu Cys Ser Thr Pro Lys Glu 340 345 350 Ala Pro Gln Glu Leu Arg Tyr Ser Trp Tyr Lys Asn His Ile Leu Leu 355 360 365 Glu Asp Ala His Ala Ser Thr Leu His Leu Pro Ala Val Thr Arg Ala 370 375 380 Asp Thr Gly Phe Tyr Phe Cys Glu Val Gln Asn Ala Gln Gly Ser Glu 385 390 395 400 Arg Ser Ser Pro Leu Ser Val Val Val Arg Tyr Pro Pro Leu Thr Pro 405 410 415 Asp Leu Thr Thr Phe Leu Glu Thr Gln Ala Gly Leu Val Gly Ile Leu 420 425 430 His Cys Ser Val Val Ser Glu Pro Leu Ala Thr Val Val Leu Ser His 435 440 445 Gly Gly Leu Thr Leu Ala Ser Asn Ser Gly Glu Asn Asp Phe Asn Pro 450 455 460 Arg Phe Arg Ile Ser Ser Ala Pro Asn Ser Leu Arg Leu Glu Ile Arg 465 470 475 480 Asp Leu Gln Pro Ala Asp Ser Gly Glu Tyr Thr Cys Leu Ala Val Asn 485 490 495 Ser Leu Gly Asn Ser Thr Ser Ser Leu Asp Phe Tyr Ala Asn Val Ala 500 505 510 Arg Leu Leu Ile Asn Pro Ser Ala Glu Val Val Glu Gly Gln Ala Val 515 520 525 Thr Leu Ser Cys Arg Ser Gly Leu Ser Pro Ala Pro Asp Thr Arg Phe 530 535 540 Ser Trp Tyr Leu Asn Gly Ala Leu Leu Leu Glu Gly Ser Ser Ser Ser 545 550 555 560 Leu Leu Leu Pro Ala Ala Ser Ser Thr Asp Ala Gly Ser Tyr Tyr Cys 565 570 575 Arg Thr Gln Ala Gly Pro Asn Thr Ser Gly Pro Ser Leu Pro Thr Val 580 585 590 Leu Thr Val Phe Tyr Pro Pro Arg Lys Pro Thr Phe Thr Ala Arg Leu 595 600 605 Asp Leu Asp Thr Ser Gly Val Gly Asp Gly Arg Arg Gly Ile Leu Leu 610 615 620 Cys His Val Asp Ser Asp Pro Pro Ala Gln Leu Arg Leu Leu His Lys 625 630 635 640 Gly His Val Val Ala Thr Ser Leu Pro Ser Arg Cys Gly Ser Cys Ser 645 650 655 Gln Arg Thr Lys Val Ser Arg Thr Ser Asn Ser Leu His Val Glu Ile 660 665 670 Gln Lys Pro Val Leu Glu Asp Glu Gly Val Tyr Leu Cys Glu Ala Ser 675 680 685 Asn Thr Leu Gly Asn Ser Ser Ala Ala Ala Ser Phe Asn Ala Lys Ala 690 695 700 Thr Val Leu Val Ile Thr Pro Ser Asn Thr Leu Arg Glu Gly Thr Glu 705 710 715 720 Ala Asn Leu Thr Cys Asn Val Asn Gln Glu Val Ala Val Ser Pro Ala 725 730 735 Asn Phe Ser Trp Phe Arg Asn Gly Val Leu Trp Thr Gln Gly Ser Leu 740 745 750 Glu Thr Val Arg Leu Gln Pro Val Ala Arg Thr Asp Ala Ala Val Tyr 755 760 765 Ala Cys Arg Leu Leu Thr Glu Asp Gly Ala Gln Leu Ser Ala Pro Val 770 775 780 Val Leu Ser Val Leu Tyr Ala Pro Asp Pro Pro Lys Leu Ser Ala Leu 785 790 795 800 Leu Asp Val Gly Gln Gly His Met Ala Val Phe Ile Cys Thr Val Asp 805 810 815 Ser Tyr Pro Leu Ala His Leu Ser Leu Phe Arg Gly Asp His Leu Leu 820 825 830 Ala Thr Asn Leu Glu Pro Gln Arg Pro Ser His Gly Arg Ile Gln Ala 835 840 845 Lys Ala Thr Ala Asn Ser Leu Gln Leu Glu Val Arg Glu Leu Gly Leu 850 855 860 Val Asp Ser Gly Asn Tyr His Cys Glu Ala Thr Asn Ile Leu Gly Ser 865 870 875 880 Ala Asn Ser Ser Leu Phe Phe Gln Val Arg Gly Ala Trp Val Gln Val 885 890 895 Ser Pro Ser Pro Glu Leu Arg Glu Gly Gln Ala Val Val Leu Ser Cys 900 905 910 Gln Val Pro Thr Gly Val Ser Glu Gly Thr Ser Tyr Ser Trp Tyr Gln 915 920 925 Asp Gly Arg Pro Leu Gln Glu Ser Thr Ser Ser Thr Leu Arg Ile Ala 930 935 940 Ala Ile Ser Leu Arg Gln Ala Gly Ala Tyr His Cys Gln Ala Gln Ala 945 950 955 960 Pro Asp Thr Ala Ile Ala Ser Leu Ala Ala Pro Val Ser Leu His Val 965 970 975 Ser Tyr Thr Pro Arg His Val Thr Leu Ser Ala Leu Leu Ser Thr Asp 980 985 990 Pro Glu Arg Leu Gly His Leu Val Cys Ser Val Gln Ser Asp Pro Pro 995 1000 1005 Ala Gln Leu Gln Leu Phe His Arg Asn Arg Leu Val Ala Ser Thr 1010 1015 1020 Leu Gln Gly Ala Asp Glu Leu Ala Gly Ser Asn Pro Arg Leu His 1025 1030 1035 Val Thr Val Leu Pro Asn Glu Leu Arg Leu Gln Ile His Phe Pro 1040 1045 1050 Glu Leu Glu Asp Asp Gly Thr Tyr Thr Cys Glu Ala Ser Asn Thr 1055 1060 1065 Leu Gly Gln Ala Ser Ala Ala Ala Asp Phe Asp Ala Gln Ala Val 1070 1075 1080 Arg Val Thr Val Trp Pro Asn Ala Thr Val Gln Glu Gly Gln Gln 1085 1090 1095 Val Asn Leu Thr Cys Leu Val Trp Ser Thr His Gln Asp Ser Leu 1100 1105 1110 Ser Tyr Thr Trp Tyr Lys Gly Gly Gln Gln Leu Leu Gly Ala Arg 1115 1120 1125 Ser Ile Thr Leu Pro Ser Val Lys Val Leu Asp Ala Thr Ser Tyr 1130 1135 1140 Arg Cys Gly Val Gly Leu Pro Gly His Ala Pro His Leu Ser Arg 1145 1150 1155 Pro Val Thr Leu Asp Val Leu His Ala Pro Arg Asn Leu Arg Leu 1160 1165 1170 Thr Tyr Leu Leu Glu Thr Gln Gly Arg Gln Leu Ala Leu Val Leu 1175 1180 1185 Cys Thr Val Asp Ser Arg Pro Pro Ala Gln Leu Thr Leu Ser His 1190 1195 1200 Gly Asp Gln Leu Val Ala Ser Ser Thr Glu Ala Ser Val Pro Asn 1205 1210 1215 Thr Leu Arg Leu Glu Leu Gln Asp Pro Arg Pro Ser Asn Glu Gly 1220 1225 1230 Leu Tyr Ser Cys Ser Ala His Ser Pro Leu Gly Lys Ala Asn Thr 1235 1240 1245 Ser Leu Glu Leu Leu Leu Glu Gly Val Arg Val Lys Met Asn Pro 1250 1255 1260 Ser Gly Ser Val Pro Glu Gly Glu Pro Val Thr Val Thr Cys Glu 1265 1270 1275 Asp Pro Ala Ala Leu Ser Ser Ala Leu Tyr Ala Trp Phe His Asn 1280 1285 1290 Gly His Trp Leu Gln Glu Gly Pro Ala Ser Ser Leu Gln Phe Leu 1295 1300 1305 Val Thr Thr Arg Ala His Ala Gly Ala Tyr Phe Cys Gln Val His 1310 1315 1320 Asp Thr Gln Gly Thr Arg Ser Ser Arg Pro Ala Ser Leu Gln Ile 1325 1330 1335 Leu Tyr Ala Pro Arg Asp Ala Val Leu Ser Ser Phe Arg Asp Ser 1340 1345 1350 Arg Thr Arg Leu Met Val Val Ile Gln Cys Thr Val Asp Ser Glu 1355 1360 1365 Pro Pro Ala Glu Met Val Leu Ser His Asn Gly Lys Val Leu Ala 1370 1375 1380 Ala Ser His Glu Arg His Ser Ser Ala Ser Gly Ile Gly His Ile 1385 1390 1395 Gln Val Ala Arg Asn Ala Leu Arg Leu Gln Val Gln Asp Val Thr 1400 1405 1410 Leu Gly Asp Gly Asn Thr Tyr Val Cys Thr Ala Gln Asn Thr Leu 1415 1420 1425 Gly Ser Ile Ser Thr Thr Gln Arg Leu Leu Thr Glu Thr Asp Ile 1430 1435 1440 Arg Val Thr Ala Glu Pro Gly Leu Asp Val Pro Glu Gly Thr Ala 1445 1450 1455 Leu Asn Leu Ser Cys Leu Leu Pro Gly Gly Ser Gly Pro Thr Gly 1460 1465 1470 Asn Ser Ser Phe Thr Trp Phe Trp Asn Arg His Arg Leu His Ser 1475 1480 1485 Ala Pro Val Pro Thr Leu Ser Phe Thr Pro Val Val Arg Ala Gln 1490 1495 1500 Ala Gly Leu Tyr His Cys Arg Ala Asp Leu Pro Thr Gly Ala Thr 1505 1510 1515 Thr Ser Ala Pro Val Met Leu Arg Val Leu Tyr Pro Pro Lys Thr 1520 1525 1530 Pro Thr Leu Ile Val Phe Val Glu Pro Gln Gly Gly His Gln Gly 1535 1540 1545 Ile Leu Asp Cys Arg Val Asp Ser Glu Pro Leu Ala Ile Leu Thr 1550 1555 1560 Leu His Arg Gly Ser Gln Leu Val Ala Ser Asn Gln Leu His Asp 1565 1570 1575 Ala Pro Thr Lys Pro His Ile Arg Val Thr Ala Pro Pro Asn Ala 1580 1585 1590 Leu Arg Val Asp Ile Glu Glu Leu Gly Pro Ser Asn Gln Gly Glu 1595 1600 1605 Tyr Val Cys Thr Ala Ser Asn Thr Leu Gly Ser Ala Ser Ala Ser 1610 1615 1620 Ala Tyr Phe Gly Thr Arg Ala Leu His Gln Leu Gln Leu Phe Gln 1625 1630 1635 Arg Leu Leu Trp Val Leu Gly Phe Leu Ala Gly Phe Leu Cys Leu 1640 1645 1650 Leu Leu Gly Leu Val Ala Tyr His Thr Trp Arg Lys Lys Ser Ser 1655 1660 1665 Thr Lys Leu Asn Glu Asp Glu Asn Ser Ala Glu Met Ala Thr Lys 1670 1675 1680 Lys Asn Thr Ile Gln Glu Glu Val Val Ala Ala Leu 1685 1690 1695 <210> SEQ ID NO 13 <211> LENGTH: 6736 <212> TYPE: DNA <213> ORGANISM: homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/NM_023068 <309> DATABASE ENTRY DATE: 2001-02-13 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(6736) <400> SEQUENCE: 13 atgggcttct tgcccaagct tctcctcctg gcctcattct tcccagcagg ccaggcctca 60 tggggcgtct ccagtcccca ggacgtgcag ggtgtgaagg ggtcttgcct gcttatcccc 120 tgcatcttca gcttccctgc cgacgtggag gtgcccgacg gcatcacggc catctggtac 180 tacgactact cgggccagcg gcaggtggtg agccactcgg cggaccccaa gctggtggag 240 gcccgcttcc gcggccgcac cgagttcatg gggaaccccg agcacagggt gtgcaacctg 300 ctgctgaagg acctgcagcc cgaggactct ggttcctaca acttccgctt cgagatcagt 360 gaggtcaacc gctggtcaga tgtgaaaggc accttggtca cagtaacaga ggagcccagg 420 gtgcccacca ttgcctcccc ggtggagctt ctcgagggca cagaggtgga cttcaactgc 480 tccactccct acgtatgcct gcaggagcag gtcagactgc agtggcaagg ccaggaccct 540 gctcgctctg tcaccttcaa cagccagaag tttgagccca ccggcgtcgg ccacctggag 600 accctccaca tggccatgtc ctggcaggac cacggccgga tcctgcgctg ccagctctcc 660 gtggccaatc acagggctca gagcgagatt cacctccaag tgaagtatgc ccccaagggt 720 gtgaagatcc tcctcagccc ctcggggagg aacatccttc caggtgagct ggtcacactc 780 acctgccagg tgaacagcag ctaccctgca gtcagttcca ttaagtggct caaggatggg 840 gtacgcctcc aaaccaagac tggtgtgctg cacctgcccc aggcagcctg gagcgatgct 900 ggcgtctaca cctgccaagc tgagaacggc gtgggctctt tggtctcacc ccccatcagc 960 ctccacatct tcatggctga ggtccaggtg agcccagcag gtcccatcct ggagaaccag 1020 acagtgacac tagtctgcaa cacacccaat gaggcaccca gtgatctccg ctacagctgg 1080 tacaagaacc atgtcctgct ggaggatgcc cactcccata ccctccggct gcacttggcc 1140 actagggctg atactggctt ctacttctgt gaggtgcaga acgtccatgg cagcgagcgc 1200 tcgggccctg tcagcgtggt agtcaaccac ccgcctctca ctccagtcct gacagccttc 1260 ctggagaccc aggcgggact tgtgggcatc cttcactgct ctgtggtcag tgagcccctg 1320 gccacactgg tgctgtcaca tgggggtcat atcctggcct ccacctccgg ggacagtgat 1380 cacagcccac gcttcagtgg tacctctggt cccaactccc tgcgcctgga gatccgagac 1440 ctggaggaaa ctgacagtgg ggagtacaag tgctcagcca ccaactccct tggaaatgca 1500 acctccaccc tggacttcca tgccaatgcc gcccgtctcc tcatcagccc ggcagccgag 1560 gtggtggaag gacaggcagt gacactgagc tgcagaagcg gcctaagccc cacacctgat 1620 gcccgcttct cctggtacct gaatggagcc ctgcttcacg agggtcccgg cagcagcctc 1680 ctgctccccg cggcctccag cactgacgcc ggctcatacc actgccgggc ccgggacggc 1740 cacagtgcca gtggcccctc ttcgccagct gttctcactg tgctctaccc ccctcgacaa 1800 ccaacattca ccaccaggct ggaccttgat gccgctgggg ccggggctgg acggcgaggc 1860 ctccttttgt gccgtgtgga cagcgacccc cccgccaggc tgcagctgct ccacaaggac 1920 cgtgttgtgg ccacttccct gccatcaggg ggtggctgca gcacctgtgg gggctgttcc 1980 ccacgcatga aggtcaccaa agcccccaac ttgctgcgtg tggagattca caaccctttg 2040 ctggaagagg agggcttgta cctctgtgag gccagcaatg ccctgggcaa cgcctccacc 2100 tcagccacct tcaatggcca ggccactgtc ctggccattg caccatcaca cacacttcag 2160 gagggcacag aagccaactt gacttgcaac gtgagccggg aagctgctgg cagccctgct 2220 aacttctcct ggttccgaaa tggggtgctg tgggcccagg gtcccctgga gaccgtgaca 2280 ctgctgcccg tggccagaac tgatgctgcc ctttacgcct gccgcatcct gactgaggct 2340 ggtgcccagc tctccactcc cgtgctcctg agtgtactct atcccccgga ccgtccaaag 2400 ctgtcagccc tcctagacat gggccagggc cacatggctc tgttcatctg cactgtggac 2460 agccgccccc tggccttgct ggccttgttc catggggagc acctcctggc caccagcctg 2520 ggtccccagg tcccatccca tggtcggttc caggctaaag ctgaggccaa ctccctgaag 2580 ttagaggtcc gagaactggg ccttggggac tctggcagct accgctgtga ggccacaaat 2640 gttcttggat catccaacac ctcactcttc ttccaggtcc gaggagcctg ggtccaggtg 2700 tcaccatcac ctgagctcca agagggccag gctgtggtcc tgagctgcca ggtacacaca 2760 ggagtcccag aggggacctc atatcgttgg tatcgggatg gccagcccct ccaggagtcg 2820 acctcggcca cgctccgctt tgcagccata actttgacac aagctggggc ctatcattgc 2880 caagcccagg ccccaggctc agccaccacg agcctagctg cacccatcag cctccacgtg 2940 tcctatgccc cacgccacgt cacactcact accctgatgg acacaggccc tggacgactg 3000 ggcctcctcc tgtgccgtgt ggacagtgac cctccggccc agctgcggct gctccacggg 3060 gatcgccttg tggcctccac cctacaaggt gtggggggac ccgaaggcag ctctcccagg 3120 ctgcatgtgg ctgtggcccc caacacactg cgtctggaga tccacggggc tatgctggag 3180 gatgagggtg tctatatctg tgaggcctcc aacaccctgg gccaggcctc ggcctcagct 3240 gacttcgacg ctcaagctgt gaatgtgcag gtgtggcccg gggctaccgt gcgggagggg 3300 cagctggtga acctgacctg ccttgtgtgg accactcacc cggcccagct cacctacaca 3360 tggtaccagg atgggcagca gcgcctggat gcccactcca tccccctgcc caacgtcaca 3420 gtcagggatg ccacctccta ccgctgcggt gtgggccccc ctggtcgggc accccgcctc 3480 tccagaccta tcaccttgga cgtcctctac gcgccccgca acctgcgcct gacctacctc 3540 ctggagagcc atggcgggca gctggccctg gtactgtgca ctgtggacag ccgcccgccc 3600 gcccagctgg ccctcagcca cgccggtcgc ctcttggcct cctcgacagc agcctctgtc 3660 cccaacaccc tgcgcctgga gctgcgaggg ccacagccca gggatgaggg tttctacagc 3720 tgctctgccc gcagccctct gggccaggcc aacacgtccc tggagctgcg gctggagggt 3780 gtgcgggtga tcctggctcc ggaggctgcc gtgcctgaag gtgcccccat cacagtgacc 3840 tgtgcggacc ctgctgccca cgcacccaca ctctatactt ggtaccacaa cggtcgttgg 3900 ctgcaggagg gtccagctgc ctcactctca ttcctggtgg ccacgcgggc tcatgcaggc 3960 gcctactctt gccaggccca ggatgcccag ggcacccgca gctcccgtcc tgctgccctg 4020 caagtcctct atgcccctca ggacgctgtc ctgtcctcct tccgggactc cagggccaga 4080 tccatggctg tgatacagtg cactgtggac agtgagccac ctgctgagct ggccctatct 4140 catgatggca aggtgctggc cacgagcagc ggggtccaca gcttggcatc agggacaggc 4200 catgtccagg tggcccgaaa cgccctacgg ctgcaggtgc aagatgtgcc tgcaggtgat 4260 gacacctatg tttgcacagc ccaaaacttg ctgggctcaa tcagcaccat cgggcggttg 4320 caggtagaag gtgcacgcgt ggtggcagag cctggcctgg acgtgcctga gggcgctgcc 4380 ctgaacctca gctgccgcct cctgggtggc cctgggcctg tgggcaactc cacctttgca 4440 tggttctgga atgaccggcg gctgcacgcg gagcctgtgc ccactctcgc cttcacccac 4500 gtggctcgtg ctcaagctgg gatgtaccac tgcctggctg agctccccac tggggctgct 4560 gcctctgctc cagtcatgct ccgtgtgctc taccctccca agacgcccac catgatggtc 4620 ttcgtggagc ctgagggtgg cctccggggc atcctggatt gccgagtgga cagcgagccg 4680 ctcgccagcc tgactctcca ccttggcagt cgactggtgg cctccagtca gccccagggt 4740 gctcctgcag agccacacat ccatgtcctg gcttccccca atgccctgag ggtggacatc 4800 gaggcgctga ggcccagcga ccaaggggaa tacatctgtt ctgcctcaaa tgtcctgggc 4860 tctgcctcta cctccaccta ctttggggtc agagccctgc accgcctgca tcagttccag 4920 cagctgctct gggtcctggg actgctggtg ggcctcctgc tcctgctgtt gggcctgggg 4980 gcctgctaca cctggagaag gaggcgtgtt tgtaagcaga gcatgggcga gaattcggtg 5040 gagatggctt ttcagaaaga gaccacgcag ctcattgatc ctgatgcagc cacatgtgag 5100 acctcaacct gtgccccacc cctgggctga ccagtggtgt tgcctgccct ccggaggaga 5160 aagtggccag aatctgtgat gactccagcc tatgaatgtg aatgaggcag tgttgagtcc 5220 tgcccgcctc tacgaaaaca gctctgtgac atctgacttt ttatgacctg gccccaagcc 5280 tcttgccccc ccaaaaatgg gtggtgagag gtctgcccag gagggtgttg accctggagg 5340 acactgaaga gcactgagct gatctcgctc tctcttctct ggatctcctc ccttctctcc 5400 atttctccct caaaggaagc cctgcccttt cacatccttc tcctcgaaag tcaccctgga 5460 ctttggttgg attgcagcat cctgcatcct cagaggctca ccaaggcatt ctgtattcaa 5520 cagagtatca gtcagcctgc tctaacaaga gaccaaatac agtgacttca acatgataga 5580 attttatttt tctctcccac gctagtctgg ctgttacgat ggtttatgat gttggggctc 5640 aggatccttc tatcttcctt ttctctatcc ctaaaatgat gcctttgatt gtgaggctca 5700 ccatggcccc gctttgtcca catgccctcc agccagaaga aggaagagtg gaggtagaag 5760 cacacccatg cccatggtgg acgcaactca gaagctgcac aggacttttc cactcacttc 5820 ccattggctg gagtattgtc acatggctac tgcaagctac aagggagact gggaaatgta 5880 gtttttattt tgagtccaga ggacatttgg aattggactt ccaaaggact cccaactgtg 5940 agctcatccc tgagactttt gacattgttg ggaatgccac cagcaggcca tgttttgtct 6000 cagtgcccat ctactgaggg ccagggtgtg cccctggcca ttctggttgt gggcttcctg 6060 gaagaggtga tcactctcac actaagactg aggaaataaa aaaggtttgg tgttttccta 6120 gggagagagc atgccaggca gtggagttgc ctaagcagac atccttgtgc cagatttggc 6180 ccctgaaaga agagatgccc tcattcccac caccaccccc cctaccccca gggactgggt 6240 actaccttac tggcccttac aagagtggag ggcagacaca gatgttgtca gcatccttat 6300 tcctgctcca gatgcatctc tgttcatgac tgtgtgagct cctgtccttt tcctggagac 6360 cctgtgtcgg gctgttaaag agaatgagtt accaagaagg aatgacgtgc ccctgcgaat 6420 cagggaccaa caggagagag ctcttgagtg ggctagtgac tccccctgca gcctggtgga 6480 gatggtgtga ggagcgaaga gccctctgct ctaggatttg ggttgaaaaa cagagagaga 6540 agtggggagt tgccacagga gctaacacgc tgggaggcag ttgggggcgg gtgaactttg 6600 tgtagccgag gccgcaccct ccctcattcc aggctcattc attttcatgc tccattgcca 6660 gactcttgct gggagcccgt ccagaatgtc ctcccaataa aactccatcc tatgacgcaa 6720 aaaaaaaaaa aaaaaa 6736 <210> SEQ ID NO 14 <211> LENGTH: 1709 <212> TYPE: PRT <213> ORGANISM: homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/NP_075556 <309> DATABASE ENTRY DATE: 2001-02-13 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1709) <400> SEQUENCE: 14 Met Gly Phe Leu Pro Lys Leu Leu Leu Leu Ala Ser Phe Phe Pro Ala 1 5 10 15 Gly Gln Ala Ser Trp Gly Val Ser Ser Pro Gln Asp Val Gln Gly Val 20 25 30 Lys Gly Ser Cys Leu Leu Ile Pro Cys Ile Phe Ser Phe Pro Ala Asp 35 40 45 Val Glu Val Pro Asp Gly Ile Thr Ala Ile Trp Tyr Tyr Asp Tyr Ser 50 55 60 Gly Gln Arg Gln Val Val Ser His Ser Ala Asp Pro Lys Leu Val Glu 65 70 75 80 Ala Arg Phe Arg Gly Arg Thr Glu Phe Met Gly Asn Pro Glu His Arg 85 90 95 Val Cys Asn Leu Leu Leu Lys Asp Leu Gln Pro Glu Asp Ser Gly Ser 100 105 110 Tyr Asn Phe Arg Phe Glu Ile Ser Glu Val Asn Arg Trp Ser Asp Val 115 120 125 Lys Gly Thr Leu Val Thr Val Thr Glu Glu Pro Arg Val Pro Thr Ile 130 135 140 Ala Ser Pro Val Glu Leu Leu Glu Gly Thr Glu Val Asp Phe Asn Cys 145 150 155 160 Ser Thr Pro Tyr Val Cys Leu Gln Glu Gln Val Arg Leu Gln Trp Gln 165 170 175 Gly Gln Asp Pro Ala Arg Ser Val Thr Phe Asn Ser Gln Lys Phe Glu 180 185 190 Pro Thr Gly Val Gly His Leu Glu Thr Leu His Met Ala Met Ser Trp 195 200 205 Gln Asp His Gly Arg Ile Leu Arg Cys Gln Leu Ser Val Ala Asn His 210 215 220 Arg Ala Gln Ser Glu Ile His Leu Gln Val Lys Tyr Ala Pro Lys Gly 225 230 235 240 Val Lys Ile Leu Leu Ser Pro Ser Gly Arg Asn Ile Leu Pro Gly Glu 245 250 255 Leu Val Thr Leu Thr Cys Gln Val Asn Ser Ser Tyr Pro Ala Val Ser 260 265 270 Ser Ile Lys Trp Leu Lys Asp Gly Val Arg Leu Gln Thr Lys Thr Gly 275 280 285 Val Leu His Leu Pro Gln Ala Ala Trp Ser Asp Ala Gly Val Tyr Thr 290 295 300 Cys Gln Ala Glu Asn Gly Val Gly Ser Leu Val Ser Pro Pro Ile Ser 305 310 315 320 Leu His Ile Phe Met Ala Glu Val Gln Val Ser Pro Ala Gly Pro Ile 325 330 335 Leu Glu Asn Gln Thr Val Thr Leu Val Cys Asn Thr Pro Asn Glu Ala 340 345 350 Pro Ser Asp Leu Arg Tyr Ser Trp Tyr Lys Asn His Val Leu Leu Glu 355 360 365 Asp Ala His Ser His Thr Leu Arg Leu His Leu Ala Thr Arg Ala Asp 370 375 380 Thr Gly Phe Tyr Phe Cys Glu Val Gln Asn Val His Gly Ser Glu Arg 385 390 395 400 Ser Gly Pro Val Ser Val Val Val Asn His Pro Pro Leu Thr Pro Val 405 410 415 Leu Thr Ala Phe Leu Glu Thr Gln Ala Gly Leu Val Gly Ile Leu His 420 425 430 Cys Ser Val Val Ser Glu Pro Leu Ala Thr Leu Val Leu Ser His Gly 435 440 445 Gly His Ile Leu Ala Ser Thr Ser Gly Asp Ser Asp His Ser Pro Arg 450 455 460 Phe Ser Gly Thr Ser Gly Pro Asn Ser Leu Arg Leu Glu Ile Arg Asp 465 470 475 480 Leu Glu Glu Thr Asp Ser Gly Glu Tyr Lys Cys Ser Ala Thr Asn Ser 485 490 495 Leu Gly Asn Ala Thr Ser Thr Leu Asp Phe His Ala Asn Ala Ala Arg 500 505 510 Leu Leu Ile Ser Pro Ala Ala Glu Val Val Glu Gly Gln Ala Val Thr 515 520 525 Leu Ser Cys Arg Ser Gly Leu Ser Pro Thr Pro Asp Ala Arg Phe Ser 530 535 540 Trp Tyr Leu Asn Gly Ala Leu Leu His Glu Gly Pro Gly Ser Ser Leu 545 550 555 560 Leu Leu Pro Ala Ala Ser Ser Thr Asp Ala Gly Ser Tyr His Cys Arg 565 570 575 Ala Arg Asp Gly His Ser Ala Ser Gly Pro Ser Ser Pro Ala Val Leu 580 585 590 Thr Val Leu Tyr Pro Pro Arg Gln Pro Thr Phe Thr Thr Arg Leu Asp 595 600 605 Leu Asp Ala Ala Gly Ala Gly Ala Gly Arg Arg Gly Leu Leu Leu Cys 610 615 620 Arg Val Asp Ser Asp Pro Pro Ala Arg Leu Gln Leu Leu His Lys Asp 625 630 635 640 Arg Val Val Ala Thr Ser Leu Pro Ser Gly Gly Gly Cys Ser Thr Cys 645 650 655 Gly Gly Cys Ser Pro Arg Met Lys Val Thr Lys Ala Pro Asn Leu Leu 660 665 670 Arg Val Glu Ile His Asn Pro Leu Leu Glu Glu Glu Gly Leu Tyr Leu 675 680 685 Cys Glu Ala Ser Asn Ala Leu Gly Asn Ala Ser Thr Ser Ala Thr Phe 690 695 700 Asn Gly Gln Ala Thr Val Leu Ala Ile Ala Pro Ser His Thr Leu Gln 705 710 715 720 Glu Gly Thr Glu Ala Asn Leu Thr Cys Asn Val Ser Arg Glu Ala Ala 725 730 735 Gly Ser Pro Ala Asn Phe Ser Trp Phe Arg Asn Gly Val Leu Trp Ala 740 745 750 Gln Gly Pro Leu Glu Thr Val Thr Leu Leu Pro Val Ala Arg Thr Asp 755 760 765 Ala Ala Leu Tyr Ala Cys Arg Ile Leu Thr Glu Ala Gly Ala Gln Leu 770 775 780 Ser Thr Pro Val Leu Leu Ser Val Leu Tyr Pro Pro Asp Arg Pro Lys 785 790 795 800 Leu Ser Ala Leu Leu Asp Met Gly Gln Gly His Met Ala Leu Phe Ile 805 810 815 Cys Thr Val Asp Ser Arg Pro Leu Ala Leu Leu Ala Leu Phe His Gly 820 825 830 Glu His Leu Leu Ala Thr Ser Leu Gly Pro Gln Val Pro Ser His Gly 835 840 845 Arg Phe Gln Ala Lys Ala Glu Ala Asn Ser Leu Lys Leu Glu Val Arg 850 855 860 Glu Leu Gly Leu Gly Asp Ser Gly Ser Tyr Arg Cys Glu Ala Thr Asn 865 870 875 880 Val Leu Gly Ser Ser Asn Thr Ser Leu Phe Phe Gln Val Arg Gly Ala 885 890 895 Trp Val Gln Val Ser Pro Ser Pro Glu Leu Gln Glu Gly Gln Ala Val 900 905 910 Val Leu Ser Cys Gln Val His Thr Gly Val Pro Glu Gly Thr Ser Tyr 915 920 925 Arg Trp Tyr Arg Asp Gly Gln Pro Leu Gln Glu Ser Thr Ser Ala Thr 930 935 940 Leu Arg Phe Ala Ala Ile Thr Leu Thr Gln Ala Gly Ala Tyr His Cys 945 950 955 960 Gln Ala Gln Ala Pro Gly Ser Ala Thr Thr Ser Leu Ala Ala Pro Ile 965 970 975 Ser Leu His Val Ser Tyr Ala Pro Arg His Val Thr Leu Thr Thr Leu 980 985 990 Met Asp Thr Gly Pro Gly Arg Leu Gly Leu Leu Leu Cys Arg Val Asp 995 1000 1005 Ser Asp Pro Pro Ala Gln Leu Arg Leu Leu His Gly Asp Arg Leu 1010 1015 1020 Val Ala Ser Thr Leu Gln Gly Val Gly Gly Pro Glu Gly Ser Ser 1025 1030 1035 Pro Arg Leu His Val Ala Val Ala Pro Asn Thr Leu Arg Leu Glu 1040 1045 1050 Ile His Gly Ala Met Leu Glu Asp Glu Gly Val Tyr Ile Cys Glu 1055 1060 1065 Ala Ser Asn Thr Leu Gly Gln Ala Ser Ala Ser Ala Asp Phe Asp 1070 1075 1080 Ala Gln Ala Val Asn Val Gln Val Trp Pro Gly Ala Thr Val Arg 1085 1090 1095 Glu Gly Gln Leu Val Asn Leu Thr Cys Leu Val Trp Thr Thr His 1100 1105 1110 Pro Ala Gln Leu Thr Tyr Thr Trp Tyr Gln Asp Gly Gln Gln Arg 1115 1120 1125 Leu Asp Ala His Ser Ile Pro Leu Pro Asn Val Thr Val Arg Asp 1130 1135 1140 Ala Thr Ser Tyr Arg Cys Gly Val Gly Pro Pro Gly Arg Ala Pro 1145 1150 1155 Arg Leu Ser Arg Pro Ile Thr Leu Asp Val Leu Tyr Ala Pro Arg 1160 1165 1170 Asn Leu Arg Leu Thr Tyr Leu Leu Glu Ser His Gly Gly Gln Leu 1175 1180 1185 Ala Leu Val Leu Cys Thr Val Asp Ser Arg Pro Pro Ala Gln Leu 1190 1195 1200 Ala Leu Ser His Ala Gly Arg Leu Leu Ala Ser Ser Thr Ala Ala 1205 1210 1215 Ser Val Pro Asn Thr Leu Arg Leu Glu Leu Arg Gly Pro Gln Pro 1220 1225 1230 Arg Asp Glu Gly Phe Tyr Ser Cys Ser Ala Arg Ser Pro Leu Gly 1235 1240 1245 Gln Ala Asn Thr Ser Leu Glu Leu Arg Leu Glu Gly Val Arg Val 1250 1255 1260 Ile Leu Ala Pro Glu Ala Ala Val Pro Glu Gly Ala Pro Ile Thr 1265 1270 1275 Val Thr Cys Ala Asp Pro Ala Ala His Ala Pro Thr Leu Tyr Thr 1280 1285 1290 Trp Tyr His Asn Gly Arg Trp Leu Gln Glu Gly Pro Ala Ala Ser 1295 1300 1305 Leu Ser Phe Leu Val Ala Thr Arg Ala His Ala Gly Ala Tyr Ser 1310 1315 1320 Cys Gln Ala Gln Asp Ala Gln Gly Thr Arg Ser Ser Arg Pro Ala 1325 1330 1335 Ala Leu Gln Val Leu Tyr Ala Pro Gln Asp Ala Val Leu Ser Ser 1340 1345 1350 Phe Arg Asp Ser Arg Ala Arg Ser Met Ala Val Ile Gln Cys Thr 1355 1360 1365 Val Asp Ser Glu Pro Pro Ala Glu Leu Ala Leu Ser His Asp Gly 1370 1375 1380 Lys Val Leu Ala Thr Ser Ser Gly Val His Ser Leu Ala Ser Gly 1385 1390 1395 Thr Gly His Val Gln Val Ala Arg Asn Ala Leu Arg Leu Gln Val 1400 1405 1410 Gln Asp Val Pro Ala Gly Asp Asp Thr Tyr Val Cys Thr Ala Gln 1415 1420 1425 Asn Leu Leu Gly Ser Ile Ser Thr Ile Gly Arg Leu Gln Val Glu 1430 1435 1440 Gly Ala Arg Val Val Ala Glu Pro Gly Leu Asp Val Pro Glu Gly 1445 1450 1455 Ala Ala Leu Asn Leu Ser Cys Arg Leu Leu Gly Gly Pro Gly Pro 1460 1465 1470 Val Gly Asn Ser Thr Phe Ala Trp Phe Trp Asn Asp Arg Arg Leu 1475 1480 1485 His Ala Glu Pro Val Pro Thr Leu Ala Phe Thr His Val Ala Arg 1490 1495 1500 Ala Gln Ala Gly Met Tyr His Cys Leu Ala Glu Leu Pro Thr Gly 1505 1510 1515 Ala Ala Ala Ser Ala Pro Val Met Leu Arg Val Leu Tyr Pro Pro 1520 1525 1530 Lys Thr Pro Thr Met Met Val Phe Val Glu Pro Glu Gly Gly Leu 1535 1540 1545 Arg Gly Ile Leu Asp Cys Arg Val Asp Ser Glu Pro Leu Ala Ser 1550 1555 1560 Leu Thr Leu His Leu Gly Ser Arg Leu Val Ala Ser Ser Gln Pro 1565 1570 1575 Gln Gly Ala Pro Ala Glu Pro His Ile His Val Leu Ala Ser Pro 1580 1585 1590 Asn Ala Leu Arg Val Asp Ile Glu Ala Leu Arg Pro Ser Asp Gln 1595 1600 1605 Gly Glu Tyr Ile Cys Ser Ala Ser Asn Val Leu Gly Ser Ala Ser 1610 1615 1620 Thr Ser Thr Tyr Phe Gly Val Arg Ala Leu His Arg Leu His Gln 1625 1630 1635 Phe Gln Gln Leu Leu Trp Val Leu Gly Leu Leu Val Gly Leu Leu 1640 1645 1650 Leu Leu Leu Leu Gly Leu Gly Ala Cys Tyr Thr Trp Arg Arg Arg 1655 1660 1665 Arg Val Cys Lys Gln Ser Met Gly Glu Asn Ser Val Glu Met Ala 1670 1675 1680 Phe Gln Lys Glu Thr Thr Gln Leu Ile Asp Pro Asp Ala Ala Thr 1685 1690 1695 Cys Glu Thr Ser Thr Cys Ala Pro Pro Leu Gly 1700 1705 <210> SEQ ID NO 15 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR forward primer CD163 <400> SEQUENCE: 15 cac cat gga caa act cag aat ggt gct aca tga aaa ctc t 40 <210> SEQ ID NO 16 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR reverse primer CD163 <400> SEQUENCE: 16 tca ttg tac ttc aga gtg gtc tcc tga ggg att 33

