Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Reexamination Certificate
1999-07-09
2001-07-24
Achutamurthy, Ponnathapu (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
C530S300000, C530S350000
Reexamination Certificate
active
06265199
ABSTRACT:
BACKGROUND OF THE INVENTION
Disintegrins have been shown to bind cell surface molecules, including integrins, on the surface of various cells, such as platelets, fibroblasts, tumor, endothelial, muscle, neuronal, bone, and sperm cells. Disintegrins are unique and potentially useful tools for investigating cell-matrix and cell-cell interactions. Additionally, they have been useful in the development of antithrombotic and antimetastatic agents due to their anti-adhesive, anti-migration of certain tumor cells, and antiangiogenesis activities.
Families of proteins which have disintegrin domains include ADAMs (A Metalloprotease and Disintegrin), MDCs (Metalloprotease/Disintegrin/Cysteine-rich) and SVMPs (Snake Venom Metalloprotease).
For a review of ADAMs, see Wolfsberg and White,
Developmental Biology,
180:389-401, 1996. ADAMs have been shown to exist as independent functional units or in conjunction with other members of this family in heterodimeric complexes. Some members of the family exist in multiple isoforms which may have resulted from alternative splicing. ADAMs proteins have been shown to have adhesive as well as anti-adhesive functions. Some members of the ADAMs family have very specific tissue distribution while others are widely distributed. Not all members of this family are capable of manifesting all of the potential functions represented by the domains common to their genetic structure.
The ADAMs are characterized by having a propeptide domain, a metalloprotease-like domain, a disintegrin-like domain, a cysteine-rich domain, an EGF-like domain, and a cytoplasmic domain.
A prototypical example of this family is ADAM 12. ADAM 12, also known as meltrin &agr;, has a truncated isoform, as well as a full-length isoform, and is involved in muscle cell fusion and differentiation (Gilpin et al.,
J. Biol. Chem.
273:157-166, 1998).
Another prototypical example of this family is ADAM 1, which forms a heterodimer with ADAM 2 and is involved in sperm/egg fusion (Wolfsberg and White, supra).
The SVMP family is represented by three classes (P-I, P-II, and P-III). All three classes contain propeptide and metalloprotease domains. The P-II and P-III classes also contain a disintegrin domain, and the P-III class further contains a cysteine-rich domain. These domains are similar in sequence to those found in the ADAMs. Some members of the SVMP family have a conserved “RGD” amino acid sequence. This tripeptide has been shown to form a hairpin loop whose conformation can disrupt the binding of fibrinogen to activated platelets. This RGD sequence may be substituted by RSE, MVD, MSE, and KGD in P-II SVMPs, and by MSEC, RSEC, IDDC, and RDDC (a tripeptide along with a carboxy-terminal cysteine residue) in P-III SVMPs. Thus, these sequences may be responsible for integrin binding in the P-II and P-III SVMPs.
A prototypical example of a SVMP is jararhagin, which mediates platelet aggregation by binding to the platelet &agr;
2
subunit (GPIa) via the disintegrin domain followed by proteolysis of the &bgr;
1
subunit (GPIIA) (Huang and Liu,
J. Toxicol
-
Toxin Reviews
16: 135-161, 1997).
The proteins of the Metalloprotease/Disintegrin/Cysteine-rich (MDCs) family are involved in diverse tasks, ranging from roles in fertilization and muscle fusion, TNFa release from plasma membranes, intracellular protein cleavage, and essential functions in neuronal development (Blobel,
Cell
90:589-592, 1997). This family is also characterized by the metalloprotease, disintegrin and cysteine-rich domains, as described above.
The present invention provides a novel disintegrin homolog and related compositions whose uses should be apparent to those skilled in the art from the teachings herein.
SUMMARY OF THE INVENTION
Within one aspect, the present invention provides an isolated polypeptide molecule comprising a contiguous sequence of
14
amino acids of SEQ ID NO:2. Within an embodiment the polypeptide molecule comprises residues 437 to 450 of SEQ ID NO:2. Within another embodiment, the polypeptide molecule is between 82 and 232 amino acids in length. Within further embodiments polypeptide molecule is residues 164 to 382 of SEQ ID NO:2; residues 383 to 464 of SEQ ID NO:2; and/or residues 465 to 696 of SEQ ID NO:2.
