title: Molecular mechanism of type I collagen homotrimer resistance to mammalian collagenases.
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 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.
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sejin
authors.initials: S
authors.lastname: Han
authors.forename: Elena
authors.initials: E
authors.lastname: Makareeva
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Kuznetsova
authors.forename: Angela M
authors.initials: AM
authors.lastname: DeRidder
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Sutter
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Losert
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Phillips
authors.forename: Robert
authors.initials: R
authors.lastname: Visse
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
mesh_terms: 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
chemical_list: D024042:Collagen Type I; D024022:Fibrillar Collagens; D011994:Recombinant Proteins; D020781:Matrix Metalloproteinase 1
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