1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 16 <210> SEQ ID NO 1 <211> LENGTH: 3400 <212> TYPE: DNA <213> ORGANISM: Sus scrofa <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AJ311716 <309> DATABASE ENTRY DATE: 2005-04-15 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(3400) <400> SEQUENCE: 1 atggtgctac ttgaagactc tggatctgca gactttagaa gatgttctgc ccatttaagt 60 tccttcactt ttgctgtagt cgctgttctc agtgcctgct tggtcactag ttctcttgga 120 ggaaaagaca aggagctgag gctaacgggt ggtgaaaaca agtgctctgg aagagtggag 180 gtgaaagtgc aggaggagtg gggaactgtg tgtaataatg gctgggacat ggatgtggtc 240 tctgttgttt gtaggcagct gggatgtcca actgctatca aagccactgg atgggctaat 300 tttagtgcag gttctggacg catttggatg gatcatgttt cttgtcgagg gaatgagtca 360 gctctctggg actgcaaaca tgatggatgg ggaaagcata actgtactca ccaacaggat 420 gctggagtaa cctgctcaga tggatctgat ttagagatga ggctggtgaa tggaggaaac 480 cggtgcttag gaagaataga agtcaaattt caagagcggt ggggaacagt gtgtgatgat 540 aacttcaaca taaatcatgc ttctgtggtt tgtaaacaac ttgaatgtgg aagtgctgtc 600 agtttctctg gttcagctaa ttttggagaa ggttctggac caatctggtt tgatgatctt 660 gtatgcaatg gaaatgagtc agctctctgg aactgcaaac atgaaggatg gggaaagcac 720 aattgcgatc atgctgagga tgctggagtg atttgcttaa atggagcaga cctgaaactg 780 agagtggtag atggactcac tgaatgttca ggaagattgg aagtgaaatt ccaaggagaa 840 tggggaacaa tctgtgatga tggctgggat agtgatgatg ccgctgtggc atgtaagcaa 900 ctgggatgtc caactgctgt cactgccatt ggtcgagtta acgccagtga gggaactgga 960 cacatttggc ttgacagtgt ttcttgccat ggacacgagt ctgctctctg gcagtgtaga 1020 caccatgaat ggggaaagca ttattgcaat cataatgaag atgctggtgt gacatgttct 1080 gatggatcag atctggaact gagacttaaa ggtggaggca gccactgtgc tgggacagtg 1140 gaggtggaaa ttcagaaact ggtaggaaaa gtgtgtgata gaagctgggg actgaaagaa 1200 gctgatgtgg tttgcaggca gctgggatgt ggatctgcac tcaaaacatc atatcaagtt 1260 tattccaaaa ccaaggcaac aaacacatgg ctgtttgtaa gcagctgtaa tggaaatgaa 1320 acttctcttt gggactgcaa gaattggcag tggggtggac ttagttgtga tcactatgac 1380 gaagccaaaa ttacctgctc agcccacagg aaacccaggc tggttggagg ggacattccc 1440 tgctctggtc gtgttgaagt acaacatgga gacacgtggg gcaccgtctg tgattctgac 1500 ttctctctgg aggcggccag cgtgctgtgc agggaactac agtgcggcac tgtggtttcc 1560 ctcctggggg gagctcactt tggagaagga agtggacaga tctgggctga agaattccag 1620 tgtgaggggc acgagtccca cctttcactc tgcccagtag caccccgccc tgacgggaca 1680 tgtagccaca gcagggacgt cggcgtagtc tgctcaagat acacacaaat ccgcttggtg 1740 aatggcaaga ccccatgtga aggaagagtg gagctcaaca ttcttgggtc ctgggggtcc 1800 ctctgcaact ctcactggga catggaagat gcccatgttt tatgccagca gcttaaatgt 1860 ggagttgccc tttctatccc gggaggagca ccttttggga aaggaagtga gcaggtctgg 1920 aggcacatgt ttcactgcac tgggactgag aagcacatgg gagattgttc cgtcactgct 1980 ctgggcgcat cactctgttc ttcagggcaa gtggcctctg taatctgctc agggaaccag 2040 agtcagacac tatccccgtg caattcatca tcctcggacc catcaagctc tattatttca 2100 gaagaaagtg gtgttgcctg catagggagt ggtcaacttc gcctggtcga tggaggtggt 2160 cgttgtgctg ggagagtaga ggtctatcct ggggcatcct ggggcaccat ctgtgatgac 2220 agctgggacc tgaatgatgc ccatgtggtg tgcaaacagc tgagctgtgg atgggccatt 2280 aatgccactg gttctgctca ttttggggaa ggaacagggc ccatttggct ggatgagata 2340 aactgtaatg gaaaagaatc tcatatttgg caatgccact cacatggttg ggggcggcac 2400 aattgcaggc ataaggagga tgcaggagtc atctgctcag agttcatgtc tctgagactg 2460 atcagtgaaa acagcagaga gacctgtgca gggcgcctgg aagtttttta caacggagct 2520 tggggcagcg ttggcaggaa tagcatgtct ccagccacag tgggggtggt atgcaggcag 2580 ctgggctgtg cagacagagg ggacatcagc cctgcatctt cagacaagac agtgtccagg 2640 cacatgtggg tggacaatgt tcagtgtcct aaaggacctg acacactatg gcagtgcccc 2700 tcatctccat ggaagaagag actggccagc ccctcagagg agacatggat cacatgtgcc 2760 aacaaaataa gacttcaaga aggaaacact aattgttctg gacgtgtgga gatctggtac 2820 ggaggttcct ggggcactgt gtgtgacgac tcctgggacc ttgaagatgc tcaggtggtg 2880 tgccgacagc tgggctgtgg ctcagctttg gaggcaggaa aagagcccgc atttggccag 2940 gggactgggc ccatatggct caatgaagtg aagtgcaagg ggaatgaacc ctccttgtgg 3000 gattgtcctg ccagatcctg gggccacagt gactgtggac acaaggagga tgctgctgtg 3060 acgtgctcag aaattgcaaa gagccgagaa tccctacatg ccacaggtcg ctcatctttt 3120 gttgcacttg caatctttgg ggtcattctg ttggcctgtc tcatcgcatt cctcatttgg 3180 actcagaagc gaagacagag gcagcggctc tcagttttct caggaggaga gaattctgtc 3240 catcaaattc aataccggga gatgaattct tgcctgaaag cagatgaaac ggatatgcta 3300 aatccctcag gagaccactc tgaagtacaa tgaaaaggaa aatgggaatt ataacctggt 3360 gagttcagcc tttaagatac cttgatgaag acctggacta 3400 <210> SEQ ID NO 2 <211> LENGTH: 1115 <212> TYPE: PRT <213> ORGANISM: Sus scrofa <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/CAC84397 <309> DATABASE ENTRY DATE: 2005-04-15 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1115) <400> SEQUENCE: 2 Met Asp Lys Leu Arg Met Val Leu His Glu Asn Ser Gly Ser Ala Asp 1 5 10 15 Phe Arg Arg Cys Ser Ala His Leu Ser Ser Phe Thr Phe Ala Val Val 20 25 30 Ala Val Leu Ser Ala Cys Leu Val Thr Ser Ser Leu Gly Gly Lys Asp 35 40 45 Lys Glu Leu Arg Leu Thr Gly Gly Glu Asn Lys Cys Ser Gly Arg Val 50 55 60 Glu Val Lys Val Gln Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp 65 70 75 80 Asp Met Asp Val Val Ser Val Val Cys Arg Gln Leu Gly Cys Pro Thr 85 90 95 Ala Ile Lys Ala Thr Gly Trp Ala Asn Phe Ser Ala Gly Ser Gly Arg 100 105 110 Ile Trp Met Asp His Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp 115 120 125 Asp Cys Lys His Asp Gly Trp Gly Lys His Asn Cys Thr His Gln Gln 130 135 140 Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asp Leu Glu Met Gly Leu 145 150 155 160 Val Asn Gly Gly Asn Arg Cys Leu Gly Arg Ile Glu Val Lys Phe Gln 165 170 175 Gly Arg Trp Gly Thr Val Cys Asp Asp Asn Phe Asn Ile Asn His Ala 180 185 190 Ser Val Val Cys Lys Gln Leu Glu Cys Gly Ser Ala Val Ser Phe Ser 195 200 205 Gly Ser Ala Asn Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp Asp 210 215 220 Leu Val Cys Asn Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His Glu 225 230 235 240 Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Ala Gly Val Ile 245 250 255 Cys Leu Asn Gly Ala Asp Leu Lys Leu Arg Val Val Asp Gly Val Thr 260 265 270 Glu Cys Ser Gly Arg Leu Glu Val Lys Phe Gln Gly Glu Trp Gly Thr 275 280 285 Ile Cys Asp Asp Gly Trp Asp Ser Asp Asp Ala Ala Val Ala Cys Lys 290 295 300 Gln Leu Gly Cys Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn Ala 305 310 315 320 Ser Glu Gly Thr Gly His Ile Trp Leu Asp Ser Val Ser Cys His Gly 325 330 335 His Glu Ser Ala Leu Trp Gln Cys Arg His His Glu Trp Gly Lys His 340 345 350 Tyr Cys Asn His Asp Glu Asp Ala Gly Val Thr Cys Ser Asp Gly Ser 355 360 365 Asp Leu Glu Leu Arg Leu Lys Gly Gly Gly Ser His Cys Ala Gly Thr 370 375 380 Val Glu Val Glu Ile Gln Lys Leu Val Gly Lys Val Cys Asp Arg Ser 385 390 395 400 Trp Gly Leu Lys Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys Gly 405 410 415 Ser Ala Leu Lys Thr Ser Tyr Gln Val Tyr Ser Lys Thr Lys Ala Thr 420 425 430 Asn Thr Trp Leu Phe Val Ser Ser Cys Asn Gly Asn Glu Thr Ser Leu 435 440 445 Trp Asp Cys Lys Asn Trp Gln Trp Gly Gly Leu Ser Cys Asp His Tyr 450 455 460 Asp Glu Ala Lys Ile Thr Cys Ser Ala His Arg Lys Pro Arg Leu Val 465 470 475 480 Gly Gly Asp Ile Pro Cys Ser Gly Arg Val Glu Val Gln His Gly Asp 485 490 495 Thr Trp Gly Thr Val Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala Ser 500 505 510 Val Leu Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Leu Leu Gly 515 520 525 Gly Ala His Phe Gly Glu Gly Ser Gly Gln Ile Trp Ala Glu Glu Phe 530 535 540 Gln Cys Glu Gly His Glu Ser His Leu Ser Leu Cys Pro Val Ala Pro 545 550 555 560 Arg Pro Asp Gly Thr Cys Ser His Ser Arg Asp Val Gly Val Val Cys 565 570 575

