Molecular mechanism of type I collagen homotrimer resistance to mammalian collagenases.
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.
Han
Sejin
S
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Makareeva
Elena
E
Kuznetsova
Natalia V
NV
DeRidder
Angela M
AM
Sutter
Mary Beth
MB
Losert
Wolfgang
W
Phillips
Charlotte L
CL
Visse
Robert
R
Nagase
Hideaki
H
Leikin
Sergey
S
D000818:Animals; D024042:Collagen Type I / Q000737:chemistry* / Q000378:metabolism*; D024022:Fibrillar Collagens / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008954:Models, Biological; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D013696:Temperature
D024042:Collagen Type I; D024022:Fibrillar Collagens; D011994:Recombinant Proteins; D020781:Matrix Metalloproteinase 1
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