Structural Basis for Matrix Metalloproteinase 1-Catalyzed Collagenolysis

The proteolysis of collagen triple-helical structure (collagenolysis) is a poorly understood yet critical physiological process. Presently, matrix metalloproteinase 1 (MMP-1) and collagen triple-helical peptide models have been utilized to characterize the events and calculate the energetics of coll...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2012-02, Vol.134 (4), p.2100-2110
Main Authors: Bertini, Ivano, Fragai, Marco, Luchinat, Claudio, Melikian, Maxime, Toccafondi, Mirco, Lauer, Janelle L, Fields, Gregg B
Format: Article
Language:English
Subjects:
Biocatalysis
Collagen - chemical synthesis
Collagen - chemistry
Collagen - metabolism
Matrix Metalloproteinase 1 - chemistry
Matrix Metalloproteinase 1 - metabolism
Models, Molecular
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
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Summary:The proteolysis of collagen triple-helical structure (collagenolysis) is a poorly understood yet critical physiological process. Presently, matrix metalloproteinase 1 (MMP-1) and collagen triple-helical peptide models have been utilized to characterize the events and calculate the energetics of collagenolysis via NMR spectroscopic analysis of 12 enzyme–substrate complexes. The triple-helix is bound initially by the MMP-1 hemopexin-like (HPX) domain via a four amino acid stretch (analogous to type I collagen residues 782–785). The triple-helix is then presented to the MMP-1 catalytic (CAT) domain in a distinct orientation. The HPX and CAT domains are rotated with respect to one another compared with the X-ray “closed” conformation of MMP-1. Back-rotation of the CAT and HPX domains to the X-ray closed conformation releases one chain out of the triple-helix, and this chain is properly positioned in the CAT domain active site for subsequent hydrolysis. The aforementioned steps provide a detailed, experimentally derived, and energetically favorable collagenolytic mechanism, as well as significant insight into the roles of distinct domains in extracellular protease function.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja208338j