Ser Arg Tyr Thr Gln Ile Arg Leu Val Asn Gly Lys Thr Pro Cys Glu 580 585 590 Gly Arg Val Glu Leu Asn Ile Leu Gly Ser Trp Gly Ser Leu Cys Asn 595 600 605 Ser His Trp Asp Met Glu Asp Ala His Val Leu Cys Gln Gln Leu Lys 610 615 620 Cys Gly Val Ala Leu Ser Ile Pro Gly Gly Ala Pro Phe Gly Lys Gly 625 630 635 640 Ser Glu Gln Val Trp Arg His Met Phe His Cys Thr Gly Thr Glu Lys 645 650 655 His Met Gly Asp Cys Ser Val Thr Ala Leu Gly Ala Ser Leu Cys Ser 660 665 670 Ser Gly Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln Thr 675 680 685 Leu Ser Pro Cys Asn Ser Ser Ser Ser Asp Pro Ser Ser Ser Ile Ile 690 695 700 Ser Glu Glu Asn Gly Val Ala Cys Ile Gly Ser Gly Gln Leu Arg Leu 705 710 715 720 Val Asp Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Val Tyr His Glu 725 730 735 Gly Ser Trp Gly Thr Ile Cys Asp Asp Ser Trp Asp Leu Asn Asp Ala 740 745 750 His Val Val Cys Lys Gln Leu Ser Cys Gly Trp Ala Ile Asn Ala Thr 755 760 765 Gly Ser Ala His Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu Asp Glu 770 775 780 Ile Asn Cys Asn Gly Lys Glu Ser His Ile Trp Gln Cys His Ser His 785 790 795 800 Gly Trp Gly Arg His Asn Cys Arg His Lys Glu Asp Ala Gly Val Ile 805 810 815 Cys Ser Glu Phe Met Ser Leu Arg Leu Ile Ser Glu Asn Ser Arg Glu 820 825 830 Thr Cys Ala Gly Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp Gly Ser 835 840 845 Val Gly Arg Asn Ser Met Ser Pro Ala Thr Val Gly Val Val Cys Arg 850 855 860 Gln Leu Gly Cys Ala Asp Arg Gly Asp Ile Ser Pro Ala Ser Ser Asp 865 870 875 880 Lys Thr Val Ser Arg His Met Trp Val Asp Asn Val Gln Cys Pro Lys 885 890 895 Gly Pro Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Lys Lys Arg 900 905 910 Leu Ala Ser Pro Ser Glu Glu Thr Trp Ile Thr Cys Ala Asn Lys Ile 915 920 925 Arg Leu Gln Glu Gly Asn Thr Asn Cys Ser Gly Arg Val Glu Ile Trp 930 935 940 Tyr Gly Gly Ser Trp Gly Thr Val Cys Asp Asp Ser Trp Asp Leu Glu 945 950 955 960 Asp Ala Gln Val Val Cys Arg Gln Leu Gly Cys Gly Ser Ala Leu Glu 965 970 975 Ala Gly Lys Glu Ala Ala Phe Gly Gln Gly Thr Gly Pro Ile Trp Leu 980 985 990 Asn Glu Val Lys Cys Lys Gly Asn Glu Thr Ser Leu Trp Asp Cys Pro 995 1000 1005 Ala Arg Ser Trp Gly His Ser Asp Cys Gly His Lys Glu Asp Ala 1010 1015 1020 Ala Val Thr Cys Ser Glu Ile Ala Lys Ser Arg Glu Ser Leu His 1025 1030 1035 Ala Thr Gly Arg Ser Ser Phe Val Ala Leu Ala Ile Phe Gly Val 1040 1045 1050 Ile Leu Leu Ala Cys Leu Ile Ala Phe Leu Ile Trp Thr Gln Lys 1055 1060 1065 Arg Arg Gln Arg Gln Arg Leu Ser Val Phe Ser Gly Gly Glu Asn 1070 1075 1080 Ser Val His Gln Ile Gln Tyr Arg Glu Met Asn Ser Cys Leu Lys 1085 1090 1095 Ala Asp Glu Thr Asp Met Leu Asn Pro Ser Gly Asp His Ser Glu 1100 1105 1110 Val Gln 1115 <210> SEQ ID NO 3 <211> LENGTH: 4405 <212> TYPE: DNA <213> ORGANISM: mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/AF274883 <309> DATABASE ENTRY DATE: 2001-05-10 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(4405) <400> SEQUENCE: 3 gtggtcatcc actttctaca gagaacacgt ctatgaaata gtatcaggag acacacggag 60 ccatcaaaat catcaagctt tggaatgggt ggacacagaa tggttcttct tggaggtgct 120 ggatctcctg gttgtaaaag gtttgtccat ctaggtttct ttgttgtggc tgtgagctca 180 cttctcagtg cctctgctgt cactaacgct cctggagaaa tgaagaagga actgagactg 240 gcgggtggtg aaaacaactg tagtgggaga gtggaactta agatccatga caagtggggc 300 acagtgtgca gtaacggctg gagcatgaat gaagtgtccg tggtttgcca gcagctggga 360 tgcccaactt ctattaaagc ccttggatgg gctaactcca gcgccggctc tggatatatc 420 tggatggaca aagtttcttg tacagggaat gagtcagctc tttgggactg caaacatgat 480 gggtggggaa agcataactg tacccatgaa aaagatgctg gagtgacctg ctcagatgga 540 tctaatttgg agatgagact ggtgaacagt gcgggccacc gatgcttagg aagagtagaa 600 ataaagttcc agggaaagtg ggggacggtg tgtgacgaca acttcagcaa agatcacgct 660 tctgtgattt gtaaacagct tggatgtgga agtgccatta gtttctctgg ctcagctaaa 720 ttgggagctg gttctggacc aatctggctc gatgacctgg catgcaatgg aaatgagtca 780 gctctctggg actgcaaaca ccggggatgg ggcaagcata actgtgacca tgctgaggat 840 gtcggtgtga tttgcttaga gggagcagat ctgagcctga gactagtgga tggagtgtcc 900 agatgttcag gaagattgga agtgagattc caaggagaat gggggaccgt gtgtgatgat 960 aactgggatc tccgggatgc ttctgtggtg tgcaagcaac tgggatgtcc aactgccatc 1020 agtgccattg gtcgagttaa tgccagtgag ggatctggac agatttggct tgacaacatt 1080 tcatgcgaag gacatgaggc aactctttgg gagtgtaaac accaagagtg gggaaagcat 1140 tactgtcatc atagagaaga cgctggtgtg acatgttctg atggagcaga tctggaactt 1200 agacttgtag gtggaggcag tcgctgtgct ggcattgtgg aggtggagat tcagaagctg 1260 actgggaaga tgtgtagccg aggctggaca ctggcagatg cggatgtggt ttgcagacag 1320 cttggatgtg gatctgcgct tcaaacccag gctaagatct actctaaaac tggggcaaca 1380 aatacgtggc tctttcctgg atcttgtaat ggaaatgaaa ctactttttg gcaatgcaaa 1440 aactggcagt ggggcggcct ttcctgtgat aatttcgaag aagccaaagt tacctgctca 1500 ggccacaggg aacccagact ggttggagga gaaatcccat gctctggtcg tgtggaagtg 1560 aaacacggag acgtgtgggg ctccgtctgt gattttgact tgtctctgga agctgccagt 1620 gtggtgtgca gggaattaca atgtggaaca gtcgtctcta tcctaggggg agcacatttt 1680 ggagaaggaa gtggacagat ctggggtgaa gaattccagt gtagtgggga tgagtcccat 1740 ctttcactat gctcagtggc gcccccgcta gacagaactt gtacccacag cagggatgtc 1800 agcgtagtct gctcacgata catagatatt cgtctggcag gcggcgagtc ctcctgtgag 1860 ggaagagtgg agctcaagac actcggagcc tggggtcccc tctgcagttc tcattgggac 1920 atggaagatg ctcatgtctt atgtcagcag ctgaagtgtg gggttgccca atctattcca 1980 gaaggagcac attttgggaa aggagctggt caggtctgga gtcacatgtt ccactgcact 2040 ggaactgagg aacatatagg agattgcctc atgactgctc tgggtgcgcc gacgtgttcc 2100 gaaggacagg tggcctctgt catctgctca ggaaaccaat cccagacact attgccatgt 2160 agttcattgt ctccagtcca aacaacaagc tctacaattc caaaggagag tgaagttccc 2220 tgcatagcaa gtggccagct tcgcttggta ggtggaggtg gtcgctgcgc tggaagagtg 2280 gaggtctgcc acgagggctc ttggggcacc gtctgtgatg acaattggga tatgactgat 2340 gccaatgtgg tgtgcaagca gctggactgt ggcgtggcaa ttaacgccac tggctctgct 2400 tacttcgggg aaggagcagg agctatctgg ctagacgaag tcatctgcac tgggaaagag 2460 tctcatattt ggcagtgcca ttcacatggc tggggacgcc ataactgcag gcacaaagaa 2520 gatgcaggtg ttatctgctc cgagttcatg tctctgaggc tgaccaacga agcccacaaa 2580 gaaaactgca caggtcgcct tgaagtgttt tacaatggta catggggcag tattggcagt 2640 agcaatatgt ctccaaccac tgtgggggtg gtgtgccgtc agctgggctg tgcagacaac 2700 gggactgtga aacccatacc ttcagacaag acaccatcca ggcccatgtg ggtagatcgt 2760 gtgcagtgtc caaaaggagt tgacactttg tggcagtgcc cctcgtcacc ttggaaacag 2820 agacaggcca gcccctcctc ccaggagtcc tggatcatct gtgacaacaa aataagactc 2880 caggaagggc atacagactg ttctggacgt gtggagatct ggcacaaagg ttcctgggga 2940 acagtgtgtg atgactcctg ggatcttaat gatgctaagg ttgtatgtaa gcagttgggc 3000 tgtggccaag ctgtgaaggc actaaaagaa gcagcatttg gtccaggaac tgggcccata 3060 tggctcaatg aaattaagtg tagagggaat gagtcttccc tgtgggattg tcctgccaaa 3120 ccgtggagtc acagcgactg tgggcacaaa gaagatgctt ccatccagtg cctcccaaaa 3180 atgacttcag aatcacatca tggcacaggt caccccaccc tcacggcact cttggtttgt 3240 ggagccattc tattggtcct cctcattgtc ttcctcctgt ggactctgaa gcgacgacgg 3300 attcagcgac ttacagtttc ctcaagagga gaggtcttga tacatcaagt tcagtaccaa 3360 gagatggatt caaaggcgga tgatctggac ttgctgaaat cctcgggggt cattcagagg 3420 cacactgaga aggaaaatga taatttataa tccactgagg ttggagttta agaagccttg 3480 acaggacagc cagctaaatg gaacaagagc ccaggcaacg cacggatgac cacagctgca 3540 tcttcatgca gtcctttgtt tcctggaact ctgctgaacc tgcaaaaacc atatttgtga 3600 atgtgaccac ttaatagaga tgggagactt ttgagggaat taaacaatat tgctattggt 3660 ttgcttgttc gcaatagggt ctcattatgt atagccctgg agatggcgat agagagcagg 3720 caagcctaga attcacagag atctgcttgt ctctgcttcc caaatgctgg gatcaaatat 3780 gtggaccacc acatgtggtt taacaattgt gtcttgattt tataaatttc tggttggttt 3840 ttctgacgtt tttagggttt cgtgaatata aaataatgtc ttttcggttg gcatgctaat 3900 ttttaaatat tatacacttc cttgtagtga gtttaagaat aatttcttat aaccaagtca 3960 attcattttc actttgaatt atttaataaa ggaatatggt cattgtgacc acacacacag 4020

cagttgtgac cgcctgtatg aggccttcaa aaaatatttt aaaaatagag ggctggagaa 4080 atggctcaga ggtcctgagt tcaattccta gcaaccacat ggtggctcac aaccatctgt 4140 aatgggaatc cgatgccctc ttccagtgta tctgaagata gtgacactgt cctcattaac 4200 ataaaataaa taaataaatc tttaaaaaaa gaaaagacaa tagaggaggg gaggggcgtg 4260 agcgtaggag tgaggactga ttgagaagaa ggttggagga agtgggggga ggtgaaaagc 4320 tagttgggaa cttatgtgat cacagtgcat catgtccaaa tatgacatgt ccaaaaatgt 4380 tattaataaa gaaacggaaa tcaaa 4405 <210> SEQ ID NO 4 <211> LENGTH: 1121 <212> TYPE: PRT <213> ORGANISM: Mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/AAK16065 <309> DATABASE ENTRY DATE: 2001-05-10 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1121) <400> SEQUENCE: 4 Met Gly Gly His Arg Met Val Leu Leu Gly Gly Ala Gly Ser Pro Gly 1 5 10 15 Cys Lys Arg Phe Val His Leu Gly Phe Phe Val Val Ala Val Ser Ser 20 25 30 Leu Leu Ser Ala Ser Ala Val Thr Asn Ala Pro Gly Glu Met Lys Lys 35 40 45 Glu Leu Arg Leu Ala Gly Gly Glu Asn Asn Cys Ser Gly Arg Val Glu 50 55 60 Leu Lys Ile His Asp Lys Trp Gly Thr Val Cys Ser Asn Gly Trp Ser 65 70 75 80 Met Asn Glu Val Ser Val Val Cys Gln Gln Leu Gly Cys Pro Thr Ser 85 90 95 Ile Lys Ala Leu Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Tyr Ile 100 105 110 Trp Met Asp Lys Val Ser Cys Thr Gly Asn Glu Ser Ala Leu Trp Asp 115 120 125 Cys Lys His Asp Gly Trp Gly Lys His Asn Cys Thr His Glu Lys Asp 130 135 140 Ala Gly Val Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg Leu Val 145 150 155 160 Asn Ser Ala Gly His Arg Cys Leu Gly Arg Val Glu Ile Lys Phe Gln 165 170 175 Gly Lys Trp Gly Thr Val Cys Asp Asp Asn Phe Ser Lys Asp His Ala 180 185 190 Ser Val Ile Cys Lys Gln Leu Gly Cys Gly Ser Ala Ile Ser Phe Ser 195 200 205 Gly Ser Ala Lys Leu Gly Ala Gly Ser Gly Pro Ile Trp Leu Asp Asp 210 215 220 Leu Ala Cys Asn Gly Asn Glu Ser Ala Leu Trp Asp Cys Lys His Arg 225 230 235 240 Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Val Gly Val Ile 245 250 255 Cys Leu Glu Gly Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val Ser 260 265 270 Arg Cys Ser Gly Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly Thr 275 280 285 Val Cys Asp Asp Asn Trp Asp Leu Arg Asp Ala Ser Val Val Cys Lys 290 295 300 Gln Leu Gly Cys Pro Thr Ala Ile Ser Ala Ile Gly Arg Val Asn Ala 305 310 315 320 Ser Glu Gly Ser Gly Gln Ile Trp Leu Asp Asn Ile Ser Cys Glu Gly 325 330 335 His Glu Ala Thr Leu Trp Glu Cys Lys His Gln Glu Trp Gly Lys His 340 345 350 Tyr Cys His His Arg Glu Asp Ala Gly Val Thr Cys Ser Asp Gly Ala 355 360 365 Asp Leu Glu Leu Arg Leu Val Gly Gly Gly Ser Arg Cys Ala Gly Ile 370 375 380 Val Glu Val Glu Ile Gln Lys Leu Thr Gly Lys Met Cys Ser Arg Gly 385 390 395 400 Trp Thr Leu Ala Asp Ala Asp Val Val Cys Arg Gln Leu Gly Cys Gly 405 410 415 Ser Ala Leu Gln Thr Gln Ala Lys Ile Tyr Ser Lys Thr Gly Ala Thr 420 425 430 Asn Thr Trp Leu Phe Pro Gly Ser Cys Asn Gly Asn Glu Thr Thr Phe 435 440 445 Trp Gln Cys Lys Asn Trp Gln Trp Gly Gly Leu Ser Cys Asp Asn Phe 450 455 460 Glu Glu Ala Lys Val Thr Cys Ser Gly His Arg Glu Pro Arg Leu Val 465 470 475 480 Gly Gly Glu Ile Pro Cys Ser Gly Arg Val Glu Val Lys His Gly Asp 485 490 495 Val Trp Gly Ser Val Cys Asp Phe Asp Leu Ser Leu Glu Ala Ala Ser 500 505 510 Val Val Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu Gly 515 520 525 Gly Ala His Phe Gly Glu Gly Ser Gly Gln Ile Trp Gly Glu Glu Phe 530 535 540 Gln Cys Ser Gly Asp Glu Ser His Leu Ser Leu Cys Ser Val Ala Pro 545 550 555 560 Pro Leu Asp Arg Thr Cys Thr His Ser Arg Asp Val Ser Val Val Cys 565 570 575 Ser Arg Tyr Ile Asp Ile Arg Leu Ala Gly Gly Glu Ser Ser Cys Glu 580 585 590 Gly Arg Val Glu Leu Lys Thr Leu Gly Ala Trp Gly Pro Leu Cys Ser 595 600 605 Ser His Trp Asp Met Glu Asp Ala His Val Leu Cys Gln Gln Leu Lys 610 615 620 Cys Gly Val Ala Gln Ser Ile Pro Glu Gly Ala His Phe Gly Lys Gly 625 630 635 640 Ala Gly Gln Val Trp Ser His Met Phe His Cys Thr Gly Thr Glu Glu 645 650 655 His Ile Gly Asp Cys Leu Met Thr Ala Leu Gly Ala Pro Thr Cys Ser 660 665 670 Glu Gly Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln Thr 675 680 685 Leu Leu Pro Cys Ser Ser Leu Ser Pro Val Gln Thr Thr Ser Ser Thr 690 695 700 Ile Pro Lys Glu Ser Glu Val Pro Cys Ile Ala Ser Gly Gln Leu Arg 705 710 715 720 Leu Val Gly Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Val Tyr His 725 730 735 Glu Gly Ser Trp Gly Thr Val Cys Asp Asp Asn Trp Asp Met Thr Asp 740 745 750 Ala Asn Val Val Cys Lys Gln Leu Asp Cys Gly Val Ala Ile Asn Ala 755 760 765 Thr Gly Ser Ala Tyr Phe Gly Glu Gly Ala Gly Ala Ile Trp Leu Asp 770 775 780 Glu Val Ile Cys Thr Gly Lys Glu Ser His Ile Trp Gln Cys His Ser 785 790 795 800 His Gly Trp Gly Arg His Asn Cys Arg His Lys Glu Asp Ala Gly Val 805 810 815 Ile Cys Ser Glu Phe Met Ser Leu Arg Leu Thr Asn Glu Ala His Lys 820 825 830 Glu Ser Cys Thr Gly Arg Leu Glu Val Phe Tyr Asn Gly Thr Trp Gly 835 840 845 Ser Ile Gly Ser Ser Asn Met Ser Pro Thr Thr Val Gly Val Val Cys 850 855 860 Arg Gln Leu Gly Cys Ala Asp Asn Gly Thr Val Lys Pro Ile Pro Ser 865 870 875 880 Asp Lys Thr Pro Ser Arg Pro Met Trp Val Asp Arg Val Gln Cys Pro 885 890 895 Lys Gly Val Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Lys Gln 900 905 910 Arg Gln Ala Ser Pro Ser Ser Gln Glu Ser Trp Ile Ile Cys Asp Asn 915 920 925 Lys Ile Arg Leu Gln Glu Gly His Thr Asp Cys Ser Gly Arg Val Glu 930 935 940 Ile Trp His Lys Gly Phe Trp Gly Thr Val Cys Asp Asp Ser Trp Asp 945 950 955 960 Leu Asn Asp Ala Lys Val Val Cys Lys Gln Leu Gly Cys Gly Gln Ala 965 970 975 Val Lys Ala Leu Lys Glu Ala Ala Phe Gly Pro Gly Thr Gly Pro Ile 980 985 990 Trp Leu Asn Glu Ile Lys Cys Arg Gly Asn Glu Ser Ser Leu Trp Asp 995 1000 1005 Cys Pro Ala Lys Pro Trp Ser His Ser Asp Cys Gly His Lys Glu 1010 1015 1020 Asp Ala Ser Ile Gln Cys Leu Pro Lys Met Thr Ser Glu Ser His 1025 1030 1035 His Gly Thr Gly His Pro Thr Leu Thr Ala Leu Leu Val Cys Gly 1040 1045 1050 Ala Ile Leu Leu Val Leu Leu Ile Val Phe Leu Leu Trp Thr Leu 1055 1060 1065 Lys Arg Arg Gln Ile Gln Arg Leu Thr Val Ser Ser Arg Gly Glu 1070 1075 1080 Val Leu Ile His Gln Val Gln Tyr Gln Glu Met Asp Ser Lys Ala 1085 1090 1095 Asp Asp Leu Asp Leu Leu Lys Ser Ser Gly Val Ile Gln Arg His 1100 1105 1110 Thr Glu Lys Glu Asn Asp Asn Leu 1115 1120 <210> SEQ ID NO 5 <211> LENGTH: 3780 <212> TYPE: DNA <213> ORGANISM: homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/BC051281 <309> DATABASE ENTRY DATE: 2006-07-15 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(3780) <400> SEQUENCE: 5

