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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

Type

Article

Change log

Authors

Farndale, Richard William 
Manka, Szymon 
Bihan, Dominique 

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

Collagen, Humans, Matrix Metalloproteinase 1, Matrix Metalloproteinase 3, Models, Molecular, Protein Binding, Protein Folding

Journal Title

Scientific Reports

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

9

Publisher

Nature Publishing Group
Sponsorship
British Heart Foundation (None)
Wellcome Trust (094470/Z/10/Z)
British Heart Foundation (RG/15/4/31268)
This work was supported by grants to R.W.F. from the Wellcome Trust (094470/Z/10/Z) and the British Heart Foundation (RG/09/003/27122)