Compounds

p101 polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing p101 polypeptides and polynucleotides in therapy, and diagnostic assays for such.

FIELD OF THE INVENTION
 This invention relates to newly identified polypeptides and polynucleotides
 encoding such polypeptides, to their use in therapy and in identifying
 compounds which may be agonists, antagonists and/or inhibitors which are
 potentially useful in therapy, and to production of such polypeptides and
 polynucleotides.
 BACKGROUND OF THE INVENTION
 The drug discovery process is currently undergoing a fundamental revolution
 as it embraces `functional genomics`, that is, high throughput genome- or
 gene-based biology. This approach as a means to identify genes and gene
 products as therapeutic targets is rapidly superceding earlier approaches
 based on `positional cloning`. A phenotype, that is a biological function
 or genetic disease, would be identified and this would then be tracked
 back to the responsible gene, based on its genetic map position.
 Functional genomics relies heavily on high-throughput DNA sequencing
 technologies and the various tools of bioinformatics to identify gene
 sequences of potential interest from the many molecular biology databases
 now available. There is a continuing need to identify and characterise
 further genes and their related polypeptides/proteins, as targets for drug
 discovery.
 SUMMARY OF THE INVENTION
 The present invention relates to p101 polypeptides and polynucleotides, in
 particular p101 splice variant polypeptides and polynucleotides,
 recombinant materials and methods for their production. In another aspect,
 the invention relates to methods for using such polypeptides and
 polynucleotides, including the treatment of diseases that involve
 leucocyte activation and infiltration including inflammatory diseases such
 as COPD, ARDS, arthritis, psoriasis and so on, hereinafter referred to as
 "the Diseases", amongst others. In a further aspect, the invention relates
 to methods for identifying agonists and antagonists/inhibitors using the
 materials provided by the invention, and treating conditions associated
 with p101 imbalance with the identified compounds. In a still further
 aspect, the invention relates to diagnostic assays for detecting diseases
 associated with inappropriate p101 activity or levels.

DESCRIPTION OF THE INVENTION
 In a first aspect, the present invention relates to p101 splice variant
 polypeptides. Such peptides include isolated polypeptides comprising an
 amino acid sequence which has at least 95% identity, preferably at least
 97-99% identity, to that of SEQ ID NO:2 or SEQ ID NO:4 over the entire
 length of SEQ ID NO:2 or SEQ ID NO:4 respectively. Such polypeptides
 include those comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID
 NO:4 respectively.
 Further peptides of the present invention include isolated polypeptides in
 which the amino acid sequence has at least 95% identity preferably at
 least 97-99% identity, to the amino acid sequence of SEQ ID NO:2 or SEQ ID
 NO:4 over the entire length of SEQ ID NO:2 or SEQ ID NO:4. Such
 polypeptides include the polypeptides of SEQ ID NO:2 or SEQ ID NO:4
 respectively.
 Further peptides of the present invention include isolated polypeptides
 encoded by a polynucleotide comprising the sequence contained in SEQ ID
 NO: 1 or SEQ ID NO: 3.
 Polypeptides of the present invention are believed to be members of the
 adaptor protein family of polypeptides. They are therefore of interest
 because they are involved in the generation of the important second
 messenger, phosphatidylinositol 3,4,5-triphosphate (PIP3); PIP3 is
 generated following the stimulation of various receptors and is involved,
 for example in leucocytes, in regulating chemotaxis, adherence and
 degranulation. PIP3 is primarily generated via the action of
 phosphatidylinositol 3-kinase, several of which are thought to exist.
 however, one that appears to be particularly relevant in leucocytes is
 directly regulated, i.e activated by G protein .beta..gamma. subunits.
 Importantly, this regulation is dependent upon an adaptor protein, p101.
 Inhibition of this activation process by, for example, preventing
 G.beta..gamma. binding to p101 should prevent PIP3 accumulation. Such an
 action would be of benefit in various disease states that involve
 leucocyte activation and infiltration. These properties are hereinafter
 referred to as "p101 activity" or "p101 polypeptide activity" or
 "biological activity of p101". Also included amongst these activities are
 antigenic and immunogenic activities of said p101 polypeptides, in
 particular the antigenic and immunogenic activities of the polypeptide of
 SEQ ID NO:2 or SEQ ID NO:4. Preferably, a polypeptide of the present
 invention exhibits at least one biological activity of p101.
 The polypeptides of the present invention may be in the form of the
 "mature" protein or may be a part of a larger protein such as a precursor
 or a fusion protein. It is often advantageous to include an additional
 amino acid sequence which contains secretory or leader sequences,
 pro-sequences, sequences which aid in purification such as multiple
 histidine residues, or an additional sequence for stability during
 recombinant production.
 The present invention also includes variants of the aforementioned
 polypeptides, that is polypeptides that vary from the referents by
 conservative amino acid substitutions, whereby a residue is substituted by
 another with like characteristics. Typical such substitutions are among
 Ala, Val, Leu and Ile; among Ser and Thr; among the acidic residues Asp
 and Glu; among Asn and Gln; and among the basic residues Lys and Arg; or
 aromatic residues Phe and Tyr. Particularly preferred are variants in
 which several, 5-10, 1-5, 1-3, 1-2 or 1 amino acids are substituted,
 deleted, or added in any combination.
 Polypeptides of the present invention can be prepared in any suitable
 manner. Such polypeptides include isolated naturally occurring
 polypeptides, recombinantly produced polypeptides, synthetically produced
 polypeptides, or polypeptides produced by a combination of these methods.
 Means for preparing such polypeptides are well understood in the art.
 In a further aspect, the present invention relates to p101 splice variant
 polynucleotides. Such polynucleotides include isolated polynucleotides
 comprising a nucleotide sequence encoding a polypeptide which has at least
 95% identity, to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4,
 over the entire length of SEQ ID NO:2 or SEQ ID NO:4 respectively. In this
 regard, polypeptides which have at least 97% identity are highly
 preferred, whilst those with at least 98-99% identity are more highly
 preferred, and those with at least 99% identity are most highly preferred.
 Such polynucleotides include a polynucleotide comprising the nucleotide
 sequence contained in SEQ ID NO: 1 or SEQ ID NO:3 encoding the polypeptide
 of SEQ ID NO:2 or SEQ ID NO:4 respectively.
 Further polynucleotides of the present invention include isolated
 polynucleotides comprising a nucleotide sequence that has at least 95%
 identity to a nucleotide sequence encoding a polypeptide of SEQ ID NO:2 or
 SEQ ID NO:4 respectively, over the entire coding region. In this regard,
 polynucleotides which have at least 97% identity are highly preferred,
 whilst those with at least 98-99% identity are more highly preferred, and
 those with at least 99% identity are most highly preferred.
 Further polynucleotides of the present invention include isolated
 polynucleotides comprising a nucleotide sequence which has at least 95%
 identity to SEQ ID NO: 1 or SEQ ID NO:3 over the entire length of SEQ ID
 NO: 1 or SEQ ID NO:3 respectively. In this regard, polynucleotides which
 have at least 97% identity are highly preferred, whilst those with at
 least 98-99% identiy are more highly preferred, and those with at least
 99% identity are most highly preferred. Such polynucleotides include a
 polynucleotide comprising the polynucleotide of SEQ ID NO: 1 or SEQ ID
 NO:3 as well as the polynucleotide of SEQ ID NO: 1 or SEQ ID NO:3
 respectively. The invention also provides polynucleotides which are
 complementary to all the above described polynucleotides.
 The nucleotide sequence of SEQ ID NO:5, the full-length human p101 cDNA
 sequence (European Patent Application No: EP98306696.0; SmithKline
 Beecham), shows homology with pig p101 (L. R. Stephens et al, Cell 89 pp
 105-114, 1997). The nucleotide sequence of SEQ ID NO:5 is a cDNA sequence
 and comprises a polypeptide encoding sequence (nucleotide 1 to 3630, Exon
 1(1-106), Exon 2 (107-205), Exon 3 (206-265), Exon 4(266-414), Exon 5
 (415-479), Exon 6 (480-648), Exon 7 (649-810), Exon 8 (811-894), Exon 9
 (895-1616), Exon 10 (1617-1778), Exon 11 (1779-1907), Exon 12 (1908-2037),
 Exon 13 (2038-2129), Exon 14 (2130-2200), Exon 15 (2201-2298), Exon 16
 (2299-2380), Exon 17 (2381-2488), Exon 18 (2489-2642)) encoding a
 polypeptide of 880 amino acids, the polypeptide of SEQ ID NO:6.
 SEQ ID NO: 1 is a CDNA which encodes a splice variant of p101, SVP-2, which
 lacks exons 6, 7, 8, 9 and 10. The polypeptide encoded by the
 polynucleotide shown in SEQ ID NO: 1 is given in SEQ ID NO:2. SEQ ID NO:3
 is a CDNA which encodes a further splice variant of p101, SVP-4, which
 lacks exons 9 and 10. The polypeptide encoded by the polynucleotide shown
 in SEQ ID NO:3 is given in SEQ ID NO:4.
 The nucleotide sequence encoding the polypeptide of SEQ ID NO:2 or SEQ ID
 NO:4 may be identical to the polypeptide encoding sequence contained in
 SEQ ID NO: 1 or SEQ ID NO:3 or it may be a sequence other than the one
 contained in SEQ ID NO: 1 or SEQ ID NO:3 which, as a result of the
 redundancy (degeneracy) of the genetic code, also encodes the polypeptide
 of SEQ ID NO:2 or SEQ ID NO:4. The polypeptide of the SEQ ID NO:2 or SEQ
 ID NO:4 is structurally related to other proteins of the adaptor protein
 family, having homology and/or structural similarity with pig p101 (L. R.
 Stephens et al, Cell 89 pp105-114, 1997).
 Preferred polypeptides and polynucleotides of the present invention are
 expected to have, inter alia, similar biological functions/properties to
 their homologous polypeptides and polynucleotides. Furthermore, preferred
 polypeptides and polynucleotides of the present invention have at least
 one p101 activity.