aacatttcta gggaataata caagaagatt taggaatcat tgaagttata aatctttgga 60 atgagcaaac tcagaatggt gctacttgaa gactctggat ctgctgactt cagaagacat 120 tttgtcaact tgagtccctt caccattact gtggtcttac ttctcagtgc ctgttttgtc 180 accagttctc ttggaggaac agacaaggag ctgaggctag tggatggtga aaacaagtgt 240 agcgggagag tggaagtgaa agtccaggag gagtggggaa cggtgtgtaa taatggctgg 300 agcatggaag cggtctctgt gatttgtaac cagctgggat gtccaactgc tatcaaagcc 360 cctggatggg ctaattccag tgcaggttct ggacgcattt ggatggatca tgtttcttgt 420 cgtgggaatg agtcagctct ttgggattgc aaacatgatg gatggggaaa gcatagtaac 480 tgtactcacc aacaagatgc tggagtgacc tgctcagatg gatccaattt ggaaatgagg 540 ctgacgcgtg gagggaatat gtgttctgga agaatagaga tcaaattcca aggacggtgg 600 ggaacagtgt gtgatgataa cttcaacata gatcatgcat ctgtcatttg tagacaactt 660 gaatgtggaa gtgctgtcag tttctctggt tcatctaatt ttggagaagg ctctggacca 720 atctggtttg atgatcttat atgcaacgga aatgagtcag ctctctggaa ctgcaaacat 780 caaggatggg gaaagcataa ctgtgatcat gctgaggatg ctggagtgat ttgctcaaag 840 ggagcagatc tgagcctgag actggtagat ggagtcactg aatgttcagg aagattagaa 900 gtgagattcc aaggagaatg ggggacaata tgtgatgacg gctgggacag ttacgatgct 960 gctgtggcat gcaagcaact gggatgtcca actgccgtca cagccattgg tcgagttaac 1020 gccagtaagg gatttggaca catctggctt gacagcgttt cttgccaggg acatgaacct 1080 gctgtctggc aatgtaaaca ccatgaatgg ggaaagcatt attgcaatca caatgaagat 1140 gctggcgtga catgttctga tggatcagat ctggagctaa gacttagagg tggaggcagc 1200 cgctgtgctg ggacagttga ggtggagatt cagagactgt tagggaaggt gtgtgacaga 1260 ggctggggac tgaaagaagc tgatgtggtt tgcaggcagc tgggatgtgg atctgcactc 1320 aaaacatctt atcaagtgta ctccaaaatc caggcaacaa acacatggct gtttctaagt 1380 agctgtaacg gaaatgaaac ttctctttgg gactgcaaga actggcaatg gggtggactt 1440 acctgtgatc actatgaaga agccaaaatt acctgctcag cccacaggga acccagactg 1500 gttggagggg acattccctg ttctggacgt gttgaagtga agcatggtga cacgtggggc 1560 tccatctgtg attcggactt ctctctggaa gctgccagcg ttctatgcag ggaattacag 1620 tgtggcacag ttgtctctat cctgggggga gctcactttg gagagggaaa tggacagatc 1680 tgggctgaag aattccagtg tgagggacat gagtcccatc tttcactctg cccagtagca 1740 ccccgcccag aaggaacttg tagccacagc agggatgttg gagtagtctg ctcaagatac 1800 acagaaattc gcttggtgaa tggcaagacc ccgtgtgagg gcagagtgga gctcaaaacg 1860 cttggtgcct ggggatccct ctgtaactct cactgggaca tagaagatgc ccatgttctt 1920 tgccagcagc ttaaatgtgg agttgccctt tctaccccag gaggagcacg ttttggaaaa 1980 ggaaatggtc agatctggag gcatatgttt cactgcactg ggactgagca gcacatggga 2040 gattgtcctg taactgctct aggtgcttca ttatgtcctt cagagcaagt ggcctctgta 2100 atctgctcag gaaaccagtc ccaaacactg tcctcgtgca attcatcgtc tttgggccca 2160 acaaggccta ccattccaga agaaagtgct gtggcctgca tagagagtgg tcaacttcgc 2220 ctggtaaatg gaggaggtcg ctgtgctggg agagtagaga tctatcatga gggctcctgg 2280 ggcaccatct gtgatgacag ctgggacctg agtgatgccc acgtggtttg cagacagctg 2340 ggctgtggag aggccattaa tgccactggt tctgctcatt ttggggaagg aacagggccc 2400 atctggctgg atgagatgaa atgcaatgga aaagaatccc gcatttggca gtgccattca 2460 cacggctggg ggcagcaaaa ttgcaggcac aaggaggatg cgggagttat ctgctcagaa 2520 ttcatgtctc tgagactgac cagtgaagcc agcagagagg cctgtgcagg gcgtctggaa 2580 gttttttaca atggagcttg gggcactgtt ggcaagagta gcatgtctga aaccactgtg 2640 ggtgtggtgt gcaggcagct gggctgtgca gacaaaggga aaatcaaccc tgcatcttta 2700 gacaaggcca tgtccattcc catgtgggtg gacaatgttc agtgtccaaa aggacctgac 2760 acgctgtggc agtgcccatc atctccatgg gagaagagac tggccagccc ctcggaggag 2820 acctggatca catgtgacaa caagataaga cttcaggaag gacccacttc ctgttctgga 2880 cgtgtggaga tctggcatgg aggttcctgg gggacagtgt gtgatgactc ttgggacttg 2940 gacgatgctc aggtggtgtg tcaacaactt ggctgtggtc cagctttgaa agcattcaaa 3000 gaagcagagt ttggtcaggg gactggaccg atatggctca atgaagtgaa gtgcaaaggg 3060 aatgagtctt ccttgtggga ttgtcctgcc agacgctggg gccatagtga gtgtgggcac 3120 aaggaagacg ctgcagtgaa ttgcacagat atttcagtgc agaaaacccc acaaaaagcc 3180 acaacaggtc gctcatcccg tcagtcatcc tttattgcag tcgggatcct tggggttgtt 3240 ctgttggcca ttttcgtcgc attattcttc ttgactaaaa agcgaagaca gagacagcgg 3300 cttgcagttt cctcaagagg agagaactta gtccaccaaa ttcaataccg ggagatgaat 3360 tcttgcctga atgcagatga tctggaccta atgaattcct cagaaaattc ccatgagtca 3420 gctgatttca gtgctgctga actaatttct gtgtctaaat ttcttcctat ttctggaatg 3480 gaaaaggagg ccattctgag ccacactgaa aaggaaaatg ggaatttata acccagtgag 3540 ttcagccttt aagatacctt gatgaagacc tggactattg aatggagcag aaattcacct 3600 ctctcactga ctattacagt tgcattttta tggagttctt cttctcctag gattcctaag 3660 actgctgctg aatttataaa aattaagttt gtgaatgtga ctacttagtg gtgtatatga 3720 gactttcaag ggaattaaat aaataaataa gaatgttatt gaaaaaaaaa aaaaaaaaaa 3780 <210> SEQ ID NO 6 <211> LENGTH: 1156 <212> TYPE: PRT <213> ORGANISM: HOMO SAPIENS <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/AAH51281 <309> DATABASE ENTRY DATE: 2006-07-15 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1156) <400> SEQUENCE: 6 Met Ser Lys Leu Arg Met Val Leu Leu Glu Asp Ser Gly Ser Ala Asp 1 5 10 15 Phe Arg Arg His Phe Val Asn Leu Ser Pro Phe Thr Ile Thr Val Val 20 25 30 Leu Leu Leu Ser Ala Cys Phe Val Thr Ser Ser Leu Gly Gly Thr Asp 35 40 45 Lys Glu Leu Arg Leu Val Asp Gly Glu Asn Lys Cys Ser Gly Arg Val 50 55 60 Glu Val Lys Val Gln Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp 65 70 75 80 Ser Met Glu Ala Val Ser Val Ile Cys Asn Gln Leu Gly Cys Pro Thr 85 90 95 Ala Ile Lys Ala Pro Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Arg 100 105 110 Ile Trp Met Asp His Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp 115 120 125 Asp Cys Lys His Asp Gly Trp Gly Lys His Ser Asn Cys Thr His Gln 130 135 140 Gln Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg 145 150 155 160 Leu Thr Arg Gly Gly Asn Met Cys Ser Gly Arg Ile Glu Ile Lys Phe 165 170 175 Gln Gly Arg Trp Gly Thr Val Cys Asp Asp Asn Phe Asn Ile Asp His 180 185 190 Ala Ser Val Ile Cys Arg Gln Leu Glu Cys Gly Ser Ala Val Ser Phe 195 200 205 Ser Gly Ser Ser Asn Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp 210 215 220 Asp Leu Ile Cys Asn Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His 225 230 235 240 Gln Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Ala Gly Val 245 250 255 Ile Cys Ser Lys Gly Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val 260 265 270 Thr Glu Cys Ser Gly Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly 275 280 285 Thr Ile Cys Asp Asp Gly Trp Asp Ser Tyr Asp Ala Ala Val Ala Cys 290 295 300 Lys Gln Leu Gly Cys Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn 305 310 315 320 Ala Ser Lys Gly Phe Gly His Ile Trp Leu Asp Ser Val Ser Cys Gln 325 330 335 Gly His Glu Pro Ala Val Trp Gln Cys Lys His His Glu Trp Gly Lys 340 345 350 His Tyr Cys Asn His Asn Glu Asp Ala Gly Val Thr Cys Ser Asp Gly 355 360 365 Ser Asp Leu Glu Leu Arg Leu Arg Gly Gly Gly Ser Arg Cys Ala Gly 370 375 380 Thr Val Glu Val Glu Ile Gln Arg Leu Leu Gly Lys Val Cys Asp Arg 385 390 395 400 Gly Trp Gly Leu Lys Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys 405 410 415 Gly Ser Ala Leu Lys Thr Ser Tyr Gln Val Tyr Ser Lys Ile Gln Ala 420 425 430 Thr Asn Thr Trp Leu Phe Leu Ser Ser Cys Asn Gly Asn Glu Thr Ser 435 440 445 Leu Trp Asp Cys Lys Asn Trp Gln Trp Gly Gly Leu Thr Cys Asp His 450 455 460 Tyr Glu Glu Ala Lys Ile Thr Cys Ser Ala His Arg Glu Pro Arg Leu 465 470 475 480 Val Gly Gly Asp Ile Pro Cys Ser Gly Arg Val Glu Val Lys His Gly 485 490 495 Asp Thr Trp Gly Ser Ile Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala 500 505 510 Ser Val Leu Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu 515 520 525 Gly Gly Ala His Phe Gly Glu Gly Asn Gly Gln Ile Trp Ala Glu Glu 530 535 540 Phe Gln Cys Glu Gly His Glu Ser His Leu Ser Leu Cys Pro Val Ala 545 550 555 560 Pro Arg Pro Glu Gly Thr Cys Ser His Ser Arg Asp Val Gly Val Val 565 570 575 Cys Ser Arg Tyr Thr Glu Ile Arg Leu Val Asn Gly Lys Thr Pro Cys 580 585 590 Glu Gly Arg Val Glu Leu Lys Thr Leu Gly Ala Trp Gly Ser Leu Cys

595 600 605 Asn Ser His Trp Asp Ile Glu Asp Ala His Val Leu Cys Gln Gln Leu 610 615 620 Lys Cys Gly Val Ala Leu Ser Thr Pro Gly Gly Ala Arg Phe Gly Lys 625 630 635 640 Gly Asn Gly Gln Ile Trp Arg His Met Phe His Cys Thr Gly Thr Glu 645 650 655 Gln His Met Gly Asp Cys Pro Val Thr Ala Leu Gly Ala Ser Leu Cys 660 665 670 Pro Ser Glu Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln 675 680 685 Thr Leu Ser Ser Cys Asn Ser Ser Ser Leu Gly Pro Thr Arg Pro Thr 690 695 700 Ile Pro Glu Glu Ser Ala Val Ala Cys Ile Glu Ser Gly Gln Leu Arg 705 710 715 720 Leu Val Asn Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Ile Tyr His 725 730 735 Glu Gly Ser Trp Gly Thr Ile Cys Asp Asp Ser Trp Asp Leu Ser Asp 740 745 750 Ala His Val Val Cys Arg Gln Leu Gly Cys Gly Glu Ala Ile Asn Ala 755 760 765 Thr Gly Ser Ala His Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu Asp 770 775 780 Glu Met Lys Cys Asn Gly Lys Glu Ser Arg Ile Trp Gln Cys His Ser 785 790 795 800 His Gly Trp Gly Gln Gln Asn Cys Arg His Lys Glu Asp Ala Gly Val 805 810 815 Ile Cys Ser Glu Phe Met Ser Leu Arg Leu Thr Ser Glu Ala Ser Arg 820 825 830 Glu Ala Cys Ala Gly Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp Gly 835 840 845 Thr Val Gly Lys Ser Ser Met Ser Glu Thr Thr Val Gly Val Val Cys 850 855 860 Arg Gln Leu Gly Cys Ala Asp Lys Gly Lys Ile Asn Pro Ala Ser Leu 865 870 875 880 Asp Lys Ala Met Ser Ile Pro Met Trp Val Asp Asn Val Gln Cys Pro 885 890 895 Lys Gly Pro Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Glu Lys 900 905 910 Arg Leu Ala Ser Pro Ser Glu Glu Thr Trp Ile Thr Cys Asp Asn Lys 915 920 925 Ile Arg Leu Gln Glu Gly Pro Thr Ser Cys Ser Gly Arg Val Glu Ile 930 935 940 Trp His Gly Gly Ser Trp Gly Thr Val Cys Asp Asp Ser Trp Asp Leu 945 950 955 960 Asp Asp Ala Gln Val Val Cys Gln Gln Leu Gly Cys Gly Pro Ala Leu 965 970 975 Lys Ala Phe Lys Glu Ala Glu Phe Gly Gln Gly Thr Gly Pro Ile Trp 980 985 990 Leu Asn Glu Val Lys Cys Lys Gly Asn Glu Ser Ser Leu Trp Asp Cys 995 1000 1005 Pro Ala Arg Arg Trp Gly His Ser Glu Cys Gly His Lys Glu Asp 1010 1015 1020 Ala Ala Val Asn Cys Thr Asp Ile Ser Val Gln Lys Thr Pro Gln 1025 1030 1035 Lys Ala Thr Thr Gly Arg Ser Ser Arg Gln Ser Ser Phe Ile Ala 1040 1045 1050 Val Gly Ile Leu Gly Val Val Leu Leu Ala Ile Phe Val Ala Leu 1055 1060 1065 Phe Phe Leu Thr Lys Lys Arg Arg Gln Arg Gln Arg Leu Ala Val 1070 1075 1080 Ser Ser Arg Gly Glu Asn Leu Val His Gln Ile Gln Tyr Arg Glu 1085 1090 1095 Met Asn Ser Cys Leu Asn Ala Asp Asp Leu Asp Leu Met Asn Ser 1100 1105 1110 Ser Glu Asn Ser His Glu Ser Ala Asp Phe Ser Ala Ala Glu Leu 1115 1120 1125 Ile Ser Val Ser Lys Phe Leu Pro Ile Ser Gly Met Glu Lys Glu 1130 1135 1140 Ala Ile Leu Ser His Thr Glu Lys Glu Asn Gly Asn Leu 1145 1150 1155 <210> SEQ ID NO 7 <211> LENGTH: 4950 <212> TYPE: DNA <213> ORGANISM: homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/Z22970 <309> DATABASE ENTRY DATE: 2005-04-18 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(4950) <400> SEQUENCE: 7 gaattcttag ttgttttctt tagaagaaca tttctaggga ataatacaag aagatttagg 60 aatcattgaa gttataaatc tttggaatga gcaaactcag aatggtgcta cttgaagact 120 ctggatctgc tgacttcaga agacattttg tcaacctgag tcccttcacc attactgtgg 180 tcttacttct cagtgcctgt tttgtcacca gttctcttgg aggaacagac aaggagctga 240 ggctagtgga tggtgaaaac aagtgtagcg ggagagtgga agtgaaagtc caggaggagt 300 ggggaacggt gtgtaataat ggctggagca tggaagcggt ctctgtgatt tgtaaccagc 360 tgggatgtcc aactgctatc aaagcccctg gatgggctaa ttccagtgca ggttctggac 420 gcatttggat ggatcatgtt tcttgtcgtg ggaatgagtc agctctttgg gattgcaaac 480 atgatggatg gggaaagcat agtaactgta ctcaccaaca agatgctgga gtgacctgct 540 cagatggatc caatttggaa atgaggctga cgcgtggagg gaatatgtgt tctggaagaa 600 tagagatcaa attccaagga cggtggggaa cagtgtgtga tgataacttc aacatagatc 660 atgcatctgt catttgtaga caacttgaat gtggaagtgc tgtcagtttc tctggttcat 720 ctaattttgg agaaggctct ggaccaatct ggtttgatga tcttatatgc aacggaaatg 780 agtcagctct ctggaactgc aaacatcaag gatggggaaa gcataactgt gatcatgctg 840 aggatgctgg agtgatttgc tcaaagggag cagatctgag cctgagactg gtagatggag 900 tcactgaatg ttcaggaaga ttagaagtga gattccaagg agaatggggg acaatatgtg 960 atgacggctg ggacagttac gatgctgctg tggcatgcaa gcaactggga tgtccaactg 1020 ccgtcacagc cattggtcga gttaacgcca gtaagggatt tggacacatc tggcttgaca 1080 gcgtttcttg ccagggacat gaacctgctg tctggcaatg taaacaccat gaatggggaa 1140 agcattattg caatcacaat gaagatgctg gcgtgacatg ttctgatgga tcagatctgg 1200 agctaagact tagaggtgga ggcagccgct gtgctgggac agttgaggtg gagattcaga 1260 gactgttagg gaaggtgtgt gacagaggct ggggactgaa agaagctgat gtggtttgca 1320 ggcagctggg atgtggatct gcactcaaaa catcttatca agtgtactcc aaaatccagg 1380 caacaaacac atggctgttt ctaagtagct gtaacggaaa tgaaacttct ctttgggact 1440 gcaagaactg gcaatggggt ggacttacct gtgatcacta tgaagaagcc aaaattacct 1500 gctcagccca cagggaaccc agactggttg gaggggacat tccctgttct ggacgtgttg 1560 aagtgaagca tggtgacacg tggggctcca tctgtgattc ggacttctct ctggaagctg 1620 ccagcgttct atgcagggaa ttacagtgtg gcacagttgt ctctatcctg gggggagctc 1680 actttggaga gggaaatgga cagatctggg ctgaagaatt ccagtgtgag ggacatgagt 1740 cccatctttc actctgccca gtagcacccc gcccagaagg aacttgtagc cacagcaggg 1800 atgttggagt agtctgctca agatacacag aaattcgctt ggtgaatggc aagaccccgt 1860 gtgagggcag agtggagctc aaaacgcttg gtgcctgggg atccctctgt aactctcact 1920 gggacataga agatgcccat gttctttgcc agcagcttaa atgtggagtt gccctttcta 1980 ccccaggagg agcacgtttt ggaaaaggaa atggtcagat ctggaggcat atgtttcact 2040 gcactgggac tgagcagcac atgggagatt gtcctgtaac tgctctaggt gcttcattat 2100 gtccttcaga gcaagtggcc tctgtaatct gctcaggaaa ccagtcccaa acactgtcct 2160 cgtgcaattc atcgtctttg ggcccaacaa ggcctaccat tccagaagaa agtgctgtgg 2220 cctgcataga gagtggtcaa cttcgcctgg taaatggagg aggtcgctgt gctgggagag 2280 tagagatcta tcatgagggc tcctggggca ccatctgtga tgacagctgg gacctgagtg 2340 atgcccacgt ggtttgcaga cagctgggct gtggagaggc cattaatgcc actggttctg 2400 ctcattttgg ggaaggaaca gggcccatct ggctggatga gatgaaatgc aatggaaaag 2460 aatcccgcat ttggcagtgc cattcacacg gctgggggca gcaaaattgc aggcacaagg 2520 aggatgcggg agttatctgc tcagaattca tgtctctgag actgaccagt gaagccagca 2580 gagaggcctg tgcagggcgt ctggaagttt tttacaatgg agcttggggc actgttggca 2640 agagtagcat gtctgaaacc actgtgggtg tggtgtgcag gcagctgggc tgtgcagaca 2700 aagggaaaat caaccctgca tctttagaca aggccatgtc cattcccatg tgggtggaca 2760 atgttcagtg tccaaaagga cctgacacgc tgtggcagtg cccatcatct ccatgggaga 2820 agagactggc cagcccctcg gaggagacct ggatcacatg tgacaacaag ataagacttc 2880 aggaaggacc cacttcctgt tctggacgtg tggagatctg gcatggaggt tcctggggga 2940 cagtgtgtga tgactcttgg gacttggacg atgctcaggt ggtgtgtcaa caacttggct 3000 gtggtccagc tttgaaagca ttcaaagaag cagagtttgg tcaggggact ggaccgatat 3060 ggctcaatga agtgaagtgc aaagggaatg agtcttcctt gtgggattgt cctgccagac 3120 gctggggcca tagtgagtgt gggcacaagg aagacgctgc agtgaattgc acagatattt 3180 cagtgcagaa aaccccacaa aaagccacaa caggtcgctc atcccgtcag tcatccttta 3240 ttgcagtcgg gatccttggg gttgttctgt tggccatttt cgtcgcatta ttcttcttga 3300 ctaaaaagcg aagacagaga cagcggcttg cagtttcctc aagaggagag aacttagtcc 3360 accaaattca ataccgggag atgaattctt gcctgaatgc agatgatctg gacctaatga 3420 attcctcagg tctgtgggtt cttggagggt ctattgccca ggggttcaga tcagtggctg 3480 cagttgaggc acagacattc tactttgata aacagttaaa aaagtctaaa aatgtaatag 3540 gaagcttaga tgcatataat ggacaagaat gactgaaaat tattcttgga gaatatcaaa 3600 attgcaatca tagggaggcc tttagcttaa gaggcctgtg attattcctg atagaggtat 3660 ggaaagaacc atgcagagga atattatgac ttggacctca ttttattaaa acagaaatta 3720 atcttacaaa agattgtcat aagtgacagt ttaacttttt tctttaaatt ttgttgtgta 3780 tatttaaggt atacaacatg attttatggg atgtatatag atagtaaaaa gcttactaaa 3840 gcaaagcaaa tgaacacacc catcatctga catagttacc cttttttgtg ttgttcttgt 3900 ggcaagagca gctaaaacct actcacttag catgaatcct acatacagca caatgttatt 3960

