title: Characterization of the mechanisms by which gelatinase A, neutrophil collagenase, and membrane-type metalloproteinase MMP-14 recognize collagen I and enzymatically process the two alpha-chains.
abstract: The turnover of native collagen has been ascribed to different members of the matrix metalloproteinase (MMP) family. Here, the mechanisms by which neutrophil collagenase (MMP-8), gelatinase A (MMP-2), and the ectodomain of MT1-MMP (ectMMP-14) degrade fibrillar collagen were examined. In particular, the hydrolysis of type I collagen at 37 degrees C was investigated to identify functional differences in the processing of the two alpha-chain types of fibrillar collagen. Thermodynamic and kinetic parameters were used for a quantitative comparison of the binding, unwinding, and hydrolysis of triple helical collagen. We demonstrate that the MMP family has developed at least two distinct mechanisms for collagen unwinding and cleavage. MMP-8 and ectMMP-14 display a similar mechanism (although with different catalytic parameters), which is characterized by binding (likely through the hemopexin-like domain) and cleavage of alpha-1 and/or alpha-2 chains without distinguishing between them and keeping the gross conformation of the triple helix (at least during the first cleavage step). On the other hand, MMP-2 binds preferentially the alpha-1 chains (likely through the fibronectin-like domain, which is not present in MMP-8 and ectMMP-14), grossly altering the whole triple helical arrangement of the collagen molecule and cleaving preferentially the alpha-2 chain. These distinctive mechanisms underly a drastically different mode of interaction with triple helical fibrillar collagen I, according to which the MMP domain is involved in binding. These findings can be related to the different role exerted by these MMPs on collagen homeostasis in the extracellular matrix.
authors: Department of Experimental Medicine and Biochemical Sciences, University of Roma Tor Vergata, Via Montpellier 1, I-00133 Rome, Italy.
authors: Magda
authors: M
authors: Gioia
authors: Susanna
authors: S
authors: Monaco
authors: Giovanni Francesco
authors: GF
authors: Fasciglione
authors: Anna
authors: A
authors: Coletti
authors: Andrea
authors: A
authors: Modesti
authors: Stefano
authors: S
authors: Marini
authors: Massimo
authors: M
authors: Coletta
mesh_terms: D000818:Animals; D002384:Catalysis; D002417:Cattle; D024042:Collagen Type I / Q000737:chemistry*; D007700:Kinetics; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry*; D051379:Mice; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D024042:Collagen Type I; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D053511:Matrix Metalloproteinase 14