 The present invention also relates to partial or other polynucleotide and
 polypeptide sequences which were first identified prior to the
 determination of the corresponding full length sequences of SEQ ID NO: 1,
 SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4.
 Accordingly, in a further aspect, the present invention provides for an
 isolated polynucleotide which:
 (a) comprises a nucleotide sequence which has at least 95% identity,
 preferably at least 97-99% identity to SEQ ID NO:7 or SEQ ID NO:9 over the
 entire length of SEQ ID NO:7 or SEQ ID NO:9;
 (b) has a nucleotide sequence which has at least 95% identity, preferably
 at least 97-99% identity, to SEQ ID NO:7 or SEQ ID NO:9 over the entire
 length of SEQ ID NO:7 or SEQ ID NO:9;
 (c) the polynucleotide of SEQ ID NO:7 or SEQ ID NO:9; or
 (d) a nucleotide sequence encoding a polypeptide which has at least 95%
 identity, preferably at least 97-99% identity, to the amino acid sequence
 of SEQ ID NO:8 or SEQ ID NO: 10 over the entire length of SEQ ID NO:8 or
 SEQ ID NO:10;
 as well as the polynucleotide of SEQ ID NO:7 or SEQ ID NO:9.
 The present invention further provides for a polypeptide which:
 (a) comprises an amino acid sequence which has at least 95% identity,
 preferably at least 97-99% identity, to that of SEQ ID NO:8 or SEQ ID NO:
 10 over the entire length of SEQ ID NO:8 or SEQ ID NO: 10;
 (b) has an amino acid sequence which is at least 95% identity, preferably
 at least 97-99% identity, to the amino acid sequence of SEQ ID NO: 8 or
 SEQ ID NO: 10 over the entire length of SEQ ID NO:8 or SEQ ID NO:10;
 (c) comprises the amino acid sequence of SEQ ID NO:8 or SEQ ID NO: 10; and
 (d) is the polypeptide of SEQ ID NO:8 or SEQ ID NO: 10;
 as well as polypeptides encoded by a polynucleotide comprising the sequence
 contained in SEQ ID NO:7 or SEQ ID NO:9.
 The nucleotide sequence of SEQ ID NO:7 or SEQ ID NO:9 and the peptide
 sequences encoded thereby are derived from EST (Expressed Sequence Tag)
 sequences. It is recognised by those skilled in the art that there will
 inevitably be some nucleotide sequence reading errors in EST sequences
 (see Adams, M. D. et al, Nature 377 (supp) 3, 1995). Accordingly, the
 nucleotide sequence of SEQ ID NO:7 or SEQ ID NO:9 and the peptide sequence
 encoded therefrom are therefore subject to the same inherent limitations
 in sequence accuracy. Furthermore, the peptide sequence encoded by SEQ ID
 NO:7 or SEQ ID NO:9 comprises a region of identity or close homology
 and/or close structural similarity (for example a conservative amino acid
 difference) with the closest homologous or structurally similar protein.
 Polynucleotides of the present invention may be obtained, using standard
 cloning and screening techniques, from a cDNA library derived from mRNA in
 cells of human primary monocytes (Sambrook et al., Molecular Cloning: A
 Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, Cold
 Spring Harbor, N.Y. (1989). Polynucleotides of the invention can also be
 obtained from natural sources such as genomic DNA libraries or can be
 synthesized using well known and commercially available techniques.
 When polynucleotides of the present invention are used for the recombinant
 production of polypeptides of the present invention, the polynucleotide
 may include the coding sequence for the mature polypeptide, by itself; or
 the coding sequence for the mature polypeptide in reading frame with other
 coding sequences, such as those encoding a leader or secretory sequence, a
 pre-, or pro- or prepro- protein sequence, or other fusion peptide
 portions. For example, a marker sequence which facilitates purification of
 the fused polypeptide can be encoded. In certain preferred embodiments of
 this aspect of the invention, the marker sequence is a hexa-histidine
 peptide, as provided in the pQE vector (Qiagen, Inc.) and described in
 Gentz et al., Proc Natl Acad Sci USA (1989) 86:821-824, or is an HA tag.
 The polynucleotide may also contain non-coding 5' and 3' sequences, such
 as transcribed, non-translated sequences, splicing and polyadenylation
 signals, ribosome binding sites and sequences that stabilize mRNA.
 Further embodiments of the present invention include polynucleotides
 encoding polypeptide variants which comprise the amino acid sequence of
 SEQ ID NO:2, 4, 6 and 8 respectively and in which several, for instance
 from 5 to 10, 1 to 5, 1 to 3, 1 to 2 or 1, amino acid residues are
 substituted, deleted or added, in any combination.
 Polynucleotides which are identical or sufficiently identical to a
 nucleotide sequence contained in SEQ ID NO: 1, 3, 7 and 9, may be used as
 hybridization probes for cDNA and genomic DNA or as primers for a nucleic
 acid amplification (PCR) reaction, to isolate full-length cDNAs and
 genomic clones encoding polypeptides of the present invention and to
 isolate cDNA and genomic clones of other genes (including genes encoding
 paralogs from human sources and orthologs and paralogs from species other
 than human) that have a high sequence similarity to SEQ ID NO: 1, 3, 7 and
 9. Typically these nucleotide sequences are 70% identical, preferably 80%
 identical, more preferably 90% identical, most preferably 95% identical to
 that of the referent. The probes or primers will generally comprise at
 least 15 nucleotides, preferably, at least 30 nucleotides and may have at
 least 50 nucleotides. Particularly preferred probes will have between 30
 and 50 nucleotides. Particularly preferred primers will have between 20
 and 25 nucleotides.
 A polynucleotide encoding a polypeptide of the present invention, including
 homologs from species other than human, may be obtained by a process which
 comprises the steps of screening an appropriate library under stringent
 hybridization conditions with a labeled probe having the sequence of SEQ
 ID NO: 1, 3, 7 and 9 respectively or a fragment thereof; and isolating
 full-length cDNA and genomic clones containing said polynucleotide
 sequence. Such hybridization techniques are well known to the skilled
 artisan. Preferred stringent hybridization conditions include overnight
 incubation at 42.degree. C. in a solution comprising: 50% formamide,
 5.times. SSC (150 nmM NaCl, 15 mM trisodium citrate), 50 mM sodium
 phosphate (pH7.6), 5.times. Denhardt's solution, 10% dextran sulfate, and
 20 microgram/ml denatured, sheared salmon sperm DNA; followed by washing
 the filters in 0.1.times. SSC at about 65.degree. C. Thus the present
 invention also includes polynucleotides obtainable by screening an
 appropriate library under stingent hybridization conditions with a labeled
 probe having the sequence of SEQ ID NO:1, 3, 7 and 9 or a fragment
 thereof.
 The skilled artisan will appreciate that, in many cases, an isolated cDNA
 sequence will be incomplete, in that the region coding for the polypeptide
 is short at the 5' end of the cDNA. This is a consequence of reverse
 transcriptase, an enzyme with inherently low `processivity` (a measure of
 the ability of the enzyme to remain attached to the template during the
 polymerisation reaction), failing to complete a DNA copy of the mRNA
 template during 1st strand cDNA synthesis.
 There are several methods available and well known to those skilled in the
 art to obtain full-length cDNAs, or extend short cDNAs, for example those
 based on the method of Rapid Amplification of cDNA ends (RACE) (see, for
 example, Frohman et al., PNAS USA 85, 8998-9002, 1988). Recent
 modifications of the technique, exemplified by the Marathon.TM. technology
 (Clontech Laboratories Inc.) for example, have significantly simplified
 the search for longer cDNAs. In the Marathon.TM. technology, cDNAs have
 been prepared from mRNA extracted from a chosen tissue and an `adaptor`
 sequence ligated onto each end. Nucleic acid amplification (PCR) is then
 carried out to amplify the `missing` 5' end of the cDNA using a
 combination of gene specific and adaptor specific oligonucleotide primers.
 The PCR reaction is then repeated using `nested` primers, that is, primers
 designed to anneal within the amplified product (typically an adaptor
 specific primer that anneals further 3' in the adaptor sequence and a gene
 specific primer that anneals further 5' in the known gene sequence). The
 products of this reaction can then be analysed by DNA sequencing and a
 full-length cDNA constructed either by joining the product directly to the
 existing cDNA to give a complete sequence, or carrying out a separate
 full-length PCR using the new sequence information for the design of the
 5' primer.
 Recombinant polypeptides of the present invention may be prepared by
 processes well known in the art from genetically engineered host cells
 comprising expression systems. Accordingly, in a further aspect, the
 present invention relates to expression systems which comprise a
 polynucleotide or polynucleotides of the present invention, to host cells
 which are genetically engineered with such expression sytems and to the
 production of polypeptides of the invention by recombinant techniques.
 Cell-free translation systems can also be employed to produce such
 proteins using RNAs derived from the DNA constructs of the present
 invention.
 For recombinant production, host cells can be genetically engineered to
 incorporate expression systems or portions thereof for polynucleotides of
 the present invention. Introduction of polynucleotides into host cells can
 be effected by methods described in many standard laboratory manuals, such
 as Davis et al., Basic Methods in Molecular Biology (1986) and Sambrook et
 al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor
 Laboratory Press, Cold Spring Harbor, N.Y. (1989). Preferred such methods
 include, for instance, calcium phosphate transfection, DEAE-dextran
 mediated transfection, transvection, microinjection, cationic
 lipid-mediated transfection, electroporation, transduction, scrape
 loading, ballistic introduction or infection.
 Representative examples of appropriate hosts include bacterial cells, such
 as Streptococci, Staphylococci, E. coli, Streptomyces and Bacillus
 subtilis cells; fungal cells, such as yeast cells and Aspergillus cells;
 insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells
 such as CHO, COS, HeLa, C127, 3T3, BHK, HEK 293 and Bowes melanoma cells;
 and plant cells.
