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.
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.
Karagiannis
Emmanouil D
ED
Department of Biomedical Engineering, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
Popel
Aleksander S
AS
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*
D020033:Protein Isoforms; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2