title: Dimerization of matrix metalloproteinase-2 (MMP-2): functional implication in MMP-2 activation.
abstract: Matrix metalloproteinase-2 (MMP-2) functions in diverse biological processes through the degradation of extracellular and non-extracellular matrix molecules. Because of its potential for tissue damage, there are several ways to regulate MMP-2 activity, including gene expression, compartmentalization, zymogen activation, and enzyme inactivation by extracellular inhibitors. Enzyme regulation through zymogen activation is important for the regulation of MMP-2 activity. In our previous studies, we showed that thrombin directly cleaved the propeptide of MMP-2 at specific sites for enzyme activation. We also demonstrated that heparan sulfate was required for thrombin-mediated activation of pro-MMP-2 by binding to thrombin, presumably through conformational changes at the active site of the enzyme. This suggests a regulatory mechanism for thrombin-mediated activation of pro-MMP-2. In this study, we found that MMP-2 formed a reduction-sensitive homodimer in a controlled manner and that Ca(2+) ion was essential for homodimerization of MMP-2. Homodimerization was not associated with protein kinase C-mediated phosphorylation of MMP-2. MMP-2 formed a homodimer through an intermolecular disulfide bond between Cys(102) and the neighboring Cys(102). Homodimerization of MMP-2 enhanced thrombin-mediated activation of pro-MMP-2. Moreover, the MMP-2 homodimer could cleave a small peptide substrate without removal of the propeptide. Taken together, our experimental data suggest a novel regulatory mechanism for pro-MMP-2 activation that is modulated through homodimerization of MMP-2.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea. k4119@yonsei.ac.kr
authors.forename: Bon-Hun
authors.initials: BH
authors.lastname: Koo
authors.forename: Yeon Hyang
authors.initials: YH
authors.lastname: Kim
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Han
authors.forename: Doo-Sik
authors.initials: DS
authors.lastname: Kim
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005354:Fibrosarcoma; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000737:chemistry / Q000378:metabolism
chemical_list: D002273:Carcinogens; D004220:Disulfides; D011493:Protein Kinase C; D013917:Thrombin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium