Heparan sulfate regulates ADAM12 through a molecular switch mechanism
| Autor: | Magnus C. Lydolph, Hans Peter Sørensen, Jonas Jacobsen, John R. Couchman, Christina Manetopoulos, Romain R. Vivès, Reidar Albrechtsen, Ulla M. Wewer |
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| Přispěvatelé: | IT University of Copenhagen (ITU), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
ADAM12 Protein
MESH: Catalytic Domain MESH: Cricetinae Plasma protein binding Biochemistry Substrate Specificity chemistry.chemical_compound MESH: Osteoarthritis Catalytic Domain Cricetinae MESH: Glucuronidase MESH: Animals Glucuronidase Glycosaminoglycans 0303 health sciences biology Chemistry 030302 biochemistry & molecular biology MESH: Glycosaminoglycans Heparan sulfate ADAM Proteins medicine.anatomical_structure MESH: Membrane Proteins Protein Binding MESH: ADAM Proteins MESH: Enzyme Activation Chondrocyte Cell Line 03 medical and health sciences Enzyme activator MESH: Heparitin Sulfate Osteoarthritis medicine Disintegrin Animals Humans MESH: Protein Binding Heparanase [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Molecular Biology 030304 developmental biology MESH: Humans Cell Membrane Membrane Proteins Cell Biology Sheddase MESH: Cell Line Enzyme Activation carbohydrates (lipids) biology.protein MESH: Substrate Specificity Heparitin Sulfate MESH: Cell Membrane |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, 2008, 283 (46), pp.31920-31932. ⟨10.1074/jbc.M804113200⟩ Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2008, 283 (46), pp.31920-32. ⟨10.1074/jbc.M804113200⟩ |
| ISSN: | 0021-9258 1083-351X |
| Popis: | International audience; The disintegrin and metalloproteases (ADAMs) are emerging as therapeutic targets in human disease, but specific drug design is hampered by potential redundancy. Unlike other metzincins, ADAM prodomains remain bound to the mature enzyme to regulate activity. Here ADAM12, a protease that promotes tumor progression and chondrocyte proliferation in osteoarthritic cartilage, is shown to possess a prodomain/catalytic domain cationic molecular switch, regulated by exogenous heparan sulfate and heparin but also endogenous cell surface proteoglycans and the polyanion, calcium pentosan polysulfate. Sheddase functions of ADAM12 are regulated by the switch, as are proteolytic functions in placental tissue and sera of pregnant women. Moreover, human heparanase, an enzyme also linked to tumorigenesis, can promote ADAM12 sheddase activity at the cell surface through cleavage of the inhibitory heparan sulfate. These data present a novel concept that might allow targeting of ADAM12 and suggest that other ADAMs may have specific regulatory activity embedded in their prodomain and catalytic domain structures. |
| Databáze: | OpenAIRE |
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