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Structural studies of the MMP-3 interaction with triple-helical collagen introduce new roles for the enzyme in tissue remodelling

Published version
Peer-reviewed

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Authors

Manka, Szymon W. 
Bihan, Dominique 
Farndale, Richard W. 

Abstract

Abstract: Matrix metalloproteinase-3 (MMP-3) participates in normal extracellular matrix turnover during embryonic development, organ morphogenesis and wound healing, and in tissue-destruction associated with aneurysm, cancer, arthritis and heart failure. Despite its inability to cleave triple-helical collagens, MMP-3 can still bind to them, but the mechanism, location and role of binding are not known. We used the Collagen Toolkits, libraries of triple-helical peptides that embrace the entire helical domains of collagens II and III, to map MMP-3 interaction sites. The enzyme recognises five sites on collagen II and three sites on collagen III. They share a glycine-phenylalanine-hydroxyproline/alanine (GFO/A) motif that is recognised by the enzyme in a context-dependent manner. Neither MMP-3 zymogen (proMMP-3) nor the individual catalytic (Cat) and hemopexin (Hpx) domains of MMP-3 interact with the peptides, revealing cooperative binding of both domains to the triple helix. The Toolkit binding data combined with molecular modelling enabled us to deduce the putative collagen-binding mode of MMP-3, where all three collagen chains make contacts with the enzyme in the valley running across both Cat and Hpx domains. The observed binding pattern casts light on how MMP-3 could regulate collagen turnover and compete with various collagen-binding proteins regulating cell adhesion and proliferation.

Description

Keywords

Article, /631/1647/2258/1267, /631/45, /631/535, article

Journal Title

Scientific Reports

Conference Name

Journal ISSN

2045-2322

Volume Title

9

Publisher

Nature Publishing Group UK
Sponsorship
Wellcome Trust (094470/Z/10/Z)
British Heart Foundation (RG/09/003/27122)