Within another aspect, the invention provides an isolated polypeptide molecule selected from the group consisting of: a) a polypeptide molecule comprising residues 164 to 382 of SEQ ID NO:2; b) a polypeptide molecule comprising residues 383 to 464 of SEQ ID NO:2; c) a polypeptide molecule comprising residues 465 to 696 of SEQ ID NO:2; d) a polypeptide molecule comprising residues 438 to 449 of SEQ ID NO:2; e) a polypeptide molecule comprising residues 164 to 464 of SEQ ID NO:2; f) a polypeptide molecule comprising residues 164 to 696 of SEQ ID NO:2; g) a polypeptide molecule comprising residues 383 to 696 of SEQ ID NO:2; h) a polypeptide molecule comprising residues 164 to 449 of SEQ ID NO:2; i) a polypeptide molecule comprising residues 438 to 696 of SEQ ID NO:2; and j) a polypeptide molecule comprising residues 1 to 696 of SEQ ID NO:2.
Within another aspect is provided an isolated polynucleotide molecule encoding a polypeptide molecule, wherein the polypeptide molecule comprises a contiguous sequence of 14 amino acids of SEQ ID NO:2. Within an embodiment, the polypeptide molecule comprises residues 437 to 450 of SEQ ID NO:2. Within a further embodiment, the polypeptide molecule is between 82 and 232 amino acids in length. Within further embodiments, the polypeptide molecule is residues 164 to 382 of SEQ ID NO:2; residues 383 to 464 of SEQ ID NO:2; and/or residues 465 to 696 of SEQ ID NO:2.
Within another aspect, the invention provides an isolated polynucleotide molecule encoding a polypeptide molecule, wherein the polypeptide molecule is selected from the group consisting of: a) a polypeptide molecule comprising residues 164 to 382 of SEQ ID NO:2; b) a polypeptide molecule comprising residues 383 to 464 of SEQ ID NO:2; c) a polypeptide molecule comprising residues 465 to 696 of SEQ ID NO:2; d) a polypeptide molecule comprising residues 438 to 449 of SEQ ID NO:2; e) a polypeptide molecule comprising residues 164 to 464 of SEQ ID NO:2; f) a polypeptide molecule comprising residues 164 to 696 of SEQ ID NO:2; g) a polypeptide molecule comprising residues 383 to 696 of SEQ ID NO:2; h) a polypeptide molecule comprising residues 164 to 449 of SEQ ID NO:2; i) a polypeptide molecule comprising residues 438 to 696 of SEQ ID NO:2; and j) a polypeptide molecule comprising residues 1 to 696 of SEQ ID NO:2.
Within another aspect is provided an isolated polynucleotide encoding a fusion protein having a first segment and a second segment, wherein the first segment comprises a first polypeptide encoding a polypeptide having a protease domain and the second segment comprises a second polynucleotide encoding a polypeptide that has a contiguous sequence of 14 amino acids between residues 383 and 464 of SEQ ID NO:2, and wherein the first segment is positioned amino-terminally to the second segment. Within an embodiment, the protease domain is selected from the group consisting of; a) a protease domain that is a member of the Disintegrin Proteases; and b) a protease domain that is at least 80% identical to amino acid residues 164 to 382 of SEQ ID NO:2.
Within another aspect the invention provides an isolated polynucleotide molecule encoding a polypeptide molecule wherein the polynucleotide molecule is selected from the group consisting of: a) a polynucleotide molecule that encodes a polypeptide molecule that is at least 80% identical to residues 383 to 464 of SEQ ID NO:2; and b) a polynucleotide molecule that is complementary to a). Within an embodiment, the polynucleotide molecule is selected from the group consisting of: a) a polynucleotide molecule that encodes a polypeptide molecule that is at least 80% identical to residues 383 to 696 of SEQ ID NO:2; and b) a polynucleotide molecule that is complementary to a). Within a further embodiment, the polynucleotide molecule is selected from the group consisting of: a) a
Baindur Nand
Bishop Paul D.
Deisher Theresa A.
Sheppard Paul O.
Taft David W.
Achutamurthy Ponnathapu
Adams Robyn
Kerr Kathleen
ZymoGenetics Inc.
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