Proteolytic Activities of Human Adamts-5: Comparative Studies with Adamts-4.
From: Kennedy Institute of Rheumatology Division, Imperial College London, London W6 8LH, United Kingdom.
The Journal of biological chemistry
- Publish Date: Jun 2007
- ISSN: 0021-9258
- Volume: 282
- Issue: 25
- Pages: 18294-306
- Medium: Print
- Language: English
- Citation (JAMA): Gendron Christi, Kashiwagi Masahide, Lim Ngee Han, et al. Proteolytic Activities of Human Adamts-5: Comparative Studies with Adamts-4.. J. Biol. Chem. Jun 2007;282:18294-306
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.
Mesh Headings (Keywords): ADAM Proteins, Alanine, Binding Sites, Catalytic Domain, Cell Line, Cell Membrane, Gene Deletion, Glutamic Acid, Humans, Hydrogen-Ion Concentration, Mutation, Procollagen N-Endopeptidase, Protein Binding, Protein Structure, Tertiary, Transfection
Check for Full Text / PubMed Unique Identifier (PMID): 17430884
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