title: Allosteric disulfide bonds in thrombosis and thrombolysis.
abstract: Allosteric disulfide bonds control protein function by mediating conformational change when they undergo reduction or oxidation. The known allosteric disulfide bonds are characterized by a particular bond geometry, the -RHStaple. A number of thrombosis and thrombolysis proteins contain one or more disulfide bonds of this type. Tissue factor (TF) was the first hemostasis protein shown to be controlled by an allosteric disulfide bond, the Cys186-Cys209 bond in the membrane-proximal fibronectin type III domain. TF exists in three forms on the cell surface: a cryptic form that is inert, a coagulant form that rapidly binds factor VIIa to initiate coagulation, and a signaling form that binds FVIIa and cleaves protease-activated receptor 2, which functions in inflammation, tumor progression and angiogenesis. Reduction and oxidation of the Cys186-Cys209 disulfide bond is central to the transition between the three forms of TF. The redox state of the bond appears to be controlled by protein disulfide isomerase and NO. Plasmin(ogen), vitronectin, glycoprotein 1balpha, integrin beta(3) and thrombomodulin also contain -RHStaple disulfides, and there is circumstantial evidence that the function of these proteins may involve cleavage/formation of these disulfide bonds.
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney.
authors.forename: V M
authors.initials: VM
authors.lastname: Chen
authors.forename: P J
authors.initials: PJ
authors.lastname: Hogg
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism*; D004789:Enzyme Activation; D005341:Fibrinolysin / Q000737:chemistry / Q000378:metabolism; D005342:Fibrinolysis; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism; D039661:Integrin beta3 / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D010958:Plasminogen / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D018180:Thrombomodulin / Q000737:chemistry / Q000378:metabolism; D013925:Thromboplastin / Q000737:chemistry / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000378:metabolism*; D019096:Vitronectin / Q000737:chemistry / Q000378:metabolism
chemical_list: C048566:A1BG protein, human; D001798:Blood Proteins; D004220:Disulfides; D006023:Glycoproteins; D007136:Immunoglobulins; D039661:Integrin beta3; D018180:Thrombomodulin; D019096:Vitronectin; D010958:Plasminogen; D013925:Thromboplastin; D005341:Fibrinolysin