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Critical Reviews™ in Eukaryotic Gene Expression
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ISSN Imprimer: 1045-4403
ISSN En ligne: 2162-6502

Critical Reviews™ in Eukaryotic Gene Expression

DOI: 10.1615/CritRevEukarGeneExpr.v6.i1.60
pages 87-101

Regulation and Regulatory Role of γ-Carboxyglutamic Acid Containing Clotting Factors

Michael Kalafatis
Department of Biochemistry, Given Building, Health Science Complex, University of Vermont, College of Medicine, Burlington, Vermont 05405-0068
Jack O. Egan
Department of Biochemistry, University of Vermont, College of Medicine, Burlington, Vermont 05405
Cornells van't Veer
Department of Biochemistry, Given Building, Health Science Complex, University of Vermont, College of Medicine, Burlington, Vermont 05405-0068
Kenneth G. Mann
Department of Biochemistry, Given Building, Health Science Complex, University of Vermont, College of Medicine, Burlington, Vermont 05405-0068

RÉSUMÉ

Blood coagulation is initiated following damage of the vessel wall. The large number of proteins that participate in the reactions that regulate blood coagulation must behave in a concerted manner to generate α-thrombin. This most abundant enzyme product of the coagulation process acts on the soluble blood protein fibrinogen to create the insoluble fibrin clot, trigger platelet activation, and initiate a variety of vascular processes ranging from coagulation inhibition and activation of fibrinolysis to cell growth. The majority of enzymes that participate in the blood-clotting process circulate in blood as inactive zymogens and procofactors. Following mechanical injury to the vessel wall, a cell-associated protein, tissue factor, is exposed and initiates a series of enzymatic reactions localized on a membrane surface generally provided by cells and accumulating platelets. The binding of the enzymes and zymogen substrates to the exposed membrane surface and their activation are in part governed by the γ-carboxyglutamic acid residues (gla) of each protein. Recently, it has been demonstrated that the gla residues are necessary for Ca2+ binding and subsequent exposure of the hydrophobic membrane binding regions to the cell bilayer. Thus, the gla residues play a preeminent role during the blood-clotting process. Absence of γ-carboxylation of one or more of the critical glutamic acid residues results in an impaired coagulation/anticoagulation process which may lead to a bleeding diathesis or thrombosis.


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