acctataatc ctcatgttgt acattagacc tctagactgg ttcattctac gtatctgcta 4020 ctttgtatcc tctgacctac atacgtcttt cacagtttct tccattccca tttcctgtca 4080 ttttttttct ctagcttgat atttattata tttttcccta aaagtctaaa accttaaact 4140 ttcaatatct ttattgcatg agaagccata caaatccaca gaactagcct tatttctcat 4200 cacatcatgc tgttttatcc ttgaacttct atttagcacc agtgcactaa ttctgcatct 4260 gggcaggatg actttactgg gttggaagaa atatcccaaa acccattgtc tttactccat 4320 gaagggtccc tgaccttctg agaggggcct gcctcacttc ttccatccaa agaattatgc 4380 atctgctact gtgtcaggga acatatttaa ggaacatgta ctgttactgt gtcaggaaac 4440 atatttaaga aataggaaag actttctctg ccccttaaat cacacatgct tttcttccta 4500 gttatgggtg gtgtttttag ttgctcaaag agcctcacag ttacgtgaga agaggtctgg 4560 tttatttccc agtaattatt ttcttccttt cagaaaattc ccatgagtca gctgatttca 4620 gtgctgctga actaatttct gtgtctaaat ttcttcctat ttctggaatg gaaaaggagg 4680 ccattctgag ccacactgaa aaggaaaatg ggaatttata acccagtgag ttcagccttt 4740 aagatacctt gatgaagacc tggactattg aatggagcag aaattcacct ctctcactga 4800 ctattacagt tgcattttta tggagttctt cttctcctag gattcctaag actgctgctg 4860 aatttataaa aattaagttt gtgaatgtga ctacttagtg gtgtatatga gactttcaag 4920 ggaattaaat aaataaataa gaatgttaaa 4950 <210> SEQ ID NO 8 <211> LENGTH: 1156 <212> TYPE: PRT <213> ORGANISM: HOMO SAPIENS <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/CAA80543 <309> DATABASE ENTRY DATE: 2005-04-18 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1156) <400> SEQUENCE: 8 Met Val Leu Leu Glu Asp Ser Gly Ser Ala Asp Phe Arg Arg His Phe 1 5 10 15 Val Asn Leu Ser Pro Phe Thr Ile Thr Val Val Leu Leu Leu Ser Ala 20 25 30 Cys Phe Val Thr Ser Ser Leu Gly Gly Thr Asp Lys Glu Leu Arg Leu 35 40 45 Val Asp Gly Glu Asn Lys Cys Ser Gly Arg Val Glu Val Lys Val Gln 50 55 60 Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp Ser Met Glu Ala Val 65 70 75 80 Ser Val Ile Cys Asn Gln Leu Gly Cys Pro Thr Ala Ile Lys Ala Pro 85 90 95 Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Arg Ile Trp Met Asp His 100 105 110 Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp Asp Cys Lys His Asp 115 120 125 Gly Trp Gly Lys His Ser Asn Cys Thr His Gln Gln Asp Ala Gly Val 130 135 140 Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg Leu Thr Arg Gly Gly 145 150 155 160 Asn Met Cys Ser Gly Arg Ile Glu Ile Lys Phe Gln Gly Arg Trp Gly 165 170 175 Thr Val Cys Asp Asp Asn Phe Asn Ile Asp His Ala Ser Val Ile Cys 180 185 190 Arg Gln Leu Glu Cys Gly Ser Ala Val Ser Phe Ser Gly Ser Ser Asn 195 200 205 Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp Asp Leu Ile Cys Asn 210 215 220 Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His Gln Gly Trp Gly Lys 225 230 235 240 His Asn Cys Asp His Ala Glu Asp Ala Gly Val Ile Cys Ser Lys Gly 245 250 255 Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val Thr Glu Cys Ser Gly 260 265 270 Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly Thr Ile Cys Asp Asp 275 280 285 Gly Trp Asp Ser Tyr Asp Ala Ala Val Ala Cys Lys Gln Leu Gly Cys 290 295 300 Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn Ala Ser Lys Gly Phe 305 310 315 320 Gly His Ile Trp Leu Asp Ser Val Ser Cys Gln Gly His Glu Pro Ala 325 330 335 Val Trp Gln Cys Lys His His Glu Trp Gly Lys His Tyr Cys Asn His 340 345 350 Asn Glu Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asp Leu Glu Leu 355 360 365 Arg Leu Arg Gly Gly Gly Ser Arg Cys Ala Gly Thr Val Glu Val Glu 370 375 380 Ile Gln Arg Leu Leu Gly Lys Val Cys Asp Arg Gly Trp Gly Leu Lys 385 390 395 400 Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys Gly Ser Ala Leu Lys 405 410 415 Thr Ser Tyr Gln Val Tyr Ser Lys Ile Gln Ala Thr Asn Thr Trp Leu 420 425 430 Phe Leu Ser Ser Cys Asn Gly Asn Glu Thr Ser Leu Trp Asp Cys Lys 435 440 445 Asn Trp Gln Trp Gly Gly Leu Thr Cys Asp His Tyr Glu Glu Ala Lys 450 455 460 Ile Thr Cys Ser Ala His Arg Glu Pro Arg Leu Val Gly Gly Asp Ile 465 470 475 480 Pro Cys Ser Gly Arg Val Glu Val Lys His Gly Asp Thr Trp Gly Ser 485 490 495 Ile Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala Ser Val Leu Cys Arg 500 505 510 Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu Gly Gly Ala His Phe 515 520 525 Gly Glu Gly Asn Gly Gln Ile Trp Ala Glu Glu Phe Gln Cys Glu Gly 530 535 540 His Glu Ser His Leu Ser Leu Cys Pro Val Ala Pro Arg Pro Glu Gly 545 550 555 560 Thr Cys Ser His Ser Arg Asp Val Gly Val Val Cys Ser Arg Tyr Thr 565 570 575 Glu Ile Arg Leu Val Asn Gly Lys Thr Pro Cys Glu Gly Arg Val Glu 580 585 590 Leu Lys Thr Leu Gly Ala Trp Gly Ser Leu Cys Asn Ser His Trp Asp 595 600 605 Ile Glu Asp Ala His Val Leu Cys Gln Gln Leu Lys Cys Gly Val Ala 610 615 620 Leu Ser Thr Pro Gly Gly Ala Arg Phe Gly Lys Gly Asn Gly Gln Ile 625 630 635 640 Trp Arg His Met Phe His Cys Thr Gly Thr Glu Gln His Met Gly Asp 645 650 655 Cys Pro Val Thr Ala Leu Gly Ala Ser Leu Cys Pro Ser Glu Gln Val 660 665 670 Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln Thr Leu Ser Ser Cys 675 680 685 Asn Ser Ser Ser Leu Gly Pro Thr Arg Pro Thr Ile Pro Glu Glu Ser 690 695 700 Ala Val Ala Cys Ile Glu Ser Gly Gln Leu Arg Leu Val Asn Gly Gly 705 710 715 720 Gly Arg Cys Ala Gly Arg Val Glu Ile Tyr His Glu Gly Ser Trp Gly 725 730 735 Thr Ile Cys Asp Asp Ser Trp Asp Leu Ser Asp Ala His Val Val Cys 740 745 750 Arg Gln Leu Gly Cys Gly Glu Ala Ile Asn Ala Thr Gly Ser Ala His 755 760 765 Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu Asp Glu Met Lys Cys Asn 770 775 780 Gly Lys Glu Ser Arg Ile Trp Gln Cys His Ser His Gly Trp Gly Gln 785 790 795 800 Gln Asn Cys Arg His Lys Glu Asp Ala Gly Val Ile Cys Ser Glu Phe 805 810 815 Met Ser Leu Arg Leu Thr Ser Glu Ala Ser Arg Glu Ala Cys Ala Gly 820 825 830 Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp Gly Thr Val Gly Lys Ser 835 840 845 Ser Met Ser Glu Thr Thr Val Gly Val Val Cys Arg Gln Leu Gly Cys 850 855 860 Ala Asp Lys Gly Lys Ile Asn Pro Ala Ser Leu Asp Lys Ala Met Ser 865 870 875 880 Ile Pro Met Trp Val Asp Asn Val Gln Cys Pro Lys Gly Pro Asp Thr 885 890 895 Leu Trp Gln Cys Pro Ser Ser Pro Trp Glu Lys Arg Leu Ala Ser Pro 900 905 910 Ser Glu Glu Thr Trp Ile Thr Cys Asp Asn Lys Ile Arg Leu Gln Glu 915 920 925 Gly Pro Thr Ser Cys Ser Gly Arg Val Glu Ile Trp His Gly Gly Ser 930 935 940 Trp Gly Thr Val Cys Asp Asp Ser Trp Asp Leu Asp Asp Ala Gln Val 945 950 955 960 Val Cys Gln Gln Leu Gly Cys Gly Pro Ala Leu Lys Ala Phe Lys Glu 965 970 975 Ala Glu Phe Gly Gln Gly Thr Gly Pro Ile Trp Leu Asn Glu Val Lys 980 985 990 Cys Lys Gly Asn Glu Ser Ser Leu Trp Asp Cys Pro Ala Arg Arg Trp 995 1000 1005 Gly His Ser Glu Cys Gly His Lys Glu Asp Ala Ala Val Asn Cys 1010 1015 1020 Thr Asp Ile Ser Val Gln Lys Thr Pro Gln Lys Ala Thr Thr Gly 1025 1030 1035 Arg Ser Ser Arg Gln Ser Ser Phe Ile Ala Val Gly Ile Leu Gly 1040 1045 1050 Val Val Leu Leu Ala Ile Phe Val Ala Leu Phe Phe Leu Thr Lys 1055 1060 1065 Lys Arg Arg Gln Arg Gln Arg Leu Ala Val Ser Ser Arg Gly Glu 1070 1075 1080 Asn Leu Val His Gln Ile Gln Tyr Arg Glu Met Asn Ser Cys Leu

1085 1090 1095 Asn Ala Asp Asp Leu Asp Leu Met Asn Ser Ser Gly Leu Trp Val 1100 1105 1110 Leu Gly Gly Ser Ile Ala Gln Gly Phe Arg Ser Val Ala Ala Val 1115 1120 1125 Glu Ala Gln Thr Phe Tyr Phe Asp Lys Gln Leu Lys Lys Ser Lys 1130 1135 1140 Asn Val Ile Gly Ser Leu Asp Ala Tyr Asn Gly Gln Glu 1145 1150 1155 <210> SEQ ID NO 9 <211> LENGTH: 5193 <212> TYPE: DNA <213> ORGANISM: sus scrofa <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/NM_214346 <309> DATABASE ENTRY DATE: 2004-08-05 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(5193) <400> SEQUENCE: 9 atggacttcc tgctcctgct cctcctcctg gcttcatctg ctctagcagg cctggcctcg 60 tggacggttt ccagccccga gaccgtgcag ggcatcaagg gctcctgcct catcatcccc 120 tgcaccttcg gcttcccggc caacgtggag gtgccccatg gcatcacagc catctggtac 180 tatgactact caggcaagcg cctggtagtg agccactcca ggaacccaaa ggtggtggag 240 aaccacttcc aaggccgggc cctgctgttg gggcaggttg aacagaggac gtgcagcctg 300 ctgctgaagg acctgcagcc ccaggactcg ggctcctata acttccgctt tgagatcagc 360 gagggcaacc gctggtcaga tgtcaaaggc acagttgtca ccgtgacaga ggtgcccagc 420 gtgcccacca ttgccttgcc agccaagctg catgagggca tggaggtgga cttcaactgc 480 tccactccct atgtgtgccc gacggagccg gtcaacctac agtggcaagg ccaggatccc 540 acccgctccg tcacctccca cctccagaag cttgagccct cgggcaccag ccacatggag 600 accctgcaca tggccctgtc ctggcaggac catggccgga tcctgagctg ccaggtctca 660 gcagccgaac gcaggatgca gaaggagatt cacctccaag tgcagtatgc ccccaagggt 720 gtggagatcc ttttcagcca ctccggacgg aacgtccttc caggtgatct ggtcaccctc 780 agctgccagg tgaatagcag caaccctcag gtcagttccg tgcagtgggt caaggatggg 840 acgaagctca aagaccagaa acgtgtactg cagttgcgcc gggcagcctg ggctgatgct 900 ggcgtctaca cctgccaagc cgggaatgcc gtgggctctt cagtctcacc cccggtcagc 960 ctccacgtct tcatggctga ggtccaggta agccctgtgg gctccatcct ggagaaccag 1020 acggtgacgc tggcctgcaa tacacctaag gaagcgccca gcgagctgcg ctacagctgg 1080 tacaagaacc acgccctgct ggagggctct cacagccgca ccctccggct gcactcagtt 1140 accagggcgg attcgggctt ctacttctgc gaggtgcaga acgcccgggg cagagagcgc 1200 tctccccctg tcagcgtggt ggtcagccac ccacccctca ccccggacct aactgccttc 1260 ctggagacac aggcggggct ggtgggcatc ctccaatgct ctgtggtcag cgagccccca 1320 gctactctgg tgttgtcaca cgggggcctc atcttggcct ctacctccgg ggagggtgac 1380 cacagcccac gcttcagtgt cgcctctgcc cccaactccc tgcgcctgga gattcaagac 1440 ctggggccaa cagacagtgg ggaatacatg tgctcagcca gcagttctct tgggaatgcg 1500 tcctccaccc tggacttcca tgccaatgca gcccgcctcc tcatcagccc agcagcagag 1560 gtggtggaag ggcaggcggt gacactgagc tgcaggagca gcctgagcct gatgcctgac 1620 acccgttttt cctggtacct gaacggggcc ctgattctcg aggggcccag cagcagcctc 1680 ctgctcccag cagcctccag cacagatgcc ggctcatacc actgccgggc ccagaacagc 1740 cacagcacca gcgggccctc ctcacctgct gttctcaccg tgctctacgc cccacgccag 1800 cccgtgttca ctgcccagct ggaccctgat actgcaggag ctggggccgg acgccaaggc 1860 ctcctcttgt gccgtgtgga cagcgacccc ccagcccagc tgcagctgct ccacaggggc 1920 cgtgttgtgg cctcttctct gtcatggggg ggcggctgct gcacctgcgg aggctgtttc 1980 caccgcatga aggtcaccaa agcacccaac ctactgcgtg tagagatccg agacccggtg 2040 ctggaggatg agggtgtgta cctgtgcgag gccagcagcg ccctgggcaa cgcctccgcc 2100 tctgcaacct tggatgccca ggccactgtc ctggtcatca caccgtcaca cacgctgcag 2160 gaaggcattg aagccaacct gacttgcaac gtgagccgtg aagccagcgg ccctgccaac 2220 ttctcctggt tccgagatgg ggcgctatgg gcccagggcc ctctggacac cgtgacgctg 2280 ctacctgtgg ccagaactga tgctgccctc tatgcttgcc gcatcgtcac cgaggctggt 2340 gctggcctct ccacccctgt ggccctgaat gtgctctatc cccccgatcc tccaaagttg 2400 tcagccctcc tggacgtgga ccagggccac acggctgtgt tcgtctgtac tgtggacagt 2460 cgccctcttg cccagttggc cctgttccgt ggggaacacc tcctggccgc cagctcggca 2520 ctccggctcc cccctcgtgg ccgcctccag gccaaagcct cggccaactc cttgcagcta 2580 gaggtccgag acttgagcct tggggactct ggcagctacc actgtgaggc caccaacatc 2640 cttggatcag ccaacacttc tcttaccttc caggtccgag gagcctgggt ccgggtgtca 2700 ccgtcgcctg agctccagga gggccaggct gtggtcctga gctgccaggt acccataggg 2760 gtcctggagg ggacctcata tcgttggtat cgggatggcc agcccctcca ggagtccact 2820 tcggccacgc tccgttttgc agccataact ctgagccagg ctggagccta ccattgccaa 2880 gcccaagctc caggctcagc caccacggac ctggctgccc ctgtcagcct ccacgtgacc 2940 tacgcacctc gccaggccac actcaccacc ctgatggact caggcctcgg gcgactgggc 3000 ctccttctgt gccgtgtgaa cagtgaccct cctgcccagc tccgactgct ccatgggagc 3060 cgcctcgtgg cctctactct acaaggtgtg gaggagcttg caggcagctc tccccgccta 3120 caggtggcca cagcccccaa cacgctgcgc ctggagatcc acaacgcagt gctggaggat 3180 gaaggcgtct acacctgcga ggccaccaac accctgggtc agaccttggc ctccgccgcc 3240 ttcgatgccc aggctatgag agtgcaggtg tggcccaatg ccaccgtgca agaggggcag 3300 ctggtgaacc tgacctgcct tgtatggacc acgcacctgg cccagctcac ctacacgtgg 3360 taccgagacc agcagcagct cccaggtgct gcccactcca tcctcctgcc caatgtcact 3420 gtcacagatg ccgcctccta ccgctgtggc atattgatcc ctggccaggc actccgcctc 3480 tccagacctg tcgccctgga tgtcctctac gcaccccgca gactgcgcct gacccatctc 3540 ttggagagcc gtggtgggca gctggccgtg gtgctgtgca ctgtggacag tcgcccagct 3600 gcccagctga ccctcagcca tgctggccgc ctcctggcct cctcaaccgc agcctctgtc 3660 cccaacaccc tgcgcctgga gctgtgggag ccccggccca gtgatgaggg tctctacagc 3720 tgctcggccc gcagtcctct gggccaggcc aacacatccc tggagctgcg gctagagggc 3780 gtgcaggtgg cactggctcc atcggccact gtgccggagg gggcccctgt cacagtgacc 3840 tgtgaagacc ctgctgcccg cccacccact ctctatgtct ggtaccacaa cagccgttgg 3900 ctgcaggagg ggtcggctgc ctccctctcg tttccagcgg ctacacgggc tcacgcgggc 3960 gcctatacct gccaggtcca ggatgcccag ggcacacgca tctcccagcc cgcagcactg 4020 cacatcctct atgcccctcg ggatgctgtc ctttcctcct tctgggactc aagggccagc 4080 cctatggccg tggtacagtg cactgtggac agcgagccac ctgccgagat gaccctgtcc 4140 catgatggca aggtgctggc caccagccat ggggtccacg gcttagcagt ggggacaggc 4200 catgtccagg tggcccgcaa cgccctgcag ctgcgggtgc agaatgtgcc ctcacgtgac 4260 aaggacacct acgtctgcat ggaccgcaac tccttgggct cagtcagcac catggggcag 4320 ctgcagccag aaggtgtgca cgtggtagct gagccagggc tggatgtgcc tgaaggcaca 4380 gcgctgaacc tgagctgtcg cctccctagt ggccctgggc acataggcaa ctccaccttt 4440 gcttggttcc ggaacggtcg gcagctacac acagagtctg tgcccaccct taccttcacc 4500 catgtggccc gcgcccaagc tggcttgtac cactgccagg ctgagctccc cgccggggct 4560 gccacctctg ctccagtctt gctccgggtg ctctaccctc ccaagacgcc caccatgact 4620 gtttttgtgg agcccgaggg tggcatccag ggcattctgg actgccgagt ggacagtgag 4680 cccctagcca gcctgaccct ccacctgggc agtcggctgg tggcctccag ccagcctcag 4740 gctgcccctg ccaagccgca catccgcgtc tcagccagtc ccaatgcctt gcgagtggac 4800 atggaggagc tgaagcccag tgaccagggg gagtatgtgt gctcggcctc caatgccctg 4860 ggctctgcct ctgctgccac ctacttcgga accagagccc tgcatcgcct gcatctgttc 4920 cagcaccttc tctggttcct ggggctgctg gcgagcctcc tcttcctact gttgggcctg 4980 ggggtctggt acgcctggag acggggaaat ttttacaagc tgagaatggg cgaatattca 5040 gtagagatgg tatctcggaa ggaaaccacg cagatgtcca ctgaccagga agaagttact 5100 ggaatcggtg atgatgcggg ctctgtgaac caggcggcat ttgatcctgc ccacctctgt 5160 gaaaacacac agtctgtgaa aagcacagtc tga 5193 <210> SEQ ID NO 10 <211> LENGTH: 1730 <212> TYPE: PRT <213> ORGANISM: sus scrofa <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/NP_999511 <309> DATABASE ENTRY DATE: 2004-08-05 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1730) <400> SEQUENCE: 10 Met Asp Phe Leu Leu Leu Leu Leu Leu Leu Ala Ser Ser Ala Leu Ala 1 5 10 15 Gly Leu Ala Ser Trp Thr Val Ser Ser Pro Glu Thr Val Gln Gly Ile 20 25 30 Lys Gly Ser Cys Leu Ile Ile Pro Cys Thr Phe Gly Phe Pro Ala Asn 35 40 45 Val Glu Val Pro His Gly Ile Thr Ala Ile Trp Tyr Tyr Asp Tyr Ser 50 55 60 Gly Lys Arg Leu Val Val Ser His Ser Arg Asn Pro Lys Val Val Glu 65 70 75 80 Asn His Phe Gln Gly Arg Ala Leu Leu Leu Gly Gln Val Glu Gln Arg 85 90 95 Thr Cys Ser Leu Leu Leu Lys Asp Leu Gln Pro Gln Asp Ser Gly Ser 100 105 110 Tyr Asn Phe Arg Phe Glu Ile Ser Glu Gly Asn Arg Trp Ser Asp Val 115 120 125 Lys Gly Thr Val Val Thr Val Thr Glu Val Pro Ser Val Pro Thr Ile 130 135 140 Ala Leu Pro Ala Lys Leu His Glu Gly Met Glu Val Asp Phe Asn Cys 145 150 155 160 Ser Thr Pro Tyr Val Cys Pro Thr Glu Pro Val Asn Leu Gln Trp Gln 165 170 175 Gly Gln Asp Pro Thr Arg Ser Val Thr Ser His Leu Gln Lys Leu Glu 180 185 190 Pro Ser Gly Thr Ser His Met Glu Thr Leu His Met Ala Leu Ser Trp 195 200 205

