Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3

Troeberg, Linda, Lazenbatt, Christopher, Anower-E-Khuda, Md Ferdous, Freeman, Craig, Federov, Oleg, Habuchi, Hiroko, Habuchi, Osami, Kimata, Koji and Nagase, Hideaki (2014) Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. Chemistry & Biology, 21 (10). pp. 1300-1309. ISSN 1074-5521

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: chemistry,animals,metabolism,chemistry,endocytosis,metabolism,metabolism,chemistry,humans,kinetics,chemistry,mice,protein binding,antagonists & inhibitors
Depositing User: LivePure Connector
Date Deposited: 04 Jan 2019 12:30
Last Modified: 22 Apr 2020 07:21
URI: https://ueaeprints.uea.ac.uk/id/eprint/69438
DOI: 10.1016/j.chembiol.2014.07.014

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