 A great variety of expression systems can be used, for instance,
 chromosomal, episomal and virus-derived systems, e.g., vectors derived
 from bacterial plasmids, from bacteriophage, from transposons, from yeast
 episomes, from insertion elements, from yeast chromosomal elements, from
 viruses such as baculoviruses, papova viruses, such as SV40, vaccinia
 viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and
 retroviruses, and vectors derived from combinations thereof, such as those
 derived from plasmid and bacteriophage genetic elements, such as cosmids
 and phagemids. The expression systems may contain control regions that
 regulate as well as engender expression. Generally, any system or vector
 which is able to maintain, propagate or express a polynucleotide to
 produce a polypeptide in a host may be used. The appropriate nucleotide
 sequence may be inserted into an expression system by any of a variety of
 well-known and routine techniques, such as, for example, those set forth
 in Sambrook et al., Molecular Cloning, A Laboratory Manual (supra).
 Appropriate secretion signals may be incorporated into the desired
 polypeptide to allow secretion of the translated protein into the lumen of
 the endoplasmic reticulum, the periplasmic space or the extracellular
 environment. These signals may be endogenous to the polypeptide or they
 may be heterologous signals.
 If a polypeptide of the present invention is to be expressed for use in
 screening assays, it is generally preferred that the polypeptide be
 produced at the surface of the cell. In this event, the cells may be
 harvested prior to use in the screening assay. If the polypeptide is
 secreted into the medium, the medium can be recovered in order to recover
 and purify the polypeptide. If produced intracellularly, the cells must
 first be lysed before the polypeptide is recovered.
 Polypeptides of the present invention can be recovered and purified from
 recombinant cell cultures by well-known methods including ammonium sulfate
 or ethanol precipitation, acid extraction, anion or cation exchange
 chromatography, phosphocellulose chromatography, hydrophobic interaction
 chromatography, affinity chromatography, hydroxylapatite chromatography
 and lectin chromatography. Most preferably, high performance liquid
 chromatography is employed for purification. Well known techniques for
 refolding proteins may be employed to regenerate active conformation when
 the polypeptide is denatured during intracellular synthesis, isolation and
 or purification.
 This invention also relates to the use of polynucleotides of the present
 invention as diagnostic reagents. Detection of a mutated form of the gene
 characterised by the polynucleotide of SEQ ID NO: 1, 3, 5 and 7
 respectively which is associated with a dysfunction will provide a
 diagnostic tool that can add to, or define, a diagnosis of a disease, or
 susceptibility to a disease, which results from under-expression,
 over-expression or altered spatial or temporal expression of the gene.
 Individuals carrying mutations in the gene may be detected at the DNA
 level by a variety of techniques.
 Nucleic acids for diagnosis may be obtained from a subject's cells, such as
 from blood, urine, saliva, tissue biopsy or autopsy material. The genomic
 DNA may be used directly for detection or may be amplified enzymatically
 by using PCR or other amplification techniques prior to analysis. RNA or
 cDNA may also be used in similar fashion. Deletions and insertions can be
 detected by a change in size of the amplified product in comparison to the
 normal genotype. Point mutations can be identified by hybridizing
 amplified DNA to labeled p101 nucleotide sequences. Perfectly matched
 sequences can be distinguished from mismatched duplexes by RNase digestion
 or by differences in melting temperatures. DNA sequence differences may
 also be detected by alterations in electrophoretic mobility of DNA
 fragments in gels, with or without denaturing agents, or by direct DNA
 sequencing (ee, e.g., Myers et al., Science (1985) 230:1242). Sequence
 changes at specific locations may also be revealed by nuclease protection
 assays, such as RNase and S1 protection or the chemical cleavage method
 (see Cotton et al., Proc Natl Acad Sci USA (1985) 85: 4397-4401). In
 another embodiment, an array of oligonucleotides probes comprising p101
 nucleotide sequence or fragments thereof can be constructed to conduct
 efficient screening of e.g., genetic mutations. Array technology methods
 are well known and have general applicability and can be used to address a
 variety of questions in molecular genetics including gene expression,
 genetic linkage, and genetic variability (see for example: M.Chee et al.,
 Science, Vol 274, pp 610-613 (1996)).
 The diagnostic assays offer a process for diagnosing or determining a
 susceptibility to the Diseases through detection of mutation in the p101
 gene by the methods described. In addition, such diseases may be diagnosed
 by methods comprising determining from a sample derived from a subject an
 abnormally decreased or increased level of polypeptide or mRNA. Decreased
 or increased expression can be measured at the RNA level using any of the
 methods well known in the art for the quantitation of polynucleotides,
 such as, for example, nucleic acid amplification, for instance PCR,
 RT-PCR, RNase protection, Northern blotting and other hybridization
 methods. Assay techniques that can be used to determine levels of a
 protein, such as a polypeptide of the present invention, in a sample
 derived from a host are well-known to those of skill in the art. Such
 assay methods include radioimmunoassays, competitive-binding assays,
 Western Blot analysis and ELISA assays.
 Thus in another aspect, the present invention relates to a diagonostic kit
 which comprises:
 (a) a polynucleotide of the present invention, preferably the nucleotide
 sequence SEQ ID NO: 1, 3, 7 and 9 respectively, or a fragment thereof;
 (b) a nucleotide sequence complementary to that of (a);
 (c) a polypeptide of the present invention, preferably the polypeptide of
 SEQ ID NO:2, 4, 8 and 10 respectively or a fragment thereof; or
 (d) an antibody to a polypeptide of the present invention, preferably to
 the polypeptide of SEQ ID NO:2, 4, 8 and 10 respectively.
 It will be appreciated that in any such kit, (a), (b), (c) or (d) may
 comprise a substantial component. Such a kit will be of use in diagnosing
 a disease or suspectability to a disease, particularly diseases that
 involve leucocyte activation and infiltration including inflammatory
 diseases such as COPD, ARDS, arthritis, psoriasis and so on, amongst
 others.
 The nucleotide sequences of the present invention are also valuable for
 chromosomal localisation. The sequence is specifically targeted to, and
 can hybridize with, a particular location on an individual human
 chromosome. The mapping of relevant sequences to chromosomes according to
 the present invention is an important first step in correlating those
 sequences with gene associated disease. Once a sequence has been mapped to
 a precise chromosomal location, the physical position of the sequence on
 the chromosome can be correlated with genetic map data. Such data are
 found in, for example, V. McKusick, Mendelian Inheritance in Man
 (available on-line through Johns Hopkins University Welch Medical
 Library). The relationship between genes and diseases that have been
 mapped to the same chromosomal region are then identified through linkage
 analysis (coinheritance of physically adjacent genes).
 The differences in the cDNA or genomic sequence between affected and
 unaffected individuals can also be determined. If a mutation is observed
 in some or all of the affected individuals but not in any normal
 individuals, then the mutation is likely to be the causative agent of the
 disease.
 The gene of the present invention maps to human chromosome 17p12-13.1.
 The nucleotide sequences of the present invention are also valuable for
 tissue localization. Such techniques allow the determination of expression
 patterns of the human p101 polypeptides in tissues by detection of the
 mRNAs that encode them. These techniques include in situ hybridziation
 techniques and nucleotide amplification techniques, for example PCR. Such
 techniques are well known in the art. Results from these studies provide
 an indication of the normal functions of the polypeptides in the organism.
 In addition, comparative studies of the normal expression pattern of human
 p101 mRNAs with that of mRNAs encoded by a human p101 gene provide
 valuable insights into the role of mutant human p101 polypeptides, or that
 of inappropriate expression of normal human p101 polypeptides, in disease.
 Such inappropriate expression may be of a temporal, spatial or simply
 quantitative nature.
 The polypeptides of the invention or their fragments or analogs thereof, or
 cells expressing them, can also be used as immunogens to produce
 antibodies immunospecific for polypeptides of the present invention. The
 term "immunospecific" means that the antibodies have substantially greater
 affinity for the polypeptides of the invention than their affinity for
 other related polypeptides in the prior art.
 Antibodies generated against polypeptides of the present invention may be
 obtained by administering the polypeptides or epitope-bearing fragments,
 analogs or cells to an animal, preferably a non-human animal, using
 routine protocols. For preparation of monoclonal antibodies, any technique
 which provides antibodies produced by continuous cell line cultures can be
 used. Examples include the hybridoma technique (Kohler, G. and Milstein,
 C., Nature (1975) 256:495-497), the trioma technique, the human B-cell
 hybridoma technique (Kozbor et al., Immunology Today (1983) 4:72) and the
 EBV-hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer
 Therapy, 77-96, Alan R. Liss, Inc., 1985).
 Techniques for the production of single chain antibodies, such as those
 described in U.S. Pat. No. 4,946,778, can also be adapted to produce
 single chain antibodies to polypeptides of this invention. Also,
 transgenic mice, or other organisms, including other mammals, may be used
 to express humanized antibodies.
 The above-described antibodies may be employed to isolate or to identify
 clones expressing the polypeptide or to purify the polypeptides by
 affinity chromatography.
 Antibodies against polypeptides of the present invention may also be
 employed to treat the Diseases, amongst others.
 In a further aspect, the present invention relates to genetically
 engineered soluble fusion proteins comprising a polypeptide of the present
 invention, or a fragment thereof, and various portions of the constant
 regions of heavy or light chains of immunoglobulins of various subclasses
 (IgG, IgM, IgA, IgE). Preferred as an immunoglobulin is the constant part
 of the heavy chain of human IgG, particularly IgG1, where fusion takes
 place at the hinge region. In a particular embodiment, the Fc part can be
 removed simply by incorporation of a cleavage sequence which can be
 cleaved with blood clotting factor x.sub.a. Furthermore, this invention
 relates to processes for the preparation of these fusion proteins by
 genetic engineering, and to the use thereof for drug screening, diagnosis
 and therapy. A further aspect of the invention also relates to
 polynucleotides encoding such fusion proteins. Examples of fusion protein
 technology can be found in International Patent Application Nos.
 WO94/29458 and WO94/22914.
 Another aspect of the invention relates to a method for inducing an
 immunological response in a mammal which comprises inoculating the mammal
 with a polypeptide of the present invention, adequate to produce antibody
 and/or T cell immune response to protect said animal from the Diseases
 hereinbefore mentioned, amongst others. Yet another aspect of the
 invention relates to a method of inducing immunological response in a
 mammal which comprises delivering a polypeptide of the present invention
 via a vector directing expression of the polynucleotide and coding for the
 polypeptide in vivo in order to induce such an immunological response to
 produce antibody to protect said animal from diseases.