Gln Asp His Gly Arg Ile Leu Ser Cys Gln Val Ser Ala Ala Glu Arg 210 215 220 Arg Met Gln Lys Glu Ile His Leu Gln Val Gln Tyr Ala Pro Lys Gly 225 230 235 240 Val Glu Ile Leu Phe Ser His Ser Gly Arg Asn Val Leu Pro Gly Asp 245 250 255 Leu Val Thr Leu Ser Cys Gln Val Asn Ser Ser Asn Pro Gln Val Ser 260 265 270 Ser Val Gln Trp Val Lys Asp Gly Thr Lys Leu Lys Asp Gln Lys Arg 275 280 285 Val Leu Gln Leu Arg Arg Ala Ala Trp Ala Asp Ala Gly Val Tyr Thr 290 295 300 Cys Gln Ala Gly Asn Ala Val Gly Ser Ser Val Ser Pro Pro Val Ser 305 310 315 320 Leu His Val Phe Met Ala Glu Val Gln Val Ser Pro Val Gly Ser Ile 325 330 335 Leu Glu Asn Gln Thr Val Thr Leu Ala Cys Asn Thr Pro Lys Glu Ala 340 345 350 Pro Ser Glu Leu Arg Tyr Ser Trp Tyr Lys Asn His Ala Leu Leu Glu 355 360 365 Gly Ser His Ser Arg Thr Leu Arg Leu His Ser Val Thr Arg Ala Asp 370 375 380 Ser Gly Phe Tyr Phe Cys Glu Val Gln Asn Ala Arg Gly Arg Glu Arg 385 390 395 400 Ser Pro Pro Val Ser Val Val Val Ser His Pro Pro Leu Thr Pro Asp 405 410 415 Leu Thr Ala Phe Leu Glu Thr Gln Ala Gly Leu Val Gly Ile Leu Gln 420 425 430 Cys Ser Val Val Ser Glu Pro Pro Ala Thr Leu Val Leu Ser His Gly 435 440 445 Gly Leu Ile Leu Ala Ser Thr Ser Gly Glu Gly Asp His Ser Pro Arg 450 455 460 Phe Ser Val Ala Ser Ala Pro Asn Ser Leu Arg Leu Glu Ile Gln Asp 465 470 475 480 Leu Gly Pro Thr Asp Ser Gly Glu Tyr Met Cys Ser Ala Ser Ser Ser 485 490 495 Leu Gly Asn Ala Ser Ser Thr Leu Asp Phe His Ala Asn Ala Ala Arg 500 505 510 Leu Leu Ile Ser Pro Ala Ala Glu Val Val Glu Gly Gln Ala Val Thr 515 520 525 Leu Ser Cys Arg Ser Ser Leu Ser Leu Met Pro Asp Thr Arg Phe Ser 530 535 540 Trp Tyr Leu Asn Gly Ala Leu Ile Leu Glu Gly Pro Ser Ser Ser Leu 545 550 555 560 Leu Leu Pro Ala Ala Ser Ser Thr Asp Ala Gly Ser Tyr His Cys Arg 565 570 575 Ala Gln Asn Ser His Ser Thr Ser Gly Pro Ser Ser Pro Ala Val Leu 580 585 590 Thr Val Leu Tyr Ala Pro Arg Gln Pro Val Phe Thr Ala Gln Leu Asp 595 600 605 Pro Asp Thr Ala Gly Ala Gly Ala Gly Arg Gln Gly Leu Leu Leu Cys 610 615 620 Arg Val Asp Ser Asp Pro Pro Ala Gln Leu Gln Leu Leu His Arg Gly 625 630 635 640 Arg Val Val Ala Ser Ser Leu Ser Trp Gly Gly Gly Cys Cys Thr Cys 645 650 655 Gly Gly Cys Phe His Arg Met Lys Val Thr Lys Ala Pro Asn Leu Leu 660 665 670 Arg Val Glu Ile Arg Asp Pro Val Leu Glu Asp Glu Gly Val Tyr Leu 675 680 685 Cys Glu Ala Ser Ser Ala Leu Gly Asn Ala Ser Ala Ser Ala Thr Leu 690 695 700 Asp Ala Gln Ala Thr Val Leu Val Ile Thr Pro Ser His Thr Leu Gln 705 710 715 720 Glu Gly Ile Glu Ala Asn Leu Thr Cys Asn Val Ser Arg Glu Ala Ser 725 730 735 Gly Pro Ala Asn Phe Ser Trp Phe Arg Asp Gly Ala Leu Trp Ala Gln 740 745 750 Gly Pro Leu Asp Thr Val Thr Leu Leu Pro Val Ala Arg Thr Asp Ala 755 760 765 Ala Leu Tyr Ala Cys Arg Ile Val Thr Glu Ala Gly Ala Gly Leu Ser 770 775 780 Thr Pro Val Ala Leu Asn Val Leu Tyr Pro Pro Asp Pro Pro Lys Leu 785 790 795 800 Ser Ala Leu Leu Asp Val Asp Gln Gly His Thr Ala Val Phe Val Cys 805 810 815 Thr Val Asp Ser Arg Pro Leu Ala Gln Leu Ala Leu Phe Arg Gly Glu 820 825 830 His Leu Leu Ala Ala Ser Ser Ala Leu Arg Leu Pro Pro Arg Gly Arg 835 840 845 Leu Gln Ala Lys Ala Ser Ala Asn Ser Leu Gln Leu Glu Val Arg Asp 850 855 860 Leu Ser Leu Gly Asp Ser Gly Ser Tyr His Cys Glu Ala Thr Asn Ile 865 870 875 880 Leu Gly Ser Ala Asn Thr Ser Leu Thr Phe Gln Val Arg Gly Ala Trp 885 890 895 Val Arg Val Ser Pro Ser Pro Glu Leu Gln Glu Gly Gln Ala Val Val 900 905 910 Leu Ser Cys Gln Val Pro Ile Gly Val Leu Glu Gly Thr Ser Tyr Arg 915 920 925 Trp Tyr Arg Asp Gly Gln Pro Leu Gln Glu Ser Thr Ser Ala Thr Leu 930 935 940 Arg Phe Ala Ala Ile Thr Leu Ser Gln Ala Gly Ala Tyr His Cys Gln 945 950 955 960 Ala Gln Ala Pro Gly Ser Ala Thr Thr Asp Leu Ala Ala Pro Val Ser 965 970 975 Leu His Val Thr Tyr Ala Pro Arg Gln Ala Thr Leu Thr Thr Leu Met 980 985 990 Asp Ser Gly Leu Gly Arg Leu Gly Leu Leu Leu Cys Arg Val Asn Ser 995 1000 1005 Asp Pro Pro Ala Gln Leu Arg Leu Leu His Gly Ser Arg Leu Val 1010 1015 1020 Ala Ser Thr Leu Gln Gly Val Glu Glu Leu Ala Gly Ser Ser Pro 1025 1030 1035 Arg Leu Gln Val Ala Thr Ala Pro Asn Thr Leu Arg Leu Glu Ile 1040 1045 1050 His Asn Ala Val Leu Glu Asp Glu Gly Val Tyr Thr Cys Glu Ala 1055 1060 1065 Thr Asn Thr Leu Gly Gln Thr Leu Ala Ser Ala Ala Phe Asp Ala 1070 1075 1080 Gln Ala Met Arg Val Gln Val Trp Pro Asn Ala Thr Val Gln Glu 1085 1090 1095 Gly Gln Leu Val Asn Leu Thr Cys Leu Val Trp Thr Thr His Leu 1100 1105 1110 Ala Gln Leu Thr Tyr Thr Trp Tyr Arg Asp Gln Gln Gln Leu Pro 1115 1120 1125 Gly Ala Ala His Ser Ile Leu Leu Pro Asn Val Thr Val Thr Asp 1130 1135 1140 Ala Ala Ser Tyr Arg Cys Gly Ile Leu Ile Pro Gly Gln Ala Leu 1145 1150 1155 Arg Leu Ser Arg Pro Val Ala Leu Asp Val Leu Tyr Ala Pro Arg 1160 1165 1170 Arg Leu Arg Leu Thr His Leu Leu Glu Ser Arg Gly Gly Gln Leu 1175 1180 1185 Ala Val Val Leu Cys Thr Val Asp Ser Arg Pro Ala Ala Gln Leu 1190 1195 1200 Thr Leu Ser His Ala Gly Arg Leu Leu Ala Ser Ser Thr Ala Ala 1205 1210 1215 Ser Val Pro Asn Thr Leu Arg Leu Glu Leu Trp Glu Pro Arg Pro 1220 1225 1230 Ser Asp Glu Gly Leu Tyr Ser Cys Ser Ala Arg Ser Pro Leu Gly 1235 1240 1245 Gln Ala Asn Thr Ser Leu Glu Leu Arg Leu Glu Gly Val Gln Val 1250 1255 1260 Ala Leu Ala Pro Ser Ala Thr Val Pro Glu Gly Ala Pro Val Thr 1265 1270 1275 Val Thr Cys Glu Asp Pro Ala Ala Arg Pro Pro Thr Leu Tyr Val 1280 1285 1290 Trp Tyr His Asn Ser Arg Trp Leu Gln Glu Gly Ser Ala Ala Ser 1295 1300 1305 Leu Ser Phe Pro Ala Ala Thr Arg Ala His Ala Gly Ala Tyr Thr 1310 1315 1320 Cys Gln Val Gln Asp Ala Gln Gly Thr Arg Ile Ser Gln Pro Ala 1325 1330 1335 Ala Leu His Ile Leu Tyr Ala Pro Arg Asp Ala Val Leu Ser Ser 1340 1345 1350 Phe Trp Asp Ser Arg Ala Ser Pro Met Ala Val Val Gln Cys Thr 1355 1360 1365 Val Asp Ser Glu Pro Pro Ala Glu Met Thr Leu Ser His Asp Gly 1370 1375 1380 Lys Val Leu Ala Thr Ser His Gly Val His Gly Leu Ala Val Gly 1385 1390 1395 Thr Gly His Val Gln Val Ala Arg Asn Ala Leu Gln Leu Arg Val 1400 1405 1410 Gln Asn Val Pro Ser Arg Asp Lys Asp Thr Tyr Val Cys Met Asp 1415 1420 1425 Arg Asn Ser Leu Gly Ser Val Ser Thr Met Gly Gln Leu Gln Pro 1430 1435 1440 Glu Gly Val His Val Val Ala Glu Pro Gly Leu Asp Val Pro Glu 1445 1450 1455 Gly Thr Ala Leu Asn Leu Ser Cys Arg Leu Pro Ser Gly Pro Gly 1460 1465 1470 His Ile Gly Asn Ser Thr Phe Ala Trp Phe Arg Asn Gly Arg Gln 1475 1480 1485 Leu His Thr Glu Ser Val Pro Thr Leu Thr Phe Thr His Val Ala 1490 1495 1500 Arg Ala Gln Ala Gly Leu Tyr His Cys Gln Ala Glu Leu Pro Ala 1505 1510 1515

Gly Ala Ala Thr Ser Ala Pro Val Leu Leu Arg Val Leu Tyr Pro 1520 1525 1530 Pro Lys Thr Pro Thr Met Thr Val Phe Val Glu Pro Glu Gly Gly 1535 1540 1545 Ile Gln Gly Ile Leu Asp Cys Arg Val Asp Ser Glu Pro Leu Ala 1550 1555 1560 Ser Leu Thr Leu His Leu Gly Ser Arg Leu Val Ala Ser Ser Gln 1565 1570 1575 Pro Gln Ala Ala Pro Ala Lys Pro His Ile Arg Val Ser Ala Ser 1580 1585 1590 Pro Asn Ala Leu Arg Val Asp Met Glu Glu Leu Lys Pro Ser Asp 1595 1600 1605 Gln Gly Glu Tyr Val Cys Ser Ala Ser Asn Ala Leu Gly Ser Ala 1610 1615 1620 Ser Ala Ala Thr Tyr Phe Gly Thr Arg Ala Leu His Arg Leu His 1625 1630 1635 Leu Phe Gln His Leu Leu Trp Phe Leu Gly Leu Leu Ala Ser Leu 1640 1645 1650 Leu Phe Leu Leu Leu Gly Leu Gly Val Trp Tyr Ala Trp Arg Arg 1655 1660 1665 Gly Asn Phe Tyr Lys Leu Arg Met Gly Glu Tyr Ser Val Glu Met 1670 1675 1680 Val Ser Arg Lys Glu Thr Thr Gln Met Ser Thr Asp Gln Glu Glu 1685 1690 1695 Val Thr Gly Ile Gly Asp Asp Ala Gly Ser Val Asn Gln Ala Ala 1700 1705 1710 Phe Asp Pro Ala His Leu Cys Glu Asn Thr Gln Ser Val Lys Ser 1715 1720 1725 Thr Val 1730 <210> SEQ ID NO 11 <211> LENGTH: 6387 <212> TYPE: DNA <213> ORGANISM: mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/NM_011426 <309> DATABASE ENTRY DATE: 2000-01-25 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(6387) <400> SEQUENCE: 11 agacaagatt aggcctagag taagtctatg aaacacagag aaaggggaca gcataggggt 60 taagaaatga ggtctttcaa aatctcaggg ggcaatgagg agttttttga gagaggaagg 120 actctttaaa ggaagttgaa ggaggattct gtgaacttga gaccaccctg agctgccaag 180 ttgagaactt tgtctacaaa caagccaggc agcctcagcg tgtgctcagt ccgacttgta 240 gctggagagg caggagacca atttccggtg cttacggtgc ttgctggatg ccctggagta 300 agtgacaggg tctcactgga ctccaggttc tgttggtttg agtaatagga ggcggcaggg 360 gagaagtgaa gagagacatg cactgctgat ctgccttgag gctgtgtcct taaggggtgg 420 agccaagggg cacagaagac tctctgggac atgccaccaa gtgagagcat ttccaatcac 480 tccctgagcc aggaacaggg gcttctggtt ccctgctggt ggctgccaca gcagtccttc 540 ctgttgggtt gaccaacaca gcaggtgaga taaaccctat agacttgggc cctggagtgc 600 tccaggcagt ctctgtgtgc ctacccaccc ggcttcccta ggcacctgaa tgcacctggg 660 cactgggatg tgtgtcctgt tctccctgct cctgctggcc tctgtcttct cactaggcca 720 gaccacatgg ggtgtctcca gtcccaagaa tgtgcagggc ttgtcgggat cctgcctgct 780 cattccctgc atcttcagct accctgccga tgtcccagtg tccaatggca tcacagccat 840 ctggtactat gactactcgg gcaagcggca ggtggtaatc cactcagggg accccaagct 900 ggtggacaag cgtttcaggg gtcgagctga actgatgggg aacatggacc acaaggtgtg 960 caacctgttg ctcaaagact tgaagcctga agactctggc acctacaact tccgctttga 1020 gatcagtgat agcaaccgct ggttagatgt caaaggcacc acggtcactg tgacaacgga 1080 tcccagcccc cccactatta ccattcctga ggagctgcgt gaaggcatgg agaggaactt 1140 caactgttcc acaccctacc tgtgcctgca ggagaagcaa gtcagcctgc agtggcgagg 1200 ccaggacccc acccactctg tcacctccag cttccagagc ctcgagccca ctggcgtcta 1260 tcaccagacg accctacata tggccctatc ctggcaggac cacggtcgga ccctgctctg 1320 ccagttctca ttgggcgcac acagtagtcg gaaagaggtt tacctgcaag tgccacatgc 1380 ccccaaaggt gtggagatcc tcctcagctc ctcagggagg aacatccttc ccggggatcc 1440 agtcacactc acctgcagag tgaacagcag ctatcctgct gtcagtgccg tgcagtgggc 1500 cagggacgga gtgaacctcg gagtcacggg acatgtgctt cggctgttct cagcagcctg 1560 gaatgattct ggggcctaca cctgccaagc aacaaatgat atgggctctc tggtgtcatc 1620 cccgctcagc ctccatgttt ttatggctga agtcaaaatg aaccccgcag ggcccgtctt 1680 ggaaaatgag acagtgactc tgctctgtag cacgccgaag gaggctcccc aggagctccg 1740 ctatagctgg tacaagaacc acattctcct ggaagatgcc catgcctcaa ccttgcacct 1800 gcctgcagtc accagggctg atactggctt ctacttctgt gaagtgcaga atgcccaggg 1860 cagtgagcgc tccagtccat tgagtgtggt ggtcagatat ccacccctta ctccagacct 1920 gaccaccttc ctggagacac aggccggact tgtgggcatc ttgcattgct ccgtggtcag 1980 tgagcccctg gctactgtgg tgctgtcaca cggaggcctc acgttggcct ccaactctgg 2040 agaaaatgac ttcaaccccc gattcaggat ctcctctgcc cccaactccc tgcgcctaga 2100 aatccgagac ttgcagccag cagacagcgg agagtacaca tgcttagctg tcaactccct 2160 tggaaactca acgtccagcc tagacttcta tgctaatgtg gcccgactcc tcatcaaccc 2220 ttcagcagag gttgtggaag ggcaggcggt gaccctgagc tgcaggagtg gcctgagccc 2280 agctcctgac actcgcttct cctggtacct gaacggagct ctacttctgg aaggatccag 2340 cagcagcctc ctgcttcctg cggcttccag cactgatgcg ggctcatact actgtaggac 2400 gcaggctggc cccaacacca gcggcccctc cctgcctact gtcctcactg tgttctatcc 2460 cccaagaaag cccacattca ctgccaggct ggatttggat acctctggag tcggggatgg 2520 acgacggggc atcctcttgt gccacgtaga cagcgatccc ccagcccagc tacggcttct 2580 ccacaaaggc catgttgtgg ccacttctct gccatcaagg tgtgggagct gttcccagcg 2640 cacaaaagtc agcagaacct ccaactcact gcacgtggag atccagaagc ctgtattaga 2700 ggatgagggc gtgtacctgt gtgaggctag caacacattg ggcaactcct cagccgcagc 2760 ctctttcaat gctaaggcca ctgtactggt catcacaccg tcaaatacac tgcgtgaagg 2820 cacagaggcc aacctaactt gcaacgtgaa ccaggaggtt gctgtcagcc ctgccaactt 2880 ctcctggttc cggaatggag tgctgtggac ccagggatca ctggagactg tgaggctgca 2940 gcctgtggcc agaactgatg ctgctgtcta tgcctgccgc ctcctcaccg aggatggggc 3000 tcagctctcg gctcctgtgg tcctaagtgt gctgtatgcc ccagaccctc caaagctgtc 3060 agccctccta gatgtgggtc agggccacat ggccgtgttc atctgcactg tggacagcta 3120 tcccctggct cacctgtctc tgttccgtgg ggaccatctc ctggccacca acttggaacc 3180 ccagcgtccc tcccatggca ggatccaggc caaggccaca gccaactccc tgcagctaga 3240 ggtccgagaa ctaggtcttg tggactctgg aaactaccac tgtgaagcca ccaatattct 3300 tgggtcagcc aacagttcac tcttcttcca ggtcagagga gcctgggtcc aggtttcacc 3360 atcacctgag ctccgggagg gccaggctgt ggtcctgagc tgccaggtgc ccacaggagt 3420 ctctgagggg acctcataca gctggtatca ggatggccgc cccctccagg agtcaacctc 3480 atctacactc cgcattgcag ccataagtct gaggcaagct ggtgcctacc attgccaagc 3540 tcaggcccca gacacagcta ttgccagcct ggctgcccct gtcagcctcc atgtgtccta 3600 taccccacgt catgttacac tcagtgccct gctgagcacg gaccctgagc gactaggcca 3660 cctggtgtgc agtgtacaaa gtgaccctcc agcgcagctg caactgtttc accggaatcg 3720 cctcgtggcc tctaccctac aaggcgcgga cgaattggca ggcagtaatc cccggctgca 3780 tgtgactgtg ctccccaatg agctgcgcct gcagatccac tttccagagc tggaggatga 3840 cgggacctat acatgcgaag ccagcaacac actgggccag gcctcggctg cagctgactt 3900 cgatgcccag gctgtgcgag tgactgtgtg gcccaatgcc actgtgcaag aggggcagca 3960 ggtgaacctg acctgcttgg tgtggagcac ccaccaggac tcactcagct acacatggta 4020 caagggcggg caacaactcc ttggtgccag atccatcacc ctgcccagtg ttaaggtttt 4080 ggatgctacc tcctaccgct gtggtgtggg gctccccggc cacgcacccc atctctccag 4140 acccgtgacc ctggatgtcc tccatgctcc ccgaaacctg cggctgacct acctcctaga 4200 gacccagggc aggcagctgg ccctggtact gtgtacggtg gatagtcgtc cacctgccca 4260 gctaactctc agccatggtg accagcttgt agcctcctca actgaagcct ctgtccccaa 4320 caccctgcgc ctagagcttc aggatccaag gcctagtaat gaggggctct atagctgctc 4380 tgcccacagc ccattgggca aggccaacac gtccctggaa cttctgctgg aaggtgtccg 4440 agtgaaaatg aatccctctg gtagtgtacc cgagggagag cctgtcacag tgacctgcga 4500 ggaccctgct gccctctcat ccgccctcta tgcctggttt cacaatggcc attggcttca 4560 ggagggaccg gcttcctcac tccagttcct ggtgactaca cgggctcacg ctggtgctta 4620 cttttgccag gtgcatgata cacaaggcac acggagctcc agacctgcca gcctgcaaat 4680 tctctatgcc ccccgggatg ctgtcctgtc ttcctttcga gactcaagga ccaggctcat 4740 ggtcgtgatt cagtgcaccg tggacagtga gccacctgct gagatggtcc tatcccacaa 4800 tggcaaggtg ctagctgcca gccacgagcg tcacagctca gcatcaggga taggccacat 4860 ccaggtagcc cgaaatgctc ttcgactaca agtgcaagat gtgactctgg gtgatggcaa 4920 cacctatgtt tgcacagccc agaatacact gggctccatc agtaccaccc agaggcttct 4980 gacggagact gatatacgtg tgacagctga gccaggcttg gatgtgccag agggcacagc 5040 tctgaactta agctgcctcc tccctggtgg ctctgggccc acgggcaact cttccttcac 5100 gtggttctgg aatcgccacc gactacattc agctcctgtg cccacactct ccttcacccc 5160 tgtggtccgg gctcaggctg ggctgtacca ctgcagggct gatctcccca ccggggccac 5220 tacctctgct ccagttatgc tccgtgtcct ctatcccccc aagacgccca ctctcatagt 5280 gtttgtggag cctcagggtg gccaccaggg catcctcgac tgtcgagtgg acagtgagcc 5340 cctggccatc ctcactcttc accggggcag tcaactagta gcctccaacc aacttcacga 5400 tgctcccacc aagccccaca tccgagtcac tgctcctccc aatgccttga gagtggacat 5460 agaggagctc ggccctagca atcaagggga gtatgtgtgc actgcctcca acactctggg 5520 ctctgcctca gcctctgcct actttgggac cagagctctg caccaactgc agctgttcca 5580 gaggctgctc tgggtcctgg gatttctggc aggcttcctg tgcctgctgc tgggtctggt 5640 ggcctatcac acctggagaa agaagagttc taccaagctg aatgaggatg agaattcagc 5700 agagatggcc actaagaaaa atactatcca ggaggaagtg gttgctgctc tctgacaact 5760 caggtgctgt gaacaagatc ctgcctacct ctgtataagc agtacagaga catctggctt 5820

tcctgacctg cccgacttgc cttccaagcc tcttgatcct aagaaaaatg gacgaaggga 5880 ggtttggggt tggaggtcaa cctgccgcct ccagggctct gagacggact cagccatgtt 5940 gcccacgtct ctctgtgtgg ttttcctctg tatccctttg cctttctctt caaagctcac 6000 cttggacttt cttggtgggt tagagcaaca tccagtttct cacagacttt ctaagacggt 6060 ctgtaccagc caggatatca gtcaggttgc tctaacagag actcaataca gtgaccacag 6120 catgacaggg tcttagtttt ccctcctggc ctggttatgt tgttgtggta tcagaatcct 6180 tcttgcttga ttttctccat tccccaagtg ttgcctttga ttatgaagct caggtaactg 6240 cagtgcccat ggaccctaca gggagaagga agagtgaagg gaagacatac ccatccccat 6300 ggtccatgga ctgtgtgtgc aattgcaccc cacccaactt ctcatccgct agaaactggt 6360 cacataaaca taccatgctg aaaggga 6387 <210> SEQ ID NO 12 <211> LENGTH: 1695 <212> TYPE: PRT <213> ORGANISM: mus musculus <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept <309> DATABASE ENTRY DATE: 2000-01-25 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1695) <400> SEQUENCE: 12 Met Cys Val Leu Phe Ser Leu Leu Leu Leu Ala Ser Val Phe Ser Leu 1 5 10 15 Gly Gln Thr Thr Trp Gly Val Ser Ser Pro Lys Asn Val Gln Gly Leu 20 25 30 Ser Gly Ser Cys Leu Leu Ile Pro Cys Ile Phe Ser Tyr Pro Ala Asp 35 40 45 Val Pro Val Ser Asn Gly Ile Thr Ala Ile Trp Tyr Tyr Asp Tyr Ser 50 55 60 Gly Lys Arg Gln Val Val Ile His Ser Gly Asp Pro Lys Leu Val Asp 65 70 75 80 Lys Arg Phe Arg Gly Arg Ala Glu Leu Met Gly Asn Met Asp His Lys 85 90 95 Val Cys Asn Leu Leu Leu Lys Asp Leu Lys Pro Glu Asp Ser Gly Thr 100 105 110 Tyr Asn Phe Arg Phe Glu Ile Ser Asp Ser Asn Arg Trp Leu Asp Val 115 120 125 Lys Gly Thr Thr Val Thr Val Thr Thr Asp Pro Ser Pro Pro Thr Ile 130 135 140 Thr Ile Pro Glu Glu Leu Arg Glu Gly Met Glu Arg Asn Phe Asn Cys 145 150 155 160 Ser Thr Pro Tyr Leu Cys Leu Gln Glu Lys Gln Val Ser Leu Gln Trp 165 170 175 Arg Gly Gln Asp Pro Thr His Ser Val Thr Ser Ser Phe Gln Ser Leu 180 185 190 Glu Pro Thr Gly Val Tyr His Gln Thr Thr Leu His Met Ala Leu Ser 195 200 205 Trp Gln Asp His Gly Arg Thr Leu Leu Cys Gln Phe Ser Leu Gly Ala 210 215 220 His Ser Ser Arg Lys Glu Val Tyr Leu Gln Val Pro His Ala Pro Lys 225 230 235 240 Gly Val Glu Ile Leu Leu Ser Ser Ser Gly Arg Asn Ile Leu Pro Gly 245 250 255 Asp Pro Val Thr Leu Thr Cys Arg Val Asn Ser Ser Tyr Pro Ala Val 260 265 270 Ser Ala Val Gln Trp Ala Arg Asp Gly Val Asn Leu Gly Val Thr Gly 275 280 285 His Val Leu Arg Leu Phe Ser Ala Ala Trp Asn Asp Ser Gly Ala Tyr 290 295 300 Thr Cys Gln Ala Thr Asn Asp Met Gly Ser Leu Val Ser Ser Pro Leu 305 310 315 320 Ser Leu His Val Phe Met Ala Glu Val Lys Met Asn Pro Ala Gly Pro 325 330 335 Val Leu Glu Asn Glu Thr Val Thr Leu Leu Cys Ser Thr Pro Lys Glu 340 345 350 Ala Pro Gln Glu Leu Arg Tyr Ser Trp Tyr Lys Asn His Ile Leu Leu 355 360 365 Glu Asp Ala His Ala Ser Thr Leu His Leu Pro Ala Val Thr Arg Ala 370 375 380 Asp Thr Gly Phe Tyr Phe Cys Glu Val Gln Asn Ala Gln Gly Ser Glu 385 390 395 400 Arg Ser Ser Pro Leu Ser Val Val Val Arg Tyr Pro Pro Leu Thr Pro 405 410 415 Asp Leu Thr Thr Phe Leu Glu Thr Gln Ala Gly Leu Val Gly Ile Leu 420 425 430 His Cys Ser Val Val Ser Glu Pro Leu Ala Thr Val Val Leu Ser His 435 440 445 Gly Gly Leu Thr Leu Ala Ser Asn Ser Gly Glu Asn Asp Phe Asn Pro 450 455 460 Arg Phe Arg Ile Ser Ser Ala Pro Asn Ser Leu Arg Leu Glu Ile Arg 465 470 475 480 Asp Leu Gln Pro Ala Asp Ser Gly Glu Tyr Thr Cys Leu Ala Val Asn 485 490 495 Ser Leu Gly Asn Ser Thr Ser Ser Leu Asp Phe Tyr Ala Asn Val Ala 500 505 510 Arg Leu Leu Ile Asn Pro Ser Ala Glu Val Val Glu Gly Gln Ala Val 515 520 525 Thr Leu Ser Cys Arg Ser Gly Leu Ser Pro Ala Pro Asp Thr Arg Phe 530 535 540 Ser Trp Tyr Leu Asn Gly Ala Leu Leu Leu Glu Gly Ser Ser Ser Ser 545 550 555 560 Leu Leu Leu Pro Ala Ala Ser Ser Thr Asp Ala Gly Ser Tyr Tyr Cys 565 570 575 Arg Thr Gln Ala Gly Pro Asn Thr Ser Gly Pro Ser Leu Pro Thr Val 580 585 590 Leu Thr Val Phe Tyr Pro Pro Arg Lys Pro Thr Phe Thr Ala Arg Leu 595 600 605 Asp Leu Asp Thr Ser Gly Val Gly Asp Gly Arg Arg Gly Ile Leu Leu 610 615 620 Cys His Val Asp Ser Asp Pro Pro Ala Gln Leu Arg Leu Leu His Lys 625 630 635 640 Gly His Val Val Ala Thr Ser Leu Pro Ser Arg Cys Gly Ser Cys Ser 645 650 655 Gln Arg Thr Lys Val Ser Arg Thr Ser Asn Ser Leu His Val Glu Ile 660 665 670 Gln Lys Pro Val Leu Glu Asp Glu Gly Val Tyr Leu Cys Glu Ala Ser 675 680 685 Asn Thr Leu Gly Asn Ser Ser Ala Ala Ala Ser Phe Asn Ala Lys Ala 690 695 700 Thr Val Leu Val Ile Thr Pro Ser Asn Thr Leu Arg Glu Gly Thr Glu 705 710 715 720 Ala Asn Leu Thr Cys Asn Val Asn Gln Glu Val Ala Val Ser Pro Ala 725 730 735 Asn Phe Ser Trp Phe Arg Asn Gly Val Leu Trp Thr Gln Gly Ser Leu 740 745 750 Glu Thr Val Arg Leu Gln Pro Val Ala Arg Thr Asp Ala Ala Val Tyr 755 760 765 Ala Cys Arg Leu Leu Thr Glu Asp Gly Ala Gln Leu Ser Ala Pro Val 770 775 780 Val Leu Ser Val Leu Tyr Ala Pro Asp Pro Pro Lys Leu Ser Ala Leu 785 790 795 800 Leu Asp Val Gly Gln Gly His Met Ala Val Phe Ile Cys Thr Val Asp 805 810 815 Ser Tyr Pro Leu Ala His Leu Ser Leu Phe Arg Gly Asp His Leu Leu 820 825 830 Ala Thr Asn Leu Glu Pro Gln Arg Pro Ser His Gly Arg Ile Gln Ala 835 840 845 Lys Ala Thr Ala Asn Ser Leu Gln Leu Glu Val Arg Glu Leu Gly Leu 850 855 860 Val Asp Ser Gly Asn Tyr His Cys Glu Ala Thr Asn Ile Leu Gly Ser 865 870 875 880 Ala Asn Ser Ser Leu Phe Phe Gln Val Arg Gly Ala Trp Val Gln Val 885 890 895 Ser Pro Ser Pro Glu Leu Arg Glu Gly Gln Ala Val Val Leu Ser Cys 900 905 910 Gln Val Pro Thr Gly Val Ser Glu Gly Thr Ser Tyr Ser Trp Tyr Gln 915 920 925 Asp Gly Arg Pro Leu Gln Glu Ser Thr Ser Ser Thr Leu Arg Ile Ala 930 935 940 Ala Ile Ser Leu Arg Gln Ala Gly Ala Tyr His Cys Gln Ala Gln Ala 945 950 955 960 Pro Asp Thr Ala Ile Ala Ser Leu Ala Ala Pro Val Ser Leu His Val 965 970 975 Ser Tyr Thr Pro Arg His Val Thr Leu Ser Ala Leu Leu Ser Thr Asp 980 985 990 Pro Glu Arg Leu Gly His Leu Val Cys Ser Val Gln Ser Asp Pro Pro 995 1000 1005 Ala Gln Leu Gln Leu Phe His Arg Asn Arg Leu Val Ala Ser Thr 1010 1015 1020 Leu Gln Gly Ala Asp Glu Leu Ala Gly Ser Asn Pro Arg Leu His 1025 1030 1035 Val Thr Val Leu Pro Asn Glu Leu Arg Leu Gln Ile His Phe Pro 1040 1045 1050 Glu Leu Glu Asp Asp Gly Thr Tyr Thr Cys Glu Ala Ser Asn Thr 1055 1060 1065 Leu Gly Gln Ala Ser Ala Ala Ala Asp Phe Asp Ala Gln Ala Val 1070 1075 1080 Arg Val Thr Val Trp Pro Asn Ala Thr Val Gln Glu Gly Gln Gln 1085 1090 1095 Val Asn Leu Thr Cys Leu Val Trp Ser Thr His Gln Asp Ser Leu 1100 1105 1110 Ser Tyr Thr Trp Tyr Lys Gly Gly Gln Gln Leu Leu Gly Ala Arg 1115 1120 1125 Ser Ile Thr Leu Pro Ser Val Lys Val Leu Asp Ala Thr Ser Tyr 1130 1135 1140 Arg Cys Gly Val Gly Leu Pro Gly His Ala Pro His Leu Ser Arg 1145 1150 1155

Pro Val Thr Leu Asp Val Leu His Ala Pro Arg Asn Leu Arg Leu 1160 1165 1170 Thr Tyr Leu Leu Glu Thr Gln Gly Arg Gln Leu Ala Leu Val Leu 1175 1180 1185 Cys Thr Val Asp Ser Arg Pro Pro Ala Gln Leu Thr Leu Ser His 1190 1195 1200 Gly Asp Gln Leu Val Ala Ser Ser Thr Glu Ala Ser Val Pro Asn 1205 1210 1215 Thr Leu Arg Leu Glu Leu Gln Asp Pro Arg Pro Ser Asn Glu Gly 1220 1225 1230 Leu Tyr Ser Cys Ser Ala His Ser Pro Leu Gly Lys Ala Asn Thr 1235 1240 1245 Ser Leu Glu Leu Leu Leu Glu Gly Val Arg Val Lys Met Asn Pro 1250 1255 1260 Ser Gly Ser Val Pro Glu Gly Glu Pro Val Thr Val Thr Cys Glu 1265 1270 1275 Asp Pro Ala Ala Leu Ser Ser Ala Leu Tyr Ala Trp Phe His Asn 1280 1285 1290 Gly His Trp Leu Gln Glu Gly Pro Ala Ser Ser Leu Gln Phe Leu 1295 1300 1305 Val Thr Thr Arg Ala His Ala Gly Ala Tyr Phe Cys Gln Val His 1310 1315 1320 Asp Thr Gln Gly Thr Arg Ser Ser Arg Pro Ala Ser Leu Gln Ile 1325 1330 1335 Leu Tyr Ala Pro Arg Asp Ala Val Leu Ser Ser Phe Arg Asp Ser 1340 1345 1350 Arg Thr Arg Leu Met Val Val Ile Gln Cys Thr Val Asp Ser Glu 1355 1360 1365 Pro Pro Ala Glu Met Val Leu Ser His Asn Gly Lys Val Leu Ala 1370 1375 1380 Ala Ser His Glu Arg His Ser Ser Ala Ser Gly Ile Gly His Ile 1385 1390 1395 Gln Val Ala Arg Asn Ala Leu Arg Leu Gln Val Gln Asp Val Thr 1400 1405 1410 Leu Gly Asp Gly Asn Thr Tyr Val Cys Thr Ala Gln Asn Thr Leu 1415 1420 1425 Gly Ser Ile Ser Thr Thr Gln Arg Leu Leu Thr Glu Thr Asp Ile 1430 1435 1440 Arg Val Thr Ala Glu Pro Gly Leu Asp Val Pro Glu Gly Thr Ala 1445 1450 1455 Leu Asn Leu Ser Cys Leu Leu Pro Gly Gly Ser Gly Pro Thr Gly 1460 1465 1470 Asn Ser Ser Phe Thr Trp Phe Trp Asn Arg His Arg Leu His Ser 1475 1480 1485 Ala Pro Val Pro Thr Leu Ser Phe Thr Pro Val Val Arg Ala Gln 1490 1495 1500 Ala Gly Leu Tyr His Cys Arg Ala Asp Leu Pro Thr Gly Ala Thr 1505 1510 1515 Thr Ser Ala Pro Val Met Leu Arg Val Leu Tyr Pro Pro Lys Thr 1520 1525 1530 Pro Thr Leu Ile Val Phe Val Glu Pro Gln Gly Gly His Gln Gly 1535 1540 1545 Ile Leu Asp Cys Arg Val Asp Ser Glu Pro Leu Ala Ile Leu Thr 1550 1555 1560 Leu His Arg Gly Ser Gln Leu Val Ala Ser Asn Gln Leu His Asp 1565 1570 1575 Ala Pro Thr Lys Pro His Ile Arg Val Thr Ala Pro Pro Asn Ala 1580 1585 1590 Leu Arg Val Asp Ile Glu Glu Leu Gly Pro Ser Asn Gln Gly Glu 1595 1600 1605 Tyr Val Cys Thr Ala Ser Asn Thr Leu Gly Ser Ala Ser Ala Ser 1610 1615 1620 Ala Tyr Phe Gly Thr Arg Ala Leu His Gln Leu Gln Leu Phe Gln 1625 1630 1635 Arg Leu Leu Trp Val Leu Gly Phe Leu Ala Gly Phe Leu Cys Leu 1640 1645 1650 Leu Leu Gly Leu Val Ala Tyr His Thr Trp Arg Lys Lys Ser Ser 1655 1660 1665 Thr Lys Leu Asn Glu Asp Glu Asn Ser Ala Glu Met Ala Thr Lys 1670 1675 1680 Lys Asn Thr Ile Gln Glu Glu Val Val Ala Ala Leu 1685 1690 1695 <210> SEQ ID NO 13 <211> LENGTH: 6736 <212> TYPE: DNA <213> ORGANISM: homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenBank/NM_023068 <309> DATABASE ENTRY DATE: 2001-02-13 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(6736) <400> SEQUENCE: 13 atgggcttct tgcccaagct tctcctcctg gcctcattct tcccagcagg ccaggcctca 60 tggggcgtct ccagtcccca ggacgtgcag ggtgtgaagg ggtcttgcct gcttatcccc 120 tgcatcttca gcttccctgc cgacgtggag gtgcccgacg gcatcacggc catctggtac 180 tacgactact cgggccagcg gcaggtggtg agccactcgg cggaccccaa gctggtggag 240 gcccgcttcc gcggccgcac cgagttcatg gggaaccccg agcacagggt gtgcaacctg 300 ctgctgaagg acctgcagcc cgaggactct ggttcctaca acttccgctt cgagatcagt 360 gaggtcaacc gctggtcaga tgtgaaaggc accttggtca cagtaacaga ggagcccagg 420 gtgcccacca ttgcctcccc ggtggagctt ctcgagggca cagaggtgga cttcaactgc 480 tccactccct acgtatgcct gcaggagcag gtcagactgc agtggcaagg ccaggaccct 540 gctcgctctg tcaccttcaa cagccagaag tttgagccca ccggcgtcgg ccacctggag 600 accctccaca tggccatgtc ctggcaggac cacggccgga tcctgcgctg ccagctctcc 660 gtggccaatc acagggctca gagcgagatt cacctccaag tgaagtatgc ccccaagggt 720 gtgaagatcc tcctcagccc ctcggggagg aacatccttc caggtgagct ggtcacactc 780 acctgccagg tgaacagcag ctaccctgca gtcagttcca ttaagtggct caaggatggg 840 gtacgcctcc aaaccaagac tggtgtgctg cacctgcccc aggcagcctg gagcgatgct 900 ggcgtctaca cctgccaagc tgagaacggc gtgggctctt tggtctcacc ccccatcagc 960 ctccacatct tcatggctga ggtccaggtg agcccagcag gtcccatcct ggagaaccag 1020 acagtgacac tagtctgcaa cacacccaat gaggcaccca gtgatctccg ctacagctgg 1080 tacaagaacc atgtcctgct ggaggatgcc cactcccata ccctccggct gcacttggcc 1140 actagggctg atactggctt ctacttctgt gaggtgcaga acgtccatgg cagcgagcgc 1200 tcgggccctg tcagcgtggt agtcaaccac ccgcctctca ctccagtcct gacagccttc 1260 ctggagaccc aggcgggact tgtgggcatc cttcactgct ctgtggtcag tgagcccctg 1320 gccacactgg tgctgtcaca tgggggtcat atcctggcct ccacctccgg ggacagtgat 1380 cacagcccac gcttcagtgg tacctctggt cccaactccc tgcgcctgga gatccgagac 1440 ctggaggaaa ctgacagtgg ggagtacaag tgctcagcca ccaactccct tggaaatgca 1500 acctccaccc tggacttcca tgccaatgcc gcccgtctcc tcatcagccc ggcagccgag 1560 gtggtggaag gacaggcagt gacactgagc tgcagaagcg gcctaagccc cacacctgat 1620 gcccgcttct cctggtacct gaatggagcc ctgcttcacg agggtcccgg cagcagcctc 1680 ctgctccccg cggcctccag cactgacgcc ggctcatacc actgccgggc ccgggacggc 1740 cacagtgcca gtggcccctc ttcgccagct gttctcactg tgctctaccc ccctcgacaa 1800 ccaacattca ccaccaggct ggaccttgat gccgctgggg ccggggctgg acggcgaggc 1860 ctccttttgt gccgtgtgga cagcgacccc cccgccaggc tgcagctgct ccacaaggac 1920 cgtgttgtgg ccacttccct gccatcaggg ggtggctgca gcacctgtgg gggctgttcc 1980 ccacgcatga aggtcaccaa agcccccaac ttgctgcgtg tggagattca caaccctttg 2040 ctggaagagg agggcttgta cctctgtgag gccagcaatg ccctgggcaa cgcctccacc 2100 tcagccacct tcaatggcca ggccactgtc ctggccattg caccatcaca cacacttcag 2160 gagggcacag aagccaactt gacttgcaac gtgagccggg aagctgctgg cagccctgct 2220 aacttctcct ggttccgaaa tggggtgctg tgggcccagg gtcccctgga gaccgtgaca 2280 ctgctgcccg tggccagaac tgatgctgcc ctttacgcct gccgcatcct gactgaggct 2340 ggtgcccagc tctccactcc cgtgctcctg agtgtactct atcccccgga ccgtccaaag 2400 ctgtcagccc tcctagacat gggccagggc cacatggctc tgttcatctg cactgtggac 2460 agccgccccc tggccttgct ggccttgttc catggggagc acctcctggc caccagcctg 2520 ggtccccagg tcccatccca tggtcggttc caggctaaag ctgaggccaa ctccctgaag 2580 ttagaggtcc gagaactggg ccttggggac tctggcagct accgctgtga ggccacaaat 2640 gttcttggat catccaacac ctcactcttc ttccaggtcc gaggagcctg ggtccaggtg 2700 tcaccatcac ctgagctcca agagggccag gctgtggtcc tgagctgcca ggtacacaca 2760 ggagtcccag aggggacctc atatcgttgg tatcgggatg gccagcccct ccaggagtcg 2820 acctcggcca cgctccgctt tgcagccata actttgacac aagctggggc ctatcattgc 2880 caagcccagg ccccaggctc agccaccacg agcctagctg cacccatcag cctccacgtg 2940 tcctatgccc cacgccacgt cacactcact accctgatgg acacaggccc tggacgactg 3000 ggcctcctcc tgtgccgtgt ggacagtgac cctccggccc agctgcggct gctccacggg 3060 gatcgccttg tggcctccac cctacaaggt gtggggggac ccgaaggcag ctctcccagg 3120 ctgcatgtgg ctgtggcccc caacacactg cgtctggaga tccacggggc tatgctggag 3180 gatgagggtg tctatatctg tgaggcctcc aacaccctgg gccaggcctc ggcctcagct 3240 gacttcgacg ctcaagctgt gaatgtgcag gtgtggcccg gggctaccgt gcgggagggg 3300 cagctggtga acctgacctg ccttgtgtgg accactcacc cggcccagct cacctacaca 3360 tggtaccagg atgggcagca gcgcctggat gcccactcca tccccctgcc caacgtcaca 3420 gtcagggatg ccacctccta ccgctgcggt gtgggccccc ctggtcgggc accccgcctc 3480 tccagaccta tcaccttgga cgtcctctac gcgccccgca acctgcgcct gacctacctc 3540 ctggagagcc atggcgggca gctggccctg gtactgtgca ctgtggacag ccgcccgccc 3600 gcccagctgg ccctcagcca cgccggtcgc ctcttggcct cctcgacagc agcctctgtc 3660 cccaacaccc tgcgcctgga gctgcgaggg ccacagccca gggatgaggg tttctacagc 3720 tgctctgccc gcagccctct gggccaggcc aacacgtccc tggagctgcg gctggagggt 3780 gtgcgggtga tcctggctcc ggaggctgcc gtgcctgaag gtgcccccat cacagtgacc 3840 tgtgcggacc ctgctgccca cgcacccaca ctctatactt ggtaccacaa cggtcgttgg 3900

ctgcaggagg gtccagctgc ctcactctca ttcctggtgg ccacgcgggc tcatgcaggc 3960 gcctactctt gccaggccca ggatgcccag ggcacccgca gctcccgtcc tgctgccctg 4020 caagtcctct atgcccctca ggacgctgtc ctgtcctcct tccgggactc cagggccaga 4080 tccatggctg tgatacagtg cactgtggac agtgagccac ctgctgagct ggccctatct 4140 catgatggca aggtgctggc cacgagcagc ggggtccaca gcttggcatc agggacaggc 4200 catgtccagg tggcccgaaa cgccctacgg ctgcaggtgc aagatgtgcc tgcaggtgat 4260 gacacctatg tttgcacagc ccaaaacttg ctgggctcaa tcagcaccat cgggcggttg 4320 caggtagaag gtgcacgcgt ggtggcagag cctggcctgg acgtgcctga gggcgctgcc 4380 ctgaacctca gctgccgcct cctgggtggc cctgggcctg tgggcaactc cacctttgca 4440 tggttctgga atgaccggcg gctgcacgcg gagcctgtgc ccactctcgc cttcacccac 4500 gtggctcgtg ctcaagctgg gatgtaccac tgcctggctg agctccccac tggggctgct 4560 gcctctgctc cagtcatgct ccgtgtgctc taccctccca agacgcccac catgatggtc 4620 ttcgtggagc ctgagggtgg cctccggggc atcctggatt gccgagtgga cagcgagccg 4680 ctcgccagcc tgactctcca ccttggcagt cgactggtgg cctccagtca gccccagggt 4740 gctcctgcag agccacacat ccatgtcctg gcttccccca atgccctgag ggtggacatc 4800 gaggcgctga ggcccagcga ccaaggggaa tacatctgtt ctgcctcaaa tgtcctgggc 4860 tctgcctcta cctccaccta ctttggggtc agagccctgc accgcctgca tcagttccag 4920 cagctgctct gggtcctggg actgctggtg ggcctcctgc tcctgctgtt gggcctgggg 4980 gcctgctaca cctggagaag gaggcgtgtt tgtaagcaga gcatgggcga gaattcggtg 5040 gagatggctt ttcagaaaga gaccacgcag ctcattgatc ctgatgcagc cacatgtgag 5100 acctcaacct gtgccccacc cctgggctga ccagtggtgt tgcctgccct ccggaggaga 5160 aagtggccag aatctgtgat gactccagcc tatgaatgtg aatgaggcag tgttgagtcc 5220 tgcccgcctc tacgaaaaca gctctgtgac atctgacttt ttatgacctg gccccaagcc 5280 tcttgccccc ccaaaaatgg gtggtgagag gtctgcccag gagggtgttg accctggagg 5340 acactgaaga gcactgagct gatctcgctc tctcttctct ggatctcctc ccttctctcc 5400 atttctccct caaaggaagc cctgcccttt cacatccttc tcctcgaaag tcaccctgga 5460 ctttggttgg attgcagcat cctgcatcct cagaggctca ccaaggcatt ctgtattcaa 5520 cagagtatca gtcagcctgc tctaacaaga gaccaaatac agtgacttca acatgataga 5580 attttatttt tctctcccac gctagtctgg ctgttacgat ggtttatgat gttggggctc 5640 aggatccttc tatcttcctt ttctctatcc ctaaaatgat gcctttgatt gtgaggctca 5700 ccatggcccc gctttgtcca catgccctcc agccagaaga aggaagagtg gaggtagaag 5760 cacacccatg cccatggtgg acgcaactca gaagctgcac aggacttttc cactcacttc 5820 ccattggctg gagtattgtc acatggctac tgcaagctac aagggagact gggaaatgta 5880 gtttttattt tgagtccaga ggacatttgg aattggactt ccaaaggact cccaactgtg 5940 agctcatccc tgagactttt gacattgttg ggaatgccac cagcaggcca tgttttgtct 6000 cagtgcccat ctactgaggg ccagggtgtg cccctggcca ttctggttgt gggcttcctg 6060 gaagaggtga tcactctcac actaagactg aggaaataaa aaaggtttgg tgttttccta 6120 gggagagagc atgccaggca gtggagttgc ctaagcagac atccttgtgc cagatttggc 6180 ccctgaaaga agagatgccc tcattcccac caccaccccc cctaccccca gggactgggt 6240 actaccttac tggcccttac aagagtggag ggcagacaca gatgttgtca gcatccttat 6300 tcctgctcca gatgcatctc tgttcatgac tgtgtgagct cctgtccttt tcctggagac 6360 cctgtgtcgg gctgttaaag agaatgagtt accaagaagg aatgacgtgc ccctgcgaat 6420 cagggaccaa caggagagag ctcttgagtg ggctagtgac tccccctgca gcctggtgga 6480 gatggtgtga ggagcgaaga gccctctgct ctaggatttg ggttgaaaaa cagagagaga 6540 agtggggagt tgccacagga gctaacacgc tgggaggcag ttgggggcgg gtgaactttg 6600 tgtagccgag gccgcaccct ccctcattcc aggctcattc attttcatgc tccattgcca 6660 gactcttgct gggagcccgt ccagaatgtc ctcccaataa aactccatcc tatgacgcaa 6720 aaaaaaaaaa aaaaaa 6736 <210> SEQ ID NO 14 <211> LENGTH: 1709 <212> TYPE: PRT <213> ORGANISM: homo sapiens <300> PUBLICATION INFORMATION: <308> DATABASE ACCESSION NUMBER: GenPept/NP_075556 <309> DATABASE ENTRY DATE: 2001-02-13 <313> RELEVANT RESIDUES IN SEQ ID NO: (1)..(1709) <400> SEQUENCE: 14 Met Gly Phe Leu Pro Lys Leu Leu Leu Leu Ala Ser Phe Phe Pro Ala 1 5 10 15 Gly Gln Ala Ser Trp Gly Val Ser Ser Pro Gln Asp Val Gln Gly Val 20 25 30 Lys Gly Ser Cys Leu Leu Ile Pro Cys Ile Phe Ser Phe Pro Ala Asp 35 40 45 Val Glu Val Pro Asp Gly Ile Thr Ala Ile Trp Tyr Tyr Asp Tyr Ser 50 55 60 Gly Gln Arg Gln Val Val Ser His Ser Ala Asp Pro Lys Leu Val Glu 65 70 75 80 Ala Arg Phe Arg Gly Arg Thr Glu Phe Met Gly Asn Pro Glu His Arg 85 90 95 Val Cys Asn Leu Leu Leu Lys Asp Leu Gln Pro Glu Asp Ser Gly Ser 100 105 110 Tyr Asn Phe Arg Phe Glu Ile Ser Glu Val Asn Arg Trp Ser Asp Val 115 120 125 Lys Gly Thr Leu Val Thr Val Thr Glu Glu Pro Arg Val Pro Thr Ile 130 135 140 Ala Ser Pro Val Glu Leu Leu Glu Gly Thr Glu Val Asp Phe Asn Cys 145 150 155 160 Ser Thr Pro Tyr Val Cys Leu Gln Glu Gln Val Arg Leu Gln Trp Gln 165 170 175 Gly Gln Asp Pro Ala Arg Ser Val Thr Phe Asn Ser Gln Lys Phe Glu 180 185 190 Pro Thr Gly Val Gly His Leu Glu Thr Leu His Met Ala Met Ser Trp 195 200 205 Gln Asp His Gly Arg Ile Leu Arg Cys Gln Leu Ser Val Ala Asn His 210 215 220 Arg Ala Gln Ser Glu Ile His Leu Gln Val Lys Tyr Ala Pro Lys Gly 225 230 235 240 Val Lys Ile Leu Leu Ser Pro Ser Gly Arg Asn Ile Leu Pro Gly Glu 245 250 255 Leu Val Thr Leu Thr Cys Gln Val Asn Ser Ser Tyr Pro Ala Val Ser 260 265 270 Ser Ile Lys Trp Leu Lys Asp Gly Val Arg Leu Gln Thr Lys Thr Gly 275 280 285 Val Leu His Leu Pro Gln Ala Ala Trp Ser Asp Ala Gly Val Tyr Thr 290 295 300 Cys Gln Ala Glu Asn Gly Val Gly Ser Leu Val Ser Pro Pro Ile Ser 305 310 315 320 Leu His Ile Phe Met Ala Glu Val Gln Val Ser Pro Ala Gly Pro Ile 325 330 335 Leu Glu Asn Gln Thr Val Thr Leu Val Cys Asn Thr Pro Asn Glu Ala 340 345 350 Pro Ser Asp Leu Arg Tyr Ser Trp Tyr Lys Asn His Val Leu Leu Glu 355 360 365 Asp Ala His Ser His Thr Leu Arg Leu His Leu Ala Thr Arg Ala Asp 370 375 380 Thr Gly Phe Tyr Phe Cys Glu Val Gln Asn Val His Gly Ser Glu Arg 385 390 395 400 Ser Gly Pro Val Ser Val Val Val Asn His Pro Pro Leu Thr Pro Val 405 410 415 Leu Thr Ala Phe Leu Glu Thr Gln Ala Gly Leu Val Gly Ile Leu His 420 425 430 Cys Ser Val Val Ser Glu Pro Leu Ala Thr Leu Val Leu Ser His Gly 435 440 445 Gly His Ile Leu Ala Ser Thr Ser Gly Asp Ser Asp His Ser Pro Arg 450 455 460 Phe Ser Gly Thr Ser Gly Pro Asn Ser Leu Arg Leu Glu Ile Arg Asp 465 470 475 480 Leu Glu Glu Thr Asp Ser Gly Glu Tyr Lys Cys Ser Ala Thr Asn Ser 485 490 495 Leu Gly Asn Ala Thr Ser Thr Leu Asp Phe His Ala Asn Ala Ala Arg 500 505 510 Leu Leu Ile Ser Pro Ala Ala Glu Val Val Glu Gly Gln Ala Val Thr 515 520 525 Leu Ser Cys Arg Ser Gly Leu Ser Pro Thr Pro Asp Ala Arg Phe Ser 530 535 540 Trp Tyr Leu Asn Gly Ala Leu Leu His Glu Gly Pro Gly Ser Ser Leu 545 550 555 560 Leu Leu Pro Ala Ala Ser Ser Thr Asp Ala Gly Ser Tyr His Cys Arg 565 570 575 Ala Arg Asp Gly His Ser Ala Ser Gly Pro Ser Ser Pro Ala Val Leu 580 585 590 Thr Val Leu Tyr Pro Pro Arg Gln Pro Thr Phe Thr Thr Arg Leu Asp 595 600 605 Leu Asp Ala Ala Gly Ala Gly Ala Gly Arg Arg Gly Leu Leu Leu Cys 610 615 620 Arg Val Asp Ser Asp Pro Pro Ala Arg Leu Gln Leu Leu His Lys Asp 625 630 635 640 Arg Val Val Ala Thr Ser Leu Pro Ser Gly Gly Gly Cys Ser Thr Cys 645 650 655 Gly Gly Cys Ser Pro Arg Met Lys Val Thr Lys Ala Pro Asn Leu Leu 660 665 670 Arg Val Glu Ile His Asn Pro Leu Leu Glu Glu Glu Gly Leu Tyr Leu 675 680 685 Cys Glu Ala Ser Asn Ala Leu Gly Asn Ala Ser Thr Ser Ala Thr Phe 690 695 700 Asn Gly Gln Ala Thr Val Leu Ala Ile Ala Pro Ser His Thr Leu Gln 705 710 715 720 Glu Gly Thr Glu Ala Asn Leu Thr Cys Asn Val Ser Arg Glu Ala Ala 725 730 735 Gly Ser Pro Ala Asn Phe Ser Trp Phe Arg Asn Gly Val Leu Trp Ala 740 745 750 Gln Gly Pro Leu Glu Thr Val Thr Leu Leu Pro Val Ala Arg Thr Asp 755 760 765

Ala Ala Leu Tyr Ala Cys Arg Ile Leu Thr Glu Ala Gly Ala Gln Leu 770 775 780 Ser Thr Pro Val Leu Leu Ser Val Leu Tyr Pro Pro Asp Arg Pro Lys 785 790 795 800 Leu Ser Ala Leu Leu Asp Met Gly Gln Gly His Met Ala Leu Phe Ile 805 810 815 Cys Thr Val Asp Ser Arg Pro Leu Ala Leu Leu Ala Leu Phe His Gly 820 825 830 Glu His Leu Leu Ala Thr Ser Leu Gly Pro Gln Val Pro Ser His Gly 835 840 845 Arg Phe Gln Ala Lys Ala Glu Ala Asn Ser Leu Lys Leu Glu Val Arg 850 855 860 Glu Leu Gly Leu Gly Asp Ser Gly Ser Tyr Arg Cys Glu Ala Thr Asn 865 870 875 880 Val Leu Gly Ser Ser Asn Thr Ser Leu Phe Phe Gln Val Arg Gly Ala 885 890 895 Trp Val Gln Val Ser Pro Ser Pro Glu Leu Gln Glu Gly Gln Ala Val 900 905 910 Val Leu Ser Cys Gln Val His Thr Gly Val Pro Glu Gly Thr Ser Tyr 915 920 925 Arg Trp Tyr Arg Asp Gly Gln Pro Leu Gln Glu Ser Thr Ser Ala Thr 930 935 940 Leu Arg Phe Ala Ala Ile Thr Leu Thr Gln Ala Gly Ala Tyr His Cys 945 950 955 960 Gln Ala Gln Ala Pro Gly Ser Ala Thr Thr Ser Leu Ala Ala Pro Ile 965 970 975 Ser Leu His Val Ser Tyr Ala Pro Arg His Val Thr Leu Thr Thr Leu 980 985 990 Met Asp Thr Gly Pro Gly Arg Leu Gly Leu Leu Leu Cys Arg Val Asp 995 1000 1005 Ser Asp Pro Pro Ala Gln Leu Arg Leu Leu His Gly Asp Arg Leu 1010 1015 1020 Val Ala Ser Thr Leu Gln Gly Val Gly Gly Pro Glu Gly Ser Ser 1025 1030 1035 Pro Arg Leu His Val Ala Val Ala Pro Asn Thr Leu Arg Leu Glu 1040 1045 1050 Ile His Gly Ala Met Leu Glu Asp Glu Gly Val Tyr Ile Cys Glu 1055 1060 1065 Ala Ser Asn Thr Leu Gly Gln Ala Ser Ala Ser Ala Asp Phe Asp 1070 1075 1080 Ala Gln Ala Val Asn Val Gln Val Trp Pro Gly Ala Thr Val Arg 1085 1090 1095 Glu Gly Gln Leu Val Asn Leu Thr Cys Leu Val Trp Thr Thr His 1100 1105 1110 Pro Ala Gln Leu Thr Tyr Thr Trp Tyr Gln Asp Gly Gln Gln Arg 1115 1120 1125 Leu Asp Ala His Ser Ile Pro Leu Pro Asn Val Thr Val Arg Asp 1130 1135 1140 Ala Thr Ser Tyr Arg Cys Gly Val Gly Pro Pro Gly Arg Ala Pro 1145 1150 1155 Arg Leu Ser Arg Pro Ile Thr Leu Asp Val Leu Tyr Ala Pro Arg 1160 1165 1170 Asn Leu Arg Leu Thr Tyr Leu Leu Glu Ser His Gly Gly Gln Leu 1175 1180 1185 Ala Leu Val Leu Cys Thr Val Asp Ser Arg Pro Pro Ala Gln Leu 1190 1195 1200 Ala Leu Ser His Ala Gly Arg Leu Leu Ala Ser Ser Thr Ala Ala 1205 1210 1215 Ser Val Pro Asn Thr Leu Arg Leu Glu Leu Arg Gly Pro Gln Pro 1220 1225 1230 Arg Asp Glu Gly Phe Tyr Ser Cys Ser Ala Arg Ser Pro Leu Gly 1235 1240 1245 Gln Ala Asn Thr Ser Leu Glu Leu Arg Leu Glu Gly Val Arg Val 1250 1255 1260 Ile Leu Ala Pro Glu Ala Ala Val Pro Glu Gly Ala Pro Ile Thr 1265 1270 1275 Val Thr Cys Ala Asp Pro Ala Ala His Ala Pro Thr Leu Tyr Thr 1280 1285 1290 Trp Tyr His Asn Gly Arg Trp Leu Gln Glu Gly Pro Ala Ala Ser 1295 1300 1305 Leu Ser Phe Leu Val Ala Thr Arg Ala His Ala Gly Ala Tyr Ser 1310 1315 1320 Cys Gln Ala Gln Asp Ala Gln Gly Thr Arg Ser Ser Arg Pro Ala 1325 1330 1335 Ala Leu Gln Val Leu Tyr Ala Pro Gln Asp Ala Val Leu Ser Ser 1340 1345 1350 Phe Arg Asp Ser Arg Ala Arg Ser Met Ala Val Ile Gln Cys Thr 1355 1360 1365 Val Asp Ser Glu Pro Pro Ala Glu Leu Ala Leu Ser His Asp Gly 1370 1375 1380 Lys Val Leu Ala Thr Ser Ser Gly Val His Ser Leu Ala Ser Gly 1385 1390 1395 Thr Gly His Val Gln Val Ala Arg Asn Ala Leu Arg Leu Gln Val 1400 1405 1410 Gln Asp Val Pro Ala Gly Asp Asp Thr Tyr Val Cys Thr Ala Gln 1415 1420 1425 Asn Leu Leu Gly Ser Ile Ser Thr Ile Gly Arg Leu Gln Val Glu 1430 1435 1440 Gly Ala Arg Val Val Ala Glu Pro Gly Leu Asp Val Pro Glu Gly 1445 1450 1455 Ala Ala Leu Asn Leu Ser Cys Arg Leu Leu Gly Gly Pro Gly Pro 1460 1465 1470 Val Gly Asn Ser Thr Phe Ala Trp Phe Trp Asn Asp Arg Arg Leu 1475 1480 1485 His Ala Glu Pro Val Pro Thr Leu Ala Phe Thr His Val Ala Arg 1490 1495 1500 Ala Gln Ala Gly Met Tyr His Cys Leu Ala Glu Leu Pro Thr Gly 1505 1510 1515 Ala Ala Ala Ser Ala Pro Val Met Leu Arg Val Leu Tyr Pro Pro 1520 1525 1530 Lys Thr Pro Thr Met Met Val Phe Val Glu Pro Glu Gly Gly Leu 1535 1540 1545 Arg Gly Ile Leu Asp Cys Arg Val Asp Ser Glu Pro Leu Ala Ser 1550 1555 1560 Leu Thr Leu His Leu Gly Ser Arg Leu Val Ala Ser Ser Gln Pro 1565 1570 1575 Gln Gly Ala Pro Ala Glu Pro His Ile His Val Leu Ala Ser Pro 1580 1585 1590 Asn Ala Leu Arg Val Asp Ile Glu Ala Leu Arg Pro Ser Asp Gln 1595 1600 1605 Gly Glu Tyr Ile Cys Ser Ala Ser Asn Val Leu Gly Ser Ala Ser 1610 1615 1620 Thr Ser Thr Tyr Phe Gly Val Arg Ala Leu His Arg Leu His Gln 1625 1630 1635 Phe Gln Gln Leu Leu Trp Val Leu Gly Leu Leu Val Gly Leu Leu 1640 1645 1650 Leu Leu Leu Leu Gly Leu Gly Ala Cys Tyr Thr Trp Arg Arg Arg 1655 1660 1665 Arg Val Cys Lys Gln Ser Met Gly Glu Asn Ser Val Glu Met Ala 1670 1675 1680 Phe Gln Lys Glu Thr Thr Gln Leu Ile Asp Pro Asp Ala Ala Thr 1685 1690 1695 Cys Glu Thr Ser Thr Cys Ala Pro Pro Leu Gly 1700 1705 <210> SEQ ID NO 15 <211> LENGTH: 40 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR forward primer CD163 <400> SEQUENCE: 15 cac cat gga caa act cag aat ggt gct aca tga aaa ctc t 40 <210> SEQ ID NO 16 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR reverse primer CD163 <400> SEQUENCE: 16 tca ttg tac ttc aga gtg gtc tcc tga ggg att 33

Claims

1.-30. (canceled)

31. A method for generating a cell that is permissive for Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), the method comprising: treating a cell to express CD 163 and sialoadhesin proteins, thereby generating the cell that is permissive for PRRSV.

32. The method according to claim 31, wherein treating the cell comprises introducing into the cell an exogenous nucleic acid encoding CD 163 protein.

33. The method according to claim 32, wherein the CD163 protein encoded by the exogenous nucleic acid is at least 70% identical to porcine CD163 encoded by SEQ ID NO:1.

34. The method according to claim 32, wherein the CD163 protein encoded by the exogenous nucleic acid includes at least one Scavenger Receptor Cysteine Rich (SRCR) domain.

35. The method according to claim 31, wherein treating the cell comprises introducing into the cell an exogenous nucleic acid encoding sialoadhesin protein.

36. The method according to claim 35, wherein the sialoadhesin protein encoded by the exogenous nucleic acid is at least 70% identical to porcine sialoadhesin encoded by SEQ ID NO:9.

37. The method according to claim 36, wherein the sialoadhesin protein encoded by the exogenous nucleic acid includes at least the N-terminal domain of porcine sialoadhesin.

38. The method according to claim 31, wherein treating the cell comprises introducing into the cell exogenous nucleic acid(s) encoding CD163 and sialoadhesin proteins.

39. The method according to claim 31, wherein treating the cell to express CD163 and sialoadhesin proteins comprises chemical treatment.

40. The method according to claim 39, wherein the chemical treatment results in the expression of sialoadhesin protein in the cell.

41. The method according to claim 31, wherein the cell is selected from the group consisting of an insect cell, a yeast cell, a porcine kidney (PK) cell, a feline kidney (FK) cell, a swine testicular (ST) cell, an African green monkey kidney cell, a MA-104 cell, a MARC-145 cell, a VERO cell, a COS cell, a Chinese hamster ovary (CHO) cell, a baby hamster kidney cell, a human 293 cell, a murine 3T3 fibroblast, and a plant-cell based production platform.

42. The method according to claim 31, wherein the cell is not an alveolar macrophage.

43. A cell that is permissive for Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), generated by the method according to claim 31.

44. The cell of claim 33, wherein the cell is selected from the group consisting of an insect cell, a yeast cell, a porcine kidney (PK) cell, a feline kidney (FK) cell, a swine testicular (ST) cell, an African green monkey kidney cell, a MA-104 cell, a MARC-145 cell, a VERO cell, a COS cell, a Chinese hamster ovary (CHO) cell, a baby hamster kidney cell, a human 293 cell, a murine 3T3 fibroblast, and a plant-cell based production platform.

45. The cell of claim 44, wherein the cell is a PK-15 cell, a CHO cell, a BHK-21 cell, a MARC-145 cell, or a Hek293t cell.

46. A method for producing Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), the method comprising: infecting the cell of claim 43 with PRRSV.

47. The method according to claim 46, wherein the method further comprises harvesting PRRSV from the cell.

48. The method according to claim 47, wherein the method further comprises inactivating the harvested PRRSV.

49. A method to determine infection of a subject with Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), the method comprising: contacting the cell of claim 43 with a sample taken from the subject; culturing the cell under conditions suitable for replication of PRRSV in the cell; and determining the presence in the cell culture of PRRSV, wherein the presence of PRRSV indicates that the subject is infected with PRRSV.

50. The method according to claim 49, wherein the method further comprises treating the subject for PRRSV infection.