title: Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin.
abstract: Secreted metalloproteases initiating proteolytic degradation of collagens and proteoglycans play a critical role in remodeling of the connective tissue. Activation of the secreted proenzymes and interaction with their specific inhibitors TIMP and TIMP-2 are responsible for regulation of enzyme activity in extracellular space. We have previously demonstrated that 92- and 72-kDa Type IV procollagenases, in contrast to interstitial collagenase (ClI), form specific complexes with TIMP and the related inhibitor TIMP-2, respectively. The physiologic significance of the proenzyme-inhibitor complex and the mechanism of activation of Type IV collagenases remained unclear. Here, we demonstrate that in the absence of TIMP, 92-kDa Type IV procollagenase (92T4Cl) can form a covalent homodimer and a novel complex with ClI. In the presence of TIMP, the formation of a 92T4Cl proenzyme complex with TIMP prevents dimerization, formation of the complex with ClI, and activation of the 92T4Cl proenzyme by stromelysin, a related metalloprotease. The proenzyme homodimer is unable to form a complex with TIMP. All TIMP-free forms of the proenzyme can be activated by stromelysin. The 92T4Cl-ClI complex can be activated to yield a complex active against both gelatin and fibrillar Type I collagen, suggesting a mechanism for cooperative action of two enzymes in reducing collagen fibrils to small peptides under physiologic conditions.
authors.affiliation: Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: G I
authors.initials: GI
authors.lastname: Goldberg
authors.forename: A
authors.initials: A
authors.lastname: Strongin
authors.forename: I E
authors.initials: IE
authors.lastname: Collier
authors.forename: L T
authors.initials: LT
authors.lastname: Genrich
authors.forename: B L
authors.initials: BL
authors.lastname: Marmer
mesh_terms: D002460:Cell Line; D017364:Collagenases; D004247:DNA / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000378:metabolism* / Q000494:pharmacology*; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology; D010957:Plasmids; D011994:Recombinant Proteins / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D014407:Tumor Cells, Cultured
chemical_list: D004792:Enzyme Precursors; D006023:Glycoproteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D004247:DNA; D005341:Fibrinolysin; D017364:Collagenases; D008666:Metalloendopeptidases; C022440:procollagenase; D019278:Matrix Metalloproteinase 3; D003012:Microbial Collagenase