 A further aspect of the invention relates to an immunological/vaccine
 formulation (composition) which, when introduced into a mammalian host,
 induces an immunological response in that mammal to a polypeptide of the
 present invention wherein the composition comprises a polypeptide or
 polynucleotide of the present invention. The vaccine formulation may
 further comprise a suitable carrier. Since a polypeptide may be broken
 down in the stomach, it is preferably administered parenterally (for
 instance, subcutaneous, intramuscular, intravenous, or intradermal
 injection). Formulations suitable for parenteral administration include
 aqueous and non-aqueous sterile injection solutions which may contain
 anti-oxidants, buffers, bacteriostats and solutes which render the
 formulation instonic with the blood of the recipient; and aqueous and
 non-aqueous sterile suspensions which may include suspending agents or
 thickening agents. The formulations may be presented in unit-dose or
 multi-dose containers, for example, sealed ampoules and vials and may be
 stored in a freeze-dried condition requiring only the addition of the
 sterile liquid carrier immediately prior to use. The vaccine formulation
 may also include adjuvant systems for enhancing the immunogenicity of the
 formulation, such as oil-in water systems and other systems known in the
 art. The dosage will depend on the specific activity of the vaccine and
 can be readily determined by routine experimentation.
 Polypeptides of the present invention are responsible for one or more
 biological functions, including one or more disease states, in particular
 the Diseases hereinbefore mentioned. It is therefore desirous to devise
 screening methods to identify compounds which stimulate or which inhibit
 the function of the polypeptide. Accordingly, in a further aspect, the
 present invention provides for a method of screening compounds to identify
 those which stimulate or which inhibit the function of the polypeptide. In
 general, agonists or antagonists may be employed for therapeutic and
 prophylactic purposes for such Diseases as hereinbefore mentioned.
 Compounds may be identified from a variety of sources, for example, cells,
 cell-free preparations, chemical libraries, and natural product mixtures.
 Such agonists, antagonists or inhibitors so-identified may be natural or
 modified substrates, ligands, receptors, enzymes, etc., as the case may
 be, of the polypeptide; or may be structural or functional mimetics
 thereof (see Coligan et al., Current Protocols in Immunology 1(2):Chapter
 5 (1991)).
 The screening method may simply measure the binding of a candidate compound
 to the polypeptide, or to cells or membranes bearing the polypeptide, or a
 fusion protein thereof by means of a label directly or indirectly
 associated with the candidate compound. Alternatively, the screening
 method may involve competition with a labeled competitor. Further, these
 screening methods may test whether the candidate compound results in a
 signal generated by activation or inhibition of the polypeptide, using
 detection systems appropriate to the cells bearing the polypeptide.
 Inhibitors of activation are generally assayed in the presence of a known
 agonist and the effect on activation by the agonist by the presence of the
 candidate compound is observed. Constitutively active polypeptides may be
 employed in screening methods for inverse agonists or inhibitors, in the
 absence of an agonist or inhibitor, by testing whether the candidate
 compound results in inhibition of activation of the polypeptide. Further,
 the screening methods may simply comprise the steps of mixing a candidate
 compound with a solution containing a polypeptide of the present
 invention, to form a mixture, measuring p101 activity in the mixture, and
 comparing the p101 activity of the mixture to a standard. Fusion proteins,
 such as those made from Fc portion and p101 polypeptide, as hereinbefore
 described, can also be used for high-throughput screening assays to
 identify antagonists for the polypeptide of the present invention (see D.
 Bennett et al., J Mol Recognition, 8:52-58 (1995); and K. Johanson et al.,
 J Biol Chem, 270(16):9459-9471 (1995)).
 The polynucleotides, polypeptides and antibodies to the polypeptide of the
 present invention may also be used to configure screening methods for
 detecting the effect of added compounds on the production of mRNA and
 polypeptide in cells. For example, an ELISA assay may be constructed for
 measuring secreted or cell associated levels of polypeptide using
 monoclonal and polyclonal antibodies by standard methods known in the art.
 This can be used to discover agents which may inhibit or enhance the
 production of polypeptide (also called antagonist or agonist,
 respectively) from suitably manipulated cells or tissues.
 The polypeptide may be used to identify membrane bound or soluble
 receptors, if any, through standard receptor binding techniques known in
 the art. These include, but are not limited to, ligand binding and
 crosslinking assays in which the polypeptide is labeled with a radioactive
 isotope (for instance, .sup.125 I), chemically modified (for instance,
 biotinylated), or fused to a peptide sequence suitable for detection or
 purification, and incubated with a source of the putative receptor (cells,
 cell membranes, cell supernatants, tissue extracts, bodily fluids). Other
 methods include biophysical techniques such as surface plasmon resonance
 and spectroscopy. These screening methods may also be used to identify
 agonists and antagonists of the polypeptide which compete with the binding
 of the polypeptide to its receptors, if any. Standard methods for
 conducting such assays are well understood in the art.
 Examples of potential polypeptide antagonists include antibodies or, in
 some cases, oligonucleotides or proteins which are closely related to the
 ligands, substrates, receptors, enzymes, etc., as the case may be, of the
 polypeptide, e.g., a fragment of the ligands, substrates, receptors,
 enzymes, etc.; or small molecules which bind to the polypeptide of the
 present invention but do not elicit a response, so that the activity of
 the polypeptide is prevented.
 Thus, in another aspect, the present invention relates to a screening kit
 for identifying agonists, antagonists, ligands, receptors, substrates,
 enzymes, etc. for polypeptides of the present invention; or compounds
 which decrease or enhance the production of such polypeptides, which
 comprises:
 (a) a polypeptide of the present invention;
 (b) a recombinant cell expressing a polypeptide of the present invention;
 (c) a cell membrane expressing a polypeptide of the present invention; or
 (d) antibody to a polypeptide of the present invention;
 which polypeptide is preferably that of SEQ ID NO:2,4, 8 and 10.
 It will be appreciated that in any such kit, (a), (b), (c) or (d) may
 comprise a substantial component.
 It will be readily appreciated by the skilled artisan that a polypeptide of
 the present invention may also be used in a method for the structure-based
 design of an agonist, antagonist or inhibitor of the polypeptide, by:
 (a) determining in the first instance the three-dimensional structure of
 the polypeptide;
 (b) deducing the three-dimensional structure for the likely reactive or
 binding site(s) of an agonist, antagonist or inhibitor;
 (c) synthesing candidate compounds that are predicted to bind to or react
 with the deduced binding or reactive site; and
 (d) testing whether the candidate compounds are indeed agonists,
 antagonists or inhibitors.
 It will be further appreciated that this will normally be an iterative
 process.
 In a further aspect, the present invention provides methods of treating
 abnormal conditions such as, for instance, diseases that involve leucocyte
 activation and infiltration including inflammatory diseases such as COPD,
 ARDS, arthritis, psoriasis and so on, related to either an excess of, or
 an under-expression of, p101 polypeptide activity.
 If the activity of the polypeptide is in excess, several approaches are
 available. One approach comprises administering to a subject in need
 thereof an inhibitor compound (antagonist) as hereinabove described,
 optionally in combination with a pharmaceutically acceptable carrier, in
 an amount effective to inhibit the function of the polypeptide, such as,
 for example, by blocking the binding of ligands, substrates, receptors,
 enzymes, etc., or by inhibiting a second signal, and thereby alleviating
 the abnormal condition. In another approach, soluble forms of the
 polypeptides still capable of binding the ligand, substrate, enzymes,
 receptors, etc. in competition with endogenous polypeptide may be
 administered. Typical examples of such competitors include fragments of
 the p101 polypeptide.
 In still another approach, expression of the gene encoding endogenous p101
 polypeptide can be inhibited using expression blocking techniques. Known
 such techniques involve the use of antisense sequences, either internally
 generated or externally administered (see, for example, O'Connor, J
 Neurochem (1991) 56:560 in Oligodeoxynucleotides as Antisense Inhibitors
 of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Alternatively,
 oligonucleotides which form triple helices ("triplexes") with the gene can
 be supplied (see, for example, Lee et al., Nucleic Acids Res (1979)
 6:3073; Cooney et al., Science (1988) 241:456; Dervan et al., Science
 (1991) 251:1360). These oligomers can be administeredper se or the
 relevant oligomers can be expressed in vivo. Synthetic antisense or
 triplex oligonucleotides may comprise modified bases or modified
 backbones. Examples of the latter include methylphosphonate,
 phosphorothioate or peptide nucleic acid backbones. Such backbones are
 incorporated in the antisense or triplex oligonucleotide in order to
 provide protection from degradation by nucleases and are well known in the
 art. Antisense and triplex molecules synthesized with these or other
 modified backbones also form part of the present invention.
 In addition, expression of the human p101 polypeptide may be prevented by
 using ribozymes specific to the human p101 mRNA sequence. Ribozymes are
 catalytically active RNAs that can be natural or synthetic (see for
 example Usman, N, et al., Curr. Opin. Struct. Biol (1996) 6(4), 527-33.)
 Synthetic ribozymes can be designed to specifically cleave human p101
 mRNAs at selected positions thereby preventing translation of the human
 p101 mRNAs into a functional polypeptide. Ribozymes may be synthesised
 with a natural ribose phosphate backbone and natural bases, as normally
 found in RNA molecules. Alternatively the ribozymes may be synthesized
 with non-natural backbones to provide protection from ribonuclease
 degradation, for example, 2'-O-methyl RNA, and may contain modified bases.
 For treating abnormal conditions related to an under-expression of p101 and
 its activity, several approaches are also available. One approach
 comprises administering to a subject a therapeutically effective amount of
 a compound which activates a polypeptide of the present invention, i.e.,
 an agonist as described above, in combination with a pharmaceutically
 acceptable carrier, to thereby alleviate the abnormal condition.
