Sulfated Glycosaminoglycans Control the Extracellular Trafficking and the Activity of the Metalloprotease Inhibitor TIMP-3
| Autor: | Craig Freeman, Oleg Federov, Hideaki Nagase, Christopher Lazenbatt, Osami Habuchi, Hiroko Habuchi, Md. Ferdous Anower-E-Khuda, Linda Troeberg, Koji Kimata |
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| Rok vydání: | 2014 |
| Předmět: |
Cartilage
Articular Clinical Biochemistry Matrix metalloproteinase Biochemistry Article Extracellular matrix chemistry.chemical_compound Mice Sulfation Drug Discovery Animals Humans Metalloprotease inhibitor Chondroitin sulfate Molecular Biology Tissue Inhibitor of Metalloproteinase-3 Pharmacology Thrombospondin Chondroitin Sulfates General Medicine Heparan sulfate Tissue inhibitor of metalloproteinase Endocytosis 3. Good health Extracellular Matrix ADAM Proteins Kinetics chemistry Molecular Medicine Heparitin Sulfate Heparan Sulfate Proteoglycans Low Density Lipoprotein Receptor-Related Protein-1 Protein Binding |
| Zdroj: | Chemistry & Biology |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2014.07.014 |
| Popis: | Summary Tissue inhibitor of metalloproteinase 3 (TIMP-3) is an important regulator of extracellular matrix (ECM) turnover. TIMP-3 binds to sulfated ECM glycosaminoglycans or is endocytosed by cells via low-density lipoprotein receptor-related protein 1 (LRP-1). Here, we report that heparan sulfate (HS) and chondroitin sulfate E (CSE) selectively regulate postsecretory trafficking of TIMP-3 by inhibiting its binding to LRP-1. HS and CSE also increased TIMP-3 affinity for glycan-binding metalloproteinases, such as adamalysin-like metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), by reducing the dissociation rate constants. The sulfation pattern was crucial for these activities because monosulfated or truncated heparin had a reduced ability to bind to TIMP-3 and increase its affinity for ADAMTS-5. Therefore, sulfation of ECM glycans regulates the levels and inhibitory activity of TIMP-3 and modulates ECM turnover, and small mimicries of sulfated glycans may protect the tissue from the excess destruction seen in diseases such as osteoarthritis, cancer, and atherosclerosis. Graphical Abstract Highlights • The metalloprotease inhibitor TIMP-3 binds to sulfated extracellular glycans • This inhibits cellular uptake of TIMP-3 by the endocytic receptor LRP-1 • Glycans also increase TIMP-3 affinity for selected target proteases • The sulfation of matrix glycans therefore modulates TIMP-3 activity and ECM turnover Tissue inhibitor of metalloproteinase (TIMP)-3 regulates extracellular matrix turnover. Troeberg et al. show that TIMP-3 levels are regulated by the balance between its binding to matrix glycans and receptor-mediated endocytosis and that glycan sulfation regulates this equilibrium. |
| Databáze: | OpenAIRE |
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