Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Reexamination Certificate
1999-08-06
2002-05-21
Nashed, Nashaat T. (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
C219S252000, C219S385000, C536S023200
Reexamination Certificate
active
06391610
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to isolated nucleic acid molecules which encode proteins belonging to a zinc metalloprotease family. The zinc metalloproteases have been implicated in a variety of diseases and development disorders that involve enhanced or depressed proteolysis of components of the extracellular matrix, receptors, or other extracellular molecules.
More particularly, the invention relates to isolated nucleic acid molecules encoding proteins belonging to a subfamily of zinc metalloproteases referred to as “ADAMTS”, an abbreviation for
A
D
isintegrin-like
A
nd
M
etalloprotease domain with
T
hrombo
S
pondin type I motifs. Proteins in the ADAMTS subfamily all possess a Zn protease catalytic site consensus sequence (HEXXH+H), which suggests an intact catalytic activity for each of these proteins. The ADAMTS proteins also have putative N-terminal signal peptides and lack transmembrane domains, which suggests that the proteins in this subfamily are secreted. The proteins in the ADAMTS subfamily also possess at least one thrombospondin type (TSP 1) motif, which suggests a binding of these proteins to components of the extracellular matrix (ECM) or to cell surface components.
Members of the ADAMTS subfamily of proteins are ADAMTS-1, ADAMTS-2, ADAMTS-3, and ADAMTS-4. ADAMTS-1 protein is selectively expressed in colon 26 adenocarcinoma cachexigenic sublines. ADAMTS-1 mRNA is induced by the inflammatory cytokine interleukin-1 in vitro and by intravenous administration of lipopolysaccharide in vivo. Thus, the ADAMTS-1 protein is believed to play a role in tumor cachexia and inflammation.
The ADAMTS-2 protein is also known as procollagen I/II amino-propetide processing enzyme or PCINP. The ADAMTS-2 protein catalyzes cleavage of native triple-helical procollagen I and procollagen II. The ADAMTS-2 protein also has an affinity for collagen XIV. Lack of the ADAMTS-2 protein is known to cause dermatosparaxis in cattle, or Ehlers-Danlos syndrome type VIIC (EDS-VIIC) in humans. EDS-VIIC is characterized clinically by severe skin fragility, and biochemically by the presence in skin of procollagen which is incompletely processed at the amino terminus. Thus, it is believed that the ADAMTS-2 protein plays a role in processing of procollagen to mature collagen, an essential step for correct assembly of collagen into collagen fibrils. The ADAMTS-3 protein is similar in sequence to ADAMTS-2 and may have similar function.
The ADAMTS-4 protein catalyzes cleavage of the core protein of the extracellular matrix proteoglycan, aggrecan. Aggrecan degradation is an important factor in the erosion of articular cartilage in arthritic disease. Aggrecan fragments have been identified in cultures undergoing cartilage matrix degradation and in arthritic synovial fluids. Therefore, overexpression or activation of ADAMTS-4 protein may be related to both inflammatory and non-inflammatory arthritis.
On the basis of the structure, location, and the demonstrated proteolytic activity of ADAMTS proteins 1-4, it is expected that other members of the ADAMTS subfamily play a role in the cleavage of proteoglycan core proteins that are found in the extracellular matrix, such as, for example, versican, brevican, neuracan, NG-2, aggrecan, as well as molecules such as collagen. It is also expected that other members of the ADAMTS subfamily play a role in embryogenesis, implantation of a fertilized egg, angiogenesis, arthritic degradation of cartilage, inflammation, nerve regeneration, tumor growth, and metastases.
Thus, it is desirable to have other members of the ADAMTS subfamily of proteins, the nucleic acids that encode such proteins, and antibodies that are specific for such proteins. Such molecules are useful research tools for studying development of the extracellular matrix during embryogenesis and fetal development, and for studying disorders or diseases that are characterized by improper development of the extracellular matrix or enhanced or reduced destruction of the extracellular matrix. Such molecules, particularly the nucleic acids and the antibodies, are also useful tools for diagnosing such diseases or for monitoring the efficacy of therapeutic agents that have been developed to treat such diseases.