 Alternatively, gene therapy may be employed to effect the endogenous
 production of p101 by the relevant cells in the subject. For example, a
 polynucleotide of the invention may be engineered for expression in a
 replication defective retroviral vector, as discussed above. The
 retroviral expression construct may then be isolated and introduced into a
 packaging cell transduced with a retroviral plasmid vector containing RNA
 encoding a polypeptide of the present invention such that the packaging
 cell now produces infectious viral particles containing the gene of
 interest. These producer cells may be administered to a subject for
 engineering cells in vivo and expression of the polypeptide in vivo. For
 an overview of gene therapy, see Chapter 20, Gene Therapy and other
 Molecular Genetic-based Therapeutic Approaches, (and references cited
 therein) in Human Molecular Genetics, T Strachan and A P Read, BIOS
 Scientific Publishers Ltd (1996). Another approach is to administer a
 therapeutic amount of a polypeptide of the present invention in
 combination with a suitable pharmaceutical carrier.
 In a further aspect, the present invention provides for pharmaceutical
 compositions comprising a therapeutically effective amount of a
 polypeptide, such as the soluble form of a polypeptide of the present
 invention, agonist/antagonist peptide or small molecule compound, in
 combination with a pharmaceutically acceptable carrier or excipient. Such
 carriers include, but are not limited to, saline, buffered saline,
 dextrose, water, glycerol, ethanol, and combinations thereof. The
 invention further relates to pharmaceutical packs and kits comprising one
 or more containers filled with one or more of the ingredients of the
 aforementioned compositions of the invention. Polypeptides and other
 compounds of the present invention may be employed alone or in conjunction
 with other compounds, such as therapeutic compounds.
 The composition will be adapted to the route of administration, for
 instance by a systemic or an oral route. Preferred forms of systemic
 administration include injection, typically by intravenous injection.
 Other injection routes, such as subcutaneous, intramuscular, or
 intraperitoneal, can be used. Alternative means for systemic
 administration include transmucosal and transdermal administration using
 penetrants such as bile salts or fusidic acids or other detergents. In
 addition, if a polypeptide or other compounds of the present invention can
 be formulated in an enteric or an encapsulated formulation, oral
 administration may also be possible. Administration of these compounds may
 also be topical and/or localized, in the form of salves, pastes, gels, and
 the like.
 The dosage range required depends on the choice of peptide or other
 compounds of the present invention, the route of administration, the
 nature of the formulation, the nature of the subject's condition, and the
 judgment of the attending practitioner. Suitable dosages, however, are in
 the range of 0.1-100 .mu.g/kg of subject. Wide variations in the needed
 dosage, however, are to be expected in view of the variety of compounds
 available and the differing efficiencies of various routes of
 administration. For example, oral administration would be expected to
 require higher dosages than administration by intravenous injection.
 Variations in these dosage levels can be adjusted using standard empirical
 routines for optimization, as is well understood in the art.
 Polypeptides used in treatment can also be generated endogenously in the
 subject, in treatment modalities often referred to as "gene therapy" as
 described above. Thus, for example, cells from a subject may be engineered
 with a polynucleotide, such as a DNA or RNA, to encode a polypeptide ex
 vivo, and for example, by the use of a retroviral plasmid vector. The
 cells are then introduced into the subject.
 Polynucleotide and polypeptide sequences form a valuable information
 resource with which to identify further sequences of similar homology.
 This is most easily facilitated by storing the sequence in a computer
 readable medium and then using the stored data to search a sequence
 database using well known searching tools, such as those in the GCG or
 Lasergene software packages. Accordingly, in a further aspect, the present
 invention provides for a computer readable medium having stored thereon a
 polynucleotide comprising the sequence of SEQ ID NO: 1 and/or a
 polypeptide sequence encoded thereby.
 The following definitions are provided to facilitate understanding of
 certain terms used frequently hereinbefore.
 "Antibodies" as used herein includes polyclonal and monoclonal antibodies,
 chimeric, single chain, and humanized antibodies, as well as Fab
 fragments, including the products of an Fab or other immunoglobulin
 expression library.
 "Isolated" means altered "by the hand of man" from the natural state. If an
 "isolated" composition or substance occurs in nature, it has been changed
 or removed from its original environment, or both. For example, a
 polynucleotide or a polypeptide naturally present in a living animal is
 not "isolated," but the same polynucleotide or polypeptide separated from
 the coexisting materials of its natural state is "isolated", as the term
 is employed herein.
 "Polynucleotide" generally refers to any polyribonucleotide or
 polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA
 or DNA. "Polynucleotides" include, without limitation, single- and
 double-stranded DNA, DNA that is a mixture of single- and double-stranded
 regions, single- and double-stranded RNA, and RNA that is mixture of
 single- and double-stranded regions, hybrid molecules comprising DNA and
 RNA that may be single-stranded or, more typically, double-stranded or a
 mixture of single- and double-stranded regions. In addition,
 "polynucleotide" refers to triple-stranded regions comprising RNA or DNA
 or both RNA and DNA. The term "polynucleotide" also includes DNAs or RNAs
 containing one or more modified bases and DNAs or RNAs with backbones
 modified for stability or for other reasons. "Modified" bases include, for
 example, tritylated bases and unusual bases such as inosine. A variety of
 modifications may be made to DNA and RNA; thus, "polynucleotide" embraces
 chemically, enzymatically or metabolically modified forms of
 polynucleotides as typically found in nature, as well as the chemical
 forms of DNA and RNA characteristic of viruses and cells. "Polynucleotide"
 also embraces relatively short polynucleotides, often referred to as
 oligonucleotides.
 "Polypeptide" refers to any peptide or protein comprising two or more amino
 acids joined to each other by peptide bonds or modified peptide bonds,
 i.e., peptide isosteres. "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. "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. Modifications may occur anywhere in a polypeptide,
 including the peptide backbone, the amino acid side-chains and 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. Polypeptides may be branched as a result of
 ubiquitination, and they may be cyclic, with or without branching. Cyclic,
 branched and branched cyclic polypeptides may result from post-translation
 natural processes or may be made by synthetic methods. Modifications
 include acetylation, acylation, ADP-ribosylation, amidation,
 biotinylation, covalent attachment of flavin, covalent attachment of a
 heme moiety, covalent attachment of a nucleotide or nucleotide derivative,
 covalent attachment of a lipid or lipid derivative, covalent attachment of
 phosphotidylinositol, cross-linking, cyclization, disulfide bond
 formation, demethylation, formation of covalent cross-links, formation of
 cystine, formation of pyroglutamate, formylation, gamma-carboxylation,
 glycosylation, GPI anchor formation, hydroxylation, iodination,
 methylation, myristoylation, oxidation, proteolytic processing,
 phosphorylation, prenylation, racemization, selenoylation, sulfation,
 transfer-RNA mediated addition of amino acids to proteins such as
 arginylation, and ubiquitination (see, for instance, Proteins--Structure
 and Molecular Properties, 2nd Ed., T. E. Creighton, W. H. Freeman and
 Company, New York, 1993; Wold, F., 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 NY
 Acad Sci (1992) 663:48-62).
 "Variant" refers to a polynucleotide or polypeptide that differs from a
 reference polynucleotide or polypeptide, but retains essential properties.
 A typical variant of a polynucleotide differs in nucleotide sequence from
 another, reference polynucleotide. Changes in the nucleotide sequence of
 the variant may or may not alter the amino acid sequence of a polypeptide
 encoded by the reference polynucleotide. Nucleotide changes may result in
 amino acid substitutions, additions, deletions, fusions and truncations in
 the polypeptide encoded by the reference sequence, as discussed below. A
 typical variant of a polypeptide differs in amino acid sequence from
 another, reference polypeptide. Generally, differences are limited so that
 the sequences of the reference polypeptide and the variant are closely
 similar overall and, in many regions, identical. A variant and reference
 polypeptide may differ in amino acid sequence by one or more
 substitutions, additions, deletions in any combination. A substituted or
 inserted amino acid residue may or may not be one encoded by the genetic
 code. A variant of a polynucleotide or polypeptide may be a naturally
 occurring such as an allelic variant, or it may be a variant that is not
 known to occur naturally. Non-naturally occurring variants of
 polynucleotides and polypeptides may be made by mutagenesis techniques or
 by direct synthesis.
 "Identity," as known in the art, is a relationship between two or more
 polypeptide sequences or two or more polynucleotide sequences, as
 determined by comparing the sequences. In the art, "identity" also means
 the degree of sequence relatedness between polypeptide or polynucleotide
 sequences, as the case may be, as determined by the match between strings
 of such sequences. "Identity" and "similarity" can be readily calculated
 by known methods, including but not limited to those described in
 (Computational Molecular Biology, Lesk, A. M., ed., Oxford University
 Press, New York, 1988; Biocomputing: Informatics and Genome Projects,
 Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of
 Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana
 Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von
 Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov,
 M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo,
 H., and Lipman, D., SIAM J. Applied Math., 48. 1073 (1988). Preferred
 methods to determine identity are designed to give the largest match
 between the sequences tested. Methods to determine identity and similarity
 are codified in publicly available computer programs. Preferred computer
 program methods to determine identity and similarity between two sequences
 include, but are not limited to, the GCG program package (Devereux, J., et
 al., Nucleic Acids Research 12(1). 387 (1984)), BLASTP, BLASTN, and FASTA
 (Atschul, S.F. et al., J. Molec. Biol. 215. 403-410 (1990). The BLAST X
 program is publicly available from NCBI and other sources (BLAST Manual,
 Altschul, S., et al., NCBI NLM NIH Bethesda, MD 20894; Altschul, S., et
 al., J. Mol. Biol. 215: 403-410 (1990). The well known Smith Waterman
 algorithm may also be used to determine identity.
 Preferred parameters for polypeptide sequence comparison include the
 following:
 1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48: 443-453 (1970)
 Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl.
 Acad. Sci. USA. 89:10915-10919 (1992)
 Gap Penalty: 12
 Gap Length Penalty: 4
 A program useful with these parameters is publicly available as the "gap"
 program from Genetics Computer Group, Madison Wis. The aforementioned
 parameters are the default parameters for peptide comparisons (along with
 no penalty for end gaps).
