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Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2007 Jun 22; Vol. 282 (25), pp. 18294-18306. Date of Electronic Publication: 2007 Apr 12. - Publication Year :
- 2007
-
Abstract
- Aggrecanases have been characterized as proteinases that cleave the Glu373-Ala374 bond of the aggrecan core protein, and they are multidomain metalloproteinases belonging to the ADAMTS (adamalysin with thrombospondin type 1 motifs) family. The first aggrecanases discovered were ADAMTS-4 (aggrecanase 1) and ADAMTS-5 (aggrecanase 2). They contain a zinc catalytic domain followed by non-catalytic ancillary domains, including a disintegrin domain, a thrombospondin domain, a cysteine-rich domain, and a spacer domain. In the case of ADAMTS-5, a second thrombospondin domain follows the spacer domain. We previously reported that the non-catalytic domains of ADAMTS-4 influence both its extracellular matrix interaction and proteolytic abilities. Here we report the effects of these domains of ADAMTS-5 on the extracellular matrix interaction and proteolytic activities and compare them with those of ADAMTS-4. Although the spacer domain was critical for ADAMTS-4 localization in the matrix, the cysteine-rich domain influenced ADAMTS-5 localization. Similar to previous reports of other ADAMTS family members, very little proteolytic activity was detected with the ADAMTS-5 catalytic domain alone. The sequential inclusion of each carboxyl-terminal domain enhanced its activity against aggrecan, carboxymethylated transferrin, fibromodulin, decorin, biglycan, and fibronectin. Both ADAMTS-4 and -5 had a broad optimal activity at pH 7.0-9.5. Aggrecanolytic activities were sensitive to the NaCl concentration, but activities on non-aggrecan substrates, e.g. carboxymethylated transferrin, were not affected. Although ADAMTS-4 and ADAMTS-5 had similar general proteolytic activities, the aggrecanase activity of ADAMTS-5 was at least 1,000-fold greater than that of ADAMTS-4 under physiological conditions. Our studies suggest that ADAMTS-5 is a major aggrecanase in cartilage metabolism and pathology.
- Subjects :
- ADAM Proteins chemistry
ADAMTS4 Protein
ADAMTS5 Protein
Alanine chemistry
Binding Sites
Catalytic Domain
Cell Line
Cell Membrane metabolism
Gene Deletion
Glutamic Acid chemistry
Humans
Hydrogen-Ion Concentration
Mutation
Procollagen N-Endopeptidase chemistry
Protein Binding
Protein Structure, Tertiary
Transfection
ADAM Proteins physiology
Procollagen N-Endopeptidase physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 282
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17430884
- Full Text :
- https://doi.org/10.1074/jbc.M701523200