Abstract
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 α1(I)3 homotrimers and normal α1(I)2α2(I) heterotrimers with fibroblast collagenase (MMP-1). Similar MMP-1 binding to the two isoforms and similar cleavage efficiency of unwound α1(I) and α2(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.
Highlights
Type I collagen cleavage is crucial for tissue remodeling, but its homotrimeric isoform is resistant to all collagenases
matrix metalloproteinase (MMP)-1 Binding Is Essential for Efficient Triple Helix Unwinding at the Cleavage Site in Type I Collagen—It is widely accepted that enzyme binding, helix unwinding at the cleavage site, and sequential hydrolysis of the chains are the three principal steps in collagen cleavage by MMPs, but two different mechanisms that account for these steps have been proposed
The unwinding is promoted by MMP binding, as summarized by Reaction 1 [24], CN ϩ E 7 ECN 7 ECU 3 E ϩ P REACTION 1 where CN and CU indicate collagen in which the MMP cleavage site is in a native state and in a locally unwound state, respectively; E is the enzyme; ECN and ECU are enzyme-collagen complexes; and P denotes triple helix cleavage products
Summary
Type I collagen cleavage is crucial for tissue remodeling, but its homotrimeric isoform is resistant to all collagenases. To understand the mechanism of this resistance, we studied interactions of ␣1(I)3 homotrimers and normal ␣1(I)2␣2(I) heterotrimers with fibroblast collagenase (MMP-1). Similar MMP-1 binding to the two isoforms and similar cleavage efficiency of unwound ␣1(I) and ␣2(I) chains suggested increased stability and less efficient unwinding of the homotrimer triple helix at the collagenase cleavage site.
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