 Preferred parameters for polynucleotide comparison include the following:
 1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48: 443-453 (1970)
 Comparison matrix: matches=+10, mismatch=0
 Gap Penalty: 50
 Gap Length Penalty: 3
 Available as: The "gap" program from Genetics Computer Group, Madison Wis.
 These are the default parameters for nucleic acid comparisons.
 By way of example, a polynucleotide sequence of the present invention may
 be identical to the reference sequence of SEQ ID NO:1, that is be 100%
 identical, or it may include up to a certain integer number of nucleotide
 alterations as compared to the reference sequence. Such alterations are
 selected from the group consisting of at least one nucleotide deletion,
 substitution, including transition and transversion, or insertion, and
 wherein said alterations may occur at the 5' or 3' terminal positions of
 the reference nucleotide sequence or anywhere between those terminal
 positions, interspersed either individually among the nucleotides in the
 reference sequence or in one or more contiguous groups within the
 reference sequence. The number of nucleotide alterations is determined by
 multiplying the total number of nucleotides in SEQ ID NO: 1 by the
 numerical percent of the respective percent identity(divided by 100) and
 subtracting that product from said total number of nucleotides in SEQ ID
 NO: 1, or:
EQU n.sub.n.ltoreq.x.sub.n -(x.sub.n.multidot.y)
 wherein n.sub.n is the number of nucleotide alterations, x.sub.n is the
 total number of nucleotides in SEQ ID NO: 1, and y is, for instance, 0.70
 for 70%, 0.80 for 80%, 0.85 for 85%, 0.90 for 90%, 0.95 for 95%,etc., and
 wherein any non-integer product of x.sub.n and y is rounded down to the
 nearest integer prior to subtracting it from x.sub.n. Alterations of a
 polynucleotide sequence encoding the polypeptide of SEQ ID NO:2 may create
 nonsense, missense or frameshift mutations in this coding sequence and
 thereby alter the polypeptide encoded by the polynucleotide following such
 alterations.
 Similarly, a polypeptide sequence of the present invention may be identical
 to the reference sequence of SEQ ID NO:2, that is be 100% identical, or it
 may include up to a certain integer number of amino acid alterations as
 compared to the reference sequence such that the % identity is less than
 100%. Such alterations are selected from the group consisting of at least
 one amino acid deletion, substitution, including conservative and
 non-conservative substitution, or insertion, and wherein said alterations
 may occur at the amino- or carboxy-terminal positions of the reference
 polypeptide sequence or anywhere between those terminal positions,
 interspersed either individually among the amino acids in the reference
 sequence or in one or more contiguous groups within the reference
 sequence. The number of amino acid alterations for a given % identity is
 determined by multiplying the total number of amino acids in SEQ ID NO:2
 by the numerical percent of the respective percent identity(divided by
 100) and then subtracting that product from said total number of amino
 acids in SEQ ID NO:2, or:
EQU n.sub.a.ltoreq.x.sub.a -(x.sub.a.multidot.y)
 wherein n.sub.a is the number of amino acid alterations, x.sub.a is the
 total number of amino acids in SEQ ID NO:2, and y is, for instance 0.70
 for 70%, 0.80 for 80%, 0.85 for 85% etc., and wherein any non-integer
 product of x.sub.a and y is rounded down to the nearest integer prior to
 subtracting it from x.sub.a.
 "Homolog" is a generic term used in the art to indicate a polynucleotide or
 polypeptide sequence possessing a high degree of sequence relatedness to a
 subject sequence. Such relatedness may be quantified by determining the
 degree of identity and/or similarity between the sequences being compared
 as hereinbefore described. Falling within this generic term are the terms
 "ortholog", meaning a polynucleotide or polypeptide that is the functional
 equivalent of a polynucleotide or polypeptide in another species, and
 "paralog" meaning a functionally similar sequence when considered within
 the same species.
 "Fusion protein" refers to a protein encoded by two, often unrelated, fused
 genes or fragments thereof. In one example, EP-A-0 464 discloses fusion
 proteins comprising various portions of constant region of immunoglobulin
 molecules together with another human protein or part thereof. In many
 cases, employing an immunoglobulin Fc region as a part of a fusion protein
 is advantageous for use in therapy and diagnosis resulting in, for
 example, improved pharmacokinetic properties [see, e.g., EP-A 0232 262].
 On the other hand, for some uses it would be desirable to be able to
 delete the Fc part after the fusion protein has been expressed, detected
 and purified.
 All publications, including but not limited to patents and patent
 applications, cited in this specification are herein incorporated by
 reference as if each individual publication were specifically and
 individually indicated to be incorporated by reference herein as though
 fully set forth.
 Sequence Information
 (SVP-2,lacks exons 6,7,8,9 and 10)
 SEQ ID NO:1
 CCCTTTCCACCTCTCTGCTCCCATTCCTGACCCCTTACTTCCCACACCTCTGTCCCGTTCTGCTGCAGGGGT
 GCTCTGTCCTGCCACTCAGATGTGGCCCTCCACATGCCATTCCTACCCTGGAGGCAGCTGTAAGGCCCCTGG
 TCCTGTTTCCACAGCACCTGAGCTATAGCTGGGCTGGGCTGATCGCGCTGCACTGTGAGCACCTGTTGTCTT
 TACTGGACCAGGTGCTCTCTGGGAAAGGAGCTCGACAAGCTGACCGGCGTCTGTCCCCCATGCAGGCGATGA
