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

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Farndale, Richard William 
Manka, Szymon 
Bihan, Dominique 


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.



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

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Scientific Reports

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Nature Publishing Group
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)