title: A theoretical model of type I collagen proteolysis by matrix metalloproteinase (MMP) 2 and membrane type 1 MMP in the presence of tissue inhibitor of metalloproteinase 2.
abstract: One well documented family of enzymes responsible for the proteolytic processes that occur in the extracellular matrix is the soluble and membrane-associated matrix metalloproteinases. Here we present the first theoretical model of the biochemical network describing the proteolysis of collagen I by matrix metalloproteinases 2 (MMP2) and membrane type 1 matrix metalloproteinases (MT1-MMP) in the presence of the tissue inhibitor of metalloproteinases 2 (TIMP2) in a bulk, cell-free, well stirred environment. The model can serve as a tool for describing quantitatively the activation of the MMP2 proenzyme (pro-MMP2), the ectodomain shedding of MT1-MMP, and the collagenolysis arising from both of the enzymes. We show that pro-MMP2 activation, a process that involves a trimer formation of the proenzyme with TIMP2 and MT1-MMP, is suppressed at high inhibitor levels and paradoxically attains maximum only at intermediate TIMP2 concentrations. We also calculate the conditions for which pro-MMP2 activation is maximal. Furthermore we demonstrate that the ectodomain shedding of MT1-MMP can serve as a mechanism controlling the MT1-MMP availability and therefore the pro-MMP2 activation. Finally the proteolytic synergism of MMP2 and MT1-MMP is introduced and described quantitatively. The model provides us a tool to determine the conditions under which the synergism is optimized. Our approach is the first step toward a more complete description of the proteolytic processes that occur in the extracellular matrix and include a wider spectrum of enzymes and substrates as well as naturally occurring or artificial inhibitors.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Emmanouil D
authors.initials: ED
authors.lastname: Karagiannis
authors.forename: Aleksander S
authors.initials: AS
authors.lastname: Popel
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000379:methods; D003094:Collagen / Q000737:chemistry*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D008956:Models, Chemical; D008962:Models, Theoretical; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012984:Software; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000737:chemistry*
chemical_list: D020033:Protein Isoforms; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2