 CCCAGGATGCAGCCAGGGGCCACGACATGCACGGAGGACCGCATCCAGCATGCCCTGGAACGCTGCCTGCAT
 GGACTCAGCCTCAGCCGCCGCTCCACCTCCTGGTCAGCTGGGCTGTGTCTGAACTGCTGGAGCCTGCAGGAG
 CTGGTCAGCAGGGACCCGGGCCACTTCCTTATCCTCCTTGAGCAGATCCTGCAGAAGACCCGAGAGGTCCAG
 GAGAAGGGCACCTACGACCTGCTCACCCCGCTGGCCCTGCTCTTCTATTCCACTGTTCTTTGTACACCACAC
 TTCCCACCAGACTCGGATCTCCTTCTGAAGGCAGCCAGCACCTACCACCGGTTCCTGACCTGGCCTGTTCCT
 TACTGCAGCATCTGCCAGGAGCTGCTCACCTTCATTGATGCTGAACTCAAGGCCCCAGGGATCTCCTACCAG
 AGACTGGTGAGGGCTGAGCAGGGCCTGCCCATCAGGAGTCACCGCAGCTCCACCGAGCTGGGCACCACCCCA
 TGGGAGGAGAGCACCAATGGCATCTCCCACTACCTCGGCATGCTGGACCCCTGGTATGAGCGCAATGTACTG
 GGCCTCATGCACCTGCCCCCTGAAGTCCTGTGCCAGCAGTCCCTGAAGGCTGAAGCCCAGGCCCTGGAGGGC
 TCCCCAACCCAGCTGCCCATCCTGGCTGACATGCTACTCTACTACTGCCGCTTTGCCGCCAGACCGGTGCTG
 CTGCAAGTCTATCAGACCGAGCTGACCTTCATCACTGGGGAGAAGACGACAGAGATCTTCATCCACTCCTTG
 GAGCTGGGTCACTCCGCTGCCACACGTGCCATCAAGGCGTCAGGTCCTGGCAGCAAGCGGCTGGGCATCGAT
 GGCGACCGGGAGGCTGTTCCTCTAACACTACAGATTATTTACAGCCAGGGGGCCATCAGTGGACGAAGTCGC
 TGGAGCAACCTGGAGAAGGTCTGTACCTCCGTGAACCTCAACAAGGCCTGCCGGAAGCAGGAGGAGCTGGAT
 TCCAGCATGGAGGCCCTGACGCTAAACCTGACAGAAGTGGTGAAAAGGCAGAACTCCAAATCCAAGAAGGGC
 TTTAACCAGATTAGCACATCGCAGATCAAAGTGGACAAGGTGCAGATCATCGGCTCCAACAGCTGCCCCTTT
 GCTGTGTGCCTCCACCAGGATGAGAGAAAGATCCTGCAGAGTGTAGTCAGATGTGAGGTCTCACCGTGCTAC
 AAGCCAGAGAAGAGCGACCTCTCCTCACCACCCCAGACGCCTCCTGACCTGCCGGCCCAGGCCGCACCTGAT
 CTCTGCTCCCTCCTCTGCCTGCCCATCATGACTTTCAGTGGAGCTCTGCCCTAGTGTGGGCCCAGCGCCACA
 CTGGACAGAAGCCCTGGGGTCATTTCTCCAGCACTAAAATGGAGTGGAGAGTTGGGGTGGAAATAAGACATC
 CTTAAAAGGTTAAATTGTCTGCAAAGCACCTAGCCCAGTGCCGAGCTCCCAGTAGGTGTTCAGTAAAGCTTA
 GTGCCTGACTTTCTGAACACTGATTCCTCCTGTTTGGAGTCACTGGGATACTCTCATTGCCGTTGGGATGTT
 CCTCACTCCTTCCCAGTTCGTGGCTGAGGCAGAACCCAGACTGAAGAGGGAAGAGACATTCCAGAGGAGGAT
 TGCCTTCGTCAGGGTAAGGGGTGGGCTGCTCAGGGGCCCTACCCTTCACCCCCTTCTGTATCAGATTGGCCC
 TCCCACTCCCATCTCACTCTGCGTGTACAATCTTCCATATCCGCAAGTTCACTGGCACTCTTCTGGCACCTG
 GGCAAGATCCCAGAACAGAGGATGGAGTGACTGGCCTCACAGAGCTTAGTGCCCGACACTGGTGCATGGGAA
 ATGGTCAGCCTAGGATAGGACACGAGAGTCTGAAATTCAAAGCAACCAGCTTGAAGTGGTTTGAGAAGCTGG
 AAGCAAACATGGGCTAGAGAGATAGGGCAGAAGTCAAGACGAGGATCTGGACTGATGTGGAGAAAGTAGCCA
 CGGAAGCATGAACTGTATCCTGCACAAAGTCCCTCTTCCCCGCCTCCTAATTCATTATGCCCAAAAGGCCTT
 ACGTGAAATTCCAGCCCACACTACTCATGACTTGAGAGACGTGGACAGAGCCAGCTTCTACCTTGCCTGGCC
 GTCTCTCCCCTGTCTTAATGTCTGCTCTTGCTCTAAGCTCCAGAAGAGTGGCGGGCCATGTATCTTCAATAT
 GTTTTTGCTGTATGGGCAGGTTGTCTTATTATGTGATCAACAGATGTCCAGGAACTAATGAGTGGAATTTAA
 TATTATTGTCAAATAAAACTTGATTTGTCCTAT
 (SVP-2 protein)
 SEQ ID NO:2
 MQOGATTCTEDRIQHALERCLHGLSLSRRSTSWSAGLCLNCWSLQELVSRDPGHFLILLEQILQKTREVQEK
 GTYDLLTPLALLFYSTVLCTPHFPPDSDLLLKAASTYHRFLTWPVPYCSICQELLTFIDAELKAPGISYQRL
 VRAEQGLPIRSHRSSTELGTTPWEESTNGISHYLGMLDPWYERNVLGLMHLPPEVLCQQSLKAEAQALEGSP
 TQLPILADMLLYYCRFAARPVLLQVYQTELTFITGEKTTEIFIHSLELGHSAATRAIKASGPGSKRLGIDGD
 REAVPLTLQIIYSQGAISGRSRWSNLEKVCTSVNLNKACRKQEELDSSMEALTLNLTEVVKRQNSKSKKGFN
 QISTSQIKVDKVQIIGSNSCPFAVCLDQDERKILQSVVRCEVSPCYKPEKSDLSSPPQTPPDLPAQAAPDLC
 SLLCLPIMTFSGALP
 (SVP-4, lacks exons 9 and 10)
 SEQ ID NO:3
 CCCTTTCCACCTCTCTGCTCCCATTCCTGACCCCTTACTTCCCACACCTCTGTCCCGTTCTGCTGCAGGGGT
 GCTCTGTCCTGCCACTCAGATGTGGCCCTCCACATGCCATTCCTACCCTGGAGGCAGCTGTAAGGCCCCTGG
 TCCTGTTTCCACAGCACCTGAGCTATAGCTGGGCTGGGCTGATCGCGCTGCACTGTGAGCACCTGTTGTCTT
 TACTGGACCAGGTGCTCTCTGGGAAAGGAGCTCGACAAGCTGACCGGCGTCTGTCCCCCATGCAGGCGATGA
 CCCAGGATGCAGCCAGGGGCCACGACATGCACGGAGGACCGCATCCAGCATGCCCTGGAACGCTGCCTGCAT
 GGACTCAGCCTCAGCCGCCGCTCCACCTCCTGGTCAGCTGGGCTGTGTCTGAACTGCTGGAGCCTGCAGGAG
 CTGGTCAGCAGGGACCCGGGCCACTTCCTTATCCTCCTTGAGCAGATCCTGCAGAAGACCCGAGAGGTCCAG
 GAGAAGGGCACCTACGACCTGCTCACCCCGCTGGCCCTGCTCTTCTATTCCACTGTTCTTTGTACACCACAC
 TTCCCACCAGACTCGGATCTCCTTCTGAAGGCAGCCAGCACCTACCACCGGTTCCTGACCTGGCCTGTTCCT
 TACTGCAGCATCTGCCAGGAGCTGCTCACCTTCATTGATGCTGAACTCAAGGCCCCAGGTATCTCCTACCAG
 AGACTGGTGAGGGCTGAGCAGGGCCTGCCCATCAGGAGTCACCGCAGCTCCACCGTCACCGTGCTGCTGCTG
 AACCCAGTGGAAGTGCAGGCCGAGTTCCTTGCTGTAGCCAATAAGCTGAGTACGCCCGGACACTCGCCTCAC
 AGTGCCTACACCACCCTGCTCCTGCACGCCTTCCAGGCCACCTTTGGGGCCCACTGTGACGTCCCGGGCCTG
 CACTGCAGGCTACAGGCCAAGACCCTGGCAGAGCTTGAGGACATCTTCACGGAGACCGCAGAGGCACAGGAG
 CTGGCATCTGGCATCGGGGATGCTGCAGAGGCCCGGCGGTGGCTCAGGACCAAGCTGCAGGCGGTGGGAGAA
 AAAGCTGGCTTCCCTGGGGTGTTAGACACTGCAAAACCAGGGAAGCTTCATACCATCCCCATCCCTGTCGCC
 AGGTGCTACACCTACAGCTGGAGCCAGGACAGCTTTGGAGCTGGGCACCACCCCATGGGAGGAGAGCACCAA
 TGGCATCTCCCACTACCTCGGCATGCTGGACCCCTGGTATGAGCGCAATGTACTGGGCCTCATGCACCTGCC
 CCCTGAAGTCCTGTGCCAGCAGTCCCTGAAGGCTGAAGCCCAGGCCCTGGAGGGCTCCCCAACCCAGCTGCC
 CATCCTGGCTGACATGCTACTCTACTACTGCCGCTTTGCCGCCAGACCGGTGCTGCTGCAAGTCTATCAGAC
 CGAGCTGACCTTCATCACTGGGGAGAAGACGACAGAGATCTTCATCCACTCCTTGGAGCTGGGTCACTCCGC
 TGCCACACGTGCCATCAAGGCGTCAGGTCCTGGCAGCAAGCGGCTGGGCATCGATGGCGACCGGGAGGCTGT
 TCCTCTAACACTACAGATTATTTACAGCCAGGGGGCCATCAGTGGACGAAGTCGCTGGAGCAACCTGGAGAA
 GGTCTGTACCTCCGTGAACCTCAACAAGGCCTGCCGGAAGCAGGAGGAGCTGGATTCCAGCATGGAGGCCCT
 GACGCTAAACCTGACAGAAGTGGTGAAAAGGCAGAACTCCAAATCCAAGAAGGGCTTTAACCAGATTAGCAC
 ATCGCAGATCAAAGTGGACAAGGTGCAGATCATCGGCTCCAACAGCTGCCCCTTTGCTGTGTGCCTGGACCA
 GGATGAGAGAAAGATCCTGCAGAGTGTAGTCAGATGTGAGGTCTCACCGTGCTACAAGCCAGAGAAGAGCGA
 CCTCTCCTCACCACCCCAGACGCCTCCTGACCTGCCGGCCCAGGCCGCACCTGATCTCTGCTCCCTCCTCTG
 CCTGCCCATCATGACTTTCAGTGGAGCTCTGCCCTAGTGTGGGCCCAGCGCCAGACTGGACAGAAGCCCTGG
 GGTCATTTCTCCAGCACTAAAATGGAGTGGAGAGTTGGGGTGGAAATAAGACATCCTTAAAAGGTTAAATTG
 TCTGCAAAGCACCTAGCCCAGTGCCGAGCTCCCAGTAGGTGTTCAGTAAAGCTTAGTGCCTGACTTTCTGAA
 CACTGATTCCTCCTGTTTGGAGTCACTGGGATACTCTCATTGCCGTTGGGATGTTCCTCACTCCTTCCCAGT
 TCGTGGCTGAGGCAGAACCCAGACTGAAGAGGGAAGAGACATTCCAGAGGAGGATTGCCTTCGTCAGGGTAA
 GGGGTGGGCTGCTCAGGGGCCCTACCCTTCACCCCCTTCTGTATCAGATTGGCCCTCCCACTCCCATCTCAC
 TCTGCGTGTACAATCTTCCATATCCGCAAGTTCACTGGCACTCTTCTGGCACCTGGGCAAGATCCCAGAACA
