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Type I collagen cleavage is crucial for tissue remodeling, but its homotrimeric isoform is resistant to all collagenases. The homotrimers occur in fetal tissues, fibrosis, and cancer, where their collagenase resistance may play an important physiological role. To understand the mechanism of this resistance, we studied interactions of alpha1(I)(3) homotrimers and normal alpha1(I)(2)alpha2(I) heterotrimers with fibroblast collagenase (MMP-1). Similar MMP-1 binding to the two isoforms and similar cleavage efficiency of unwound alpha1(I) and alpha2(I) chains suggested increased stability and less efficient unwinding of the homotrimer triple helix at the collagenase cleavage site. The unwinding, necessary for placing individual chains inside the catalytic cleft of the enzyme, was the rate-limiting cleavage step for both collagen isoforms. Comparative analysis of the homo- and heterotrimer cleavage kinetics revealed that MMP-1 binding promotes stochastic helix unwinding, resolving the controversy between different models of collagenase action.

Original publication

DOI

10.1074/jbc.m110.102079

Type

Journal article

Journal

The Journal of biological chemistry

Publication Date

07/2010

Volume

285

Pages

22276 - 22281

Addresses

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.

Keywords

Animals, Humans, Mice, Fibrillar Collagens, Collagen Type I, Recombinant Proteins, Microscopy, Confocal, Temperature, Protein Structure, Tertiary, Protein Binding, Kinetics, Models, Biological, Matrix Metalloproteinase 1, Protein Multimerization