Thrombin-cofactor interactions: structural insights into regulatory mechanisms.
Precise modulation of thrombin activity throughout the hemostatic response is essential for efficient cessation of bleeding while preventing inappropriate clot growth or dissemination which causes thrombosis. Regulating thrombin activity is made difficult by its ability to diffuse from the surface on which it was generated and its ability to cleave at least 12 substrates. To overcome this challenge, thrombin recognition of substrates is largely controlled by cofactors that act by localizing thrombin to various surfaces, blocking substrate binding to critical exosites, engendering new exosites for substrate recognition and by allosterically modulating the properties of the active site of thrombin. Thrombin cofactors can be classified as either pro- or anticoagulants, depending on how substrate preference is altered. The procoagulant cofactors include glycoprotein Ibalpha, fibrin, and Na+, and the anticoagulants are heparin and thrombomodulin. Over the last few years, crystal structures have been reported for all of the thrombin-cofactor complexes. The purpose of this article is to summarize the features of these structures and to discuss the mechanisms and physiological relevance of cofactor binding in thrombin regulation.
Adams
Ty E
TE
University of Cambridge, Department of Haematology, Division of Structural Medicine, Thrombosis Research Unit, Cambridge Institute for Medical Research, Cambridge CB2 2XY, UK.
Huntington
James A
JA
D001667:Binding, Competitive; D001779:Blood Coagulation Factors / Q000502:physiology*; D005337:Fibrin / Q000502:physiology; D006025:Glycosaminoglycans / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013917:Thrombin / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D018180:Thrombomodulin / Q000378:metabolism
D001779:Blood Coagulation Factors; D006025:Glycosaminoglycans; D019038:Platelet Glycoprotein GPIb-IX Complex; D018180:Thrombomodulin; D005337:Fibrin; D006493:Heparin; D012964:Sodium; D013917:Thrombin