 GAGGATGGAGTGACTGGCCTCACAGAGCTTAGTGCCCGACACTGGTGCATGGGAAATGGTCAGCCTAGGATA
 GGACACGAGAGTCTGAAATTCAAAGCAACCAGCTTGAAGTGGTTTGAGAAGCTGGAAGCAAACATGGGCTAG
 AGAGATAGGGCAGAAGTCAAGACGAGGATGTGGACTGATGTGGAGAAAGTAGCCACGGAAGCATGAACTGTA
 TCCTGCACAAAGTCCCTCTTCCCCGCCTCCTAATTCATTATGCCCAAAAGGCCTTACGTGAAATTCCAGCCC
 AGAGTACTCATGACTTGAGAGACGTGGACAGAGCCAGCTTCTACCTTGCCTGGCCGTCTCTCCCCTGTCTTA
 ATGTCTGCTCTTGCTCTAAGCTCCAGAAGAGTGGCGGGCCATGTATCTTCAATATGTTTTTGCTGTATGGGC
 AGGTTGTCTTATTATGTGATCAACAGATGTCCAGGAACTAATGAGTGGAATTTAATATTATTGTCAAATAAA
 ACTTGATTTGTCCTAT
 (SVP-4 protein)
 SEQ ID NO:4
 MQPGATTCTEDRIQHALERCLHGLSLSRRSTSWSAGLCLNCWSLQELVSRDPGHFLILLEQILQKTREVQEK
 GTYDLLTPLALLFYSTVLCTPHFPPDSDLLLKAASTYHRFLTWPVPYCSISQWLLTFIDAELKAPGISYQRL
 VRAEQGLPIRSHRSSTVTVLLLNPVEVQAEFLAVANKLSTPGHSPHSAYTTLLLHAFQATFGAHCDVPGLHC
 RLQAKTLAELEDIFTETAEAQELASGIGDAAEARRWLRTKLQAVGEKAGFPGVLDTAKPGKLHTIPIPVARC
 YTYSWSQDSFGAGHHPMGGEHQWHLPLPRHAGPLV
 (Full-length human p101 DNA)
 SEQ ID NO:5
 ATGCAGCCAGGGGCCACGACATGCACGGAGGACCGCATCCAGCATGCCCTGGAACGCTGCCTGCATGGACTC
 AGCCTCAGCCGCCGCTCCACCTCCTGGTCAGCTGGGCTGTGTCTGAACTGCTGGAGCCTGCAGGAGCTGGTC
 AGCAGGGACCCGGGCCACTTCCTTATCCTCCTTGAGCAGATCCTGCAGAAGACCCGAGAGGTCCAGGAGAAG
 GGCACCTACGACCTGCTCACCCCGCTGGCCCTGCTCTTCTATTCCACTGTTCTTTGTACACCACACTTCCCA
 CCAGACTCGGATCTCCTTCTGAAGGCAGCCAGCACCTACCACCGGTTCCTGACCTGGCCTGTTCCTTACTGC
 AGCATCTGCCAGGAGCTGCTCACCTTCATTGATGCTGAACTCAAGGCCCCAGGGATCTCCTACCAGAGACTG
 GTGAGGGCTGAGCAGGGCCTGCCCATCAGGAGTCACCGCAGCTCCACCGTCACCGTGCTGCTGCTGAACCCA
 GTGGAAGTGCAGGCCGAGTTCCTTGCTGTAGCCAATAAGCTGAGTACGCCCGGACACTCGCCTCACAGTGCC
 TACACCACCCTGCTCCTGCACGCCTTCCAGGCCACCTTTGGGGCCCACTGTGACGTCCCGGGCCTGCACTGC
 AGGCTACAGGCCAAGACCCTGGCAGAGCTTGAGGACATCTTCACGGAGACCGCAGAGGCACAGGAGCTGGCA
 TCTGGCATCGGGGATGCTGCAGAGGCCCGGCGGTGGCTCAGGACCAAGCTGCAGGCGGTGGGAGAAAAAGCT
 GGCTTCCCTGGGGTGTTAGACACTGCAAAACCAGGGAAGCTTCATACCATCCCCATCCCTGTCGCCAGGTGC
 TACACCTACAGCTGGAGCCAGGACAGCTTTGACATCCTGCAGGAAATCCTGCTCAAGGAACAGGAGCTACTC
 CAGCCAGGGATCCTGGGAGATGATGAAGAGGAGGAAGAGGAGGAGGAGGAGGTGGAGGAGGACTTGGAAACT
 GACGGGCACTGTGCCGAGAGAGATTCCCTGCTCTCCACCAGCTCTTTGGCGTCCCATGACTCCACCTTGTCC
 CTTGCATCCTCCCAGGCCTCGGGGCCGGCCCTCTCGCGCCATCTGCTGACTTCCTTTGTCTCAGGCCTCTCT
 GATGGCATGGACAGCGGCTACGTGGAGGACAGCGAGGAGAGCTCCTCCGAGTGGCCTTGGAGGCGTGGCAGC
 CAGGAACGCCGAGGCCACCGCAGGCCTGGGCAGAAGTTCATCAGGATCTATAAACTCTTCAAGAGCACCAGC
 CAGCTGGTACTGCGGAGGGACTCTCGGAGCCTGGAGGGCAGCTCGGACACGGCCCTGCCCCTGAGGCGGGCA
 GGGAGCCTCTGCAGCCCCCTGGACGAACCAGTATCACCCCCTTCCCGGGCCCAGCGCTCCCGCTCCCTGCCC
 CAGCCCAAACTCGGTACCCAGCTGCCCAGCTGGCTTCTGGCCCCTGCTTCACGCCCCCAGCGCCGCCGCCCC
 TTCCTGAGTGGAGATGAGGATCCCAAGGCTTCCACGCTACGTGTTGTGGTCTTTGGCTCCGATCGGATTTCA
 GGGAAGGTGGCTCGGGCGTACAGCAACCTTCGGCGGCTGGAGAACAATCGCCCACTCCTCACACGGTTCTTC
 AAACTTCAGTTCTTCTACGTGCCTGTGAAGCGAAGTCGTGGGACCAGCCCTGGTGCCTGTCCACCCCCTCGG
 AGCCAGACGCCCTCACCCCCGACAGACTCCCCTAGGCACGCCAGCCCTGGAGAGCTGGGCACCACCCCATGG
 GAGGAGAGCACCAATGGCATCTCCCACTACCTCGGCATGCTGGACCCCTGGTATGAGCGCAATGTACTGGGC
 CTCATGCACCTGCCCCCTGAAGTCCTGTGCCAGCAGTCCCTGAAGGCTGAAGCCCAGGCCCTGGAGGGCTCC
 CCAACCCAGCTGCCCATCCTGGCTGACATGCTACTCTACTACTGCCGCTTTGCCGCCAGACCGGTGCTGCTG
 CAAGTCTATCAGACCGAGCTGACCTTCATCACTGGGGAGAAGACGACAGAGATCTTCATCCACTCCTTGGAG
 CTGGGTCACTCCGCTGCCACACGTGCCATCAAGGCGTCAGGTCCTGGCAGCAAGCGGCTGGGCATCGATGGC
 GACCGGGAGGCTGTTCCTCTAACACTACAGATTATTTACAGCCAGGGGGCCATCAGTGGACGAAGTCGCTGG
 AGCAACCTGGAGAAGGTCTGTACCTCCGTGAACCTCAACAAGGCCTGCCGGAAGCAGGAGGAGCTGGATTCC
 AGCATGGAGGCCCTGACGCTAAACCTGACAGAAGTGGTGAAAAGGCAGAACTCCAAATCCAAGAAGGGCTTT
 AACCAGATTAGCACATCGCAGATCAAAGTGGACAAGGTGCAGATCATCGGCTCCAACAGCTGCCCCTTTGCT
 GTGTGCCTGGACCAGGATGAGAGAAAGATCCTGCAGAGTGTAGTCAGATGTGAGGTCTCACCGTGCTACAAG
 CCAGAGAAGAGCGACCTCTCCTCACCACCCCAGACGCCTCCTGACCTGCCGGCCCAGGCCGCACCTGATCTC
 TGCTCCCTCCTCTGCCTGCCCATCATGACTTTCAGTGGAGCTCTGCCCTAGTGTGGGCCCAGCGCCACACTG
 GACAGAAGCCCTGGGGTCATTTCTCCAGCACTAAAATGGAGTGGAGAGTTGGGGTGGAAATAAGACATCCTT
 AAAAGGTTAAATTGTCTGCAAAGCACCTAGCCCAGTGCCGAGCTCCCAGTAGGTGTTCAGTAAAGCTTAGTG
 CCTGACTTTCTGAACACTGATTCCTCCTGTTTGGAGTCACTGGGATACTCTCATTGCCGTTGGGATGTTCCT
 CACTCCTTCCCAGTTCGTGGCTGAGGCAGAACCCAGACTGAAGAGGGAAGAGACATTCCAGAGGAGGATTGC
 CTTCGTCAGGGTAAGGGGTGGGCTGCTCAGGGGCCCTACCCTTCACCCCCTTCTGTATCAGATTGGCCCTCC
 CACTCCCATCTCACTCTGCGTGTACAATCTTCCATATCCGCAAGTTCACTGGCACTCTTCTGGCACCTGGGC
 AAGATCCCAGAACAGAGGATGGAGTGACTGGCCTCACAGAGCTTAGTGCCCGACACTGGTGCATGGGAAATG
 GTCAGCCTAGGATAGGACACGAGAGTCTGAAATTCAAAGCAACCAGCTTGAAGTGGTTTGAGAAGCTGGAAG
 CAAACATGGGCTAGAGAGATAGGGCAGAAGTCAAGACGAGGATCTGGACTGATGTGGAGAAAGTAGCCACGG
 AAGCATGAACTGTATCCTGCACAAAGTCCCTCTTCCCCGCCTCCTAATTCATTATGCCCAAAAGGCCTTACG
 TGAAATTCCAGCCCAGAGTACTCATGACTTGAGAGACGTGGACAGAGCCAGCTTCTACCTTGCCTGGCCGTC
 TCTCCCCTGTCTTAATGTCTGCTCTTGCTCTAAGCTCCAGAAGAGTGGCGGGCCATGTATCTTCAATATGTT
 TTTGCTGTATGGGCAGGTTGTCTTATTATGTGATCAACAGATGTCCAGGAACTAATGAGTGGAATTTAATAT
 TATTGTCAAATAAAACTTGATTTGTCCTAT
 (Full-length human p101 protein)
 SEQ ID NO:6
 MQPGATTCTEDRIQHALERCLHGLSLSRRSTSWSAGLCLNCWSLQELVSRDPGHFLILLEQILQKTREVQEK
 GTYDLLTPLALLFYSTVLCTPHFPPDSDLLLKAASTYHRFLTWPVPYCSICQELLTFIDAELKAPGISYQRL
 VRAEQGLPIRSHRSSTVTVLLLNPVEVQAEFLAVANKLSTPGHSPHSAYTTLLLHAFQATFGAHCDVPGLHC
 RLQAKTLAELEDIFTETAEAQELASGIGDAAEARRWLRTKLQAVGEKAGFPGVLDTAKPGKLHTIPIPVARC
 YTYSWSQDSFDILQEILLKEQELLQPGILGDDEEEEEEEEEVEEDLETDGHCAERDSLLSTSSLASHDSTLS
 LASSQASGSRHLLTSFVSGLSDGMDSGYVEDSEEDDDEWPWRRGSQERRGHRRPGQKFIRIYKLFKSTS
 QLVLRRDSRSLEGSSDTALPLRRAGSLCSPLDEPVSPPSRAQRSRSLPQPKLGTQLPSWLLAPASRPQRRRP
 FLSGDEDPKASTLRVVVFGSDRISGKVARAYSNLRRLENNRPLLTRFFKLQFFYVPVKRSRGTSPGACPPPR
 PTQLPILADMLLYYCRFAARPVLLQVYQTELTFEITGEKTTEFIHSLELGHSAATRAIKASGPGSKRLGIDG
 DREAVPLTLQIIYSQGAISGRSRWSNLEKVCTSVNLNKACRKQEELDSSMEALTLNLTEVVKRQNSKSKKGF
 NQISTSQIKVDKVQIIGSNSCPFAVCLDQDERKILQSVVRCEVSPCYKPEKSDLSSPPQTPPDLPAQAAPDL
 CSLLCLPIMTFSGALP