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| Subject Categories: Cell & Tissue Architecture | Proteins |
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| The EMBO Journal
(2004) 23, 3020–3030, doi:10.1038/sj.emboj.7600318 Published online 15 July 2004 |
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| Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis |
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| Linda Chung1, 2, Deendayal Dinakarpandian2, Naoto Yoshida2, Janelle L Lauer-Fields1, 3, Gregg B Fields1, 3, Robert Visse1 and Hideaki Nagase1, 2 |
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1 Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London, UK 2 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA 3 Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL, USA To whom correspondence should be addressed Hideaki Nagase, Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, London W6 8LH, UK. Tel.: +44 20 8383 4488; Fax: +44 20 8383 4994; E-mail: h.nagase@imperial.ac.uk Received 4 March 2004; Accepted 18 June 2004; Published online 15 July 2004. |
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| Abstract |
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Breakdown of triple-helical interstitial collagens is essential in embryonic development, organ morphogenesis and tissue remodelling and repair. Aberrant collagenolysis may result in diseases such as arthritis, cancer, atherosclerosis, aneurysm and fibrosis. In vertebrates, it is initiated by collagenases belonging to the matrix metalloproteinase (MMP) family. The three-dimensional structure of a prototypic collagenase, MMP-1, indicates that the substrate-binding site of the enzyme is too narrow to accommodate triple-helical collagen. Here we report that collagenases bind and locally unwind the triple-helical structure before hydrolyzing the peptide bonds. Mutation of the catalytically essential residue Glu200 of MMP-1 to Ala resulted in a catalytically inactive enzyme, but in its presence noncollagenolytic proteinases digested collagen into typical 3/4 and 1/4 fragments, indicating that the MMP-1(E200A) mutant unwinds the triple-helical collagen. The study also shows that MMP-1 preferentially interacts with the  2(I) chain of type I collagen and cleaves the three chains in succession. Our results throw light on the basic mechanisms that control a wide range of biological and pathological processes associated with tissue remodelling. |
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| Keywords: collagenase, enzyme mechanism, matrix metalloproteinase, protein unfolding, triple helix |
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