SUMMARY OF THE INVENTION
The present invention provides novel, isolated, and substantially purified proteins having the characteristics of an ADAMTS protein. The novel proteins are referred to hereinafter individually as “ADAMTS-5”, “ADAMTS-6”, “ADAMTS-7”, “ADAMTS-8”, “ADAMTS-9” and “ADAMTS-10”, and collectively as “ADAMTS-N”. In one embodiment, the ADAMTS-5 protein is a mature mouse protein which comprises amino acid 231 through amino acid 930 of the sequence set forth in SEQ ID NO: 2. In another embodiment, ADAMTS-5 is a human ADAMTS-5 protein which comprises amino acid 1 through amino acid 518 of the sequence set forth in SEQ ID NO: 4. In one embodiment, mature human ADAMTS-6 protein comprises amino acid 245 through amino acid 860 of SEQ ID NO:6. In one embodiment, mature human ADAMTS-7 protein comprises amino acid 233 through amino acid 997 of the sequence set forth in SEQ ID NO: 8. In one embodiment, mature ADAMTS-8 protein is a mouse protein which comprises amino acid 229 through amino acid 905 of the sequence set forth in SEQ ID NO: 10. In another embodiment, ADAMTS-8 protein is a human protein which comprises amino acid 1 through amino acid 245 of the sequence set forth in SEQ ID NO: 12. In one embodiment, mature ADAMTS-9 protein is a human protein which comprises amino acid 236 through amino acid 1882 of the sequence set forth in SEQ ID NO: 14. In another embodiment, ADAMTS-9 protein is a mouse protein which comprises amino acid 1 through amino acid 874 of the sequence set forth in SEQ ID NO: 16. In one embodiment, mature ADAMTS-10 protein is a human protein which comprises amino acid 212 through amino acid 1081 of the sequence set forth in SEQ ID NO: 18. In another embodiment, ADAMTS-10 protein is a mouse protein which comprises amino acid 1 through amino acid 547 of the sequence set forth in SEQ ID NO: 20.
The present invention also provides isolated polynucleotides which encode an ADAMTS-N protein or a variant thereof, polynucleotide sequences complementary to such polynucleotides, vectors containing such polynucleotides, and host cells transformed or transfected with such vectors. The present invention also relates to antibodies which are immunospecific for one or more of the ADAMTS-N proteins. The present invention also relates to a protein referred to hereinafter as ADAMTS-R1 (ADAM-TS
R
elated protein -1) and the polynucleotides which encode such protein. In one embodiment, the ADAMTS-R1 protein comprises amino acid 1 through amino acid 525 of the sequence set forth in SEQ. ID NO: 22.
REFERENCES:
patent: 6046031 (2000-04-01), Ni et al.
patent: 99/05291 (1999-02-01), None
“cDNA cloning and expression of bovine procollagen I N-preteinase: A new member of the superfamily of zinc-metalloproteinases with binding sites for cells and other matrix components” by Colige, et al.,Proc. Natl. Acad. Sci. USA, vol. 94, Mar. 1997, pp. 2374-2379.
“Purification and Cloning of Aggrecanase-1: A Member of the ADAMTS Family of Proteins” of Tortorella, et al.,Science, vol. 284, Jun. 4, 1999, pp. 664-666.
“ADAM-TS5, ADAM-TS6, and ADAM-TS7, Novel Members of a New Family of Zinc Metalloproteases” by Hurskainen, et al.,The Journal of Biological Chemistry, vol. 274, No. 36, Sep. 3, 1999, pp. 25555-25563.
“The Exon/Intron Organization and Chromosomal Mapping of the Mouse ADAMTS-1 Gene Encoding an ADAM Family Protein with TSP Motifs” by Kuno, et al.,Gemonics, 46, (1997), pp. 466-471.
“Molecular Cloning of a Gene Encoding a New Type of Metalloproteinase-disintegrin Family Protein with Thrombospondin Motifs as an Inflammation Associated Gene” by Kuno, et al.,the Journal of Biological Chemistry,vol. 272, No. 1, Jan. 3, 1997, pp. 556-562.
“ADAMTS-1 Protein Anchors at the Extracellular Matrix through the Thrombospondin Type 1 Motifs and Its Spacing Region” by Kuno, et al.,The Journal of Biologica
Apte Suneel S.
Hirohata Satoshi
Hurskainen Tiina L.
Calfee Halter & Griswold LLP
Fronda Christian L.
Nashed Nashaat T.
The Cleveland Clinic Foundation
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