Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4.
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...
| المؤلفون الرئيسيون: | , , , , , , , |
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| التنسيق: | Journal article |
| اللغة: | English |
| منشور في: |
2007
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| _version_ | 1826276228136435712 |
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| author | Gendron, C Kashiwagi, M Lim, N Enghild, J Thøgersen, I Hughes, C Caterson, B Nagase, H |
| author_facet | Gendron, C Kashiwagi, M Lim, N Enghild, J Thøgersen, I Hughes, C Caterson, B Nagase, H |
| author_sort | Gendron, C |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:10:52Z |
| format | Journal article |
| id | oxford-uuid:656b9cf1-06e0-4f74-b5e4-64618ca9a18c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:10:52Z |
| publishDate | 2007 |
| record_format | dspace |
| spelling | oxford-uuid:656b9cf1-06e0-4f74-b5e4-64618ca9a18c2022-03-26T18:25:25ZProteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:656b9cf1-06e0-4f74-b5e4-64618ca9a18cEnglishSymplectic Elements at Oxford2007Gendron, CKashiwagi, MLim, NEnghild, JThøgersen, IHughes, CCaterson, BNagase, HAggrecanases 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. |
| spellingShingle | Gendron, C Kashiwagi, M Lim, N Enghild, J Thøgersen, I Hughes, C Caterson, B Nagase, H Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. |
| title | Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. |
| title_full | Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. |
| title_fullStr | Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. |
| title_full_unstemmed | Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. |
| title_short | Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. |
| title_sort | proteolytic activities of human adamts 5 comparative studies with adamts 4 |
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