Crystal structures of the membrane-binding C2 domain of human coagulation factor V

Rapid and controlled clot formation is achieved through sequential activati on of circulating serine proteinase precursors on phosphatidylserine-rich p rocoagulant membranes of activated platelets and endothelial cells(1). The homologous complexes Xase and prothrombinase, each consisting of an active proteinase and a non-enzymatic cofactor, perform critical steps within this coagulation cascade. The activated cofactors VIIIa and Va, highly specific for their cognate proteinases, are each derived from precursors with the s ame A1-A2-B-A3-C1-C2 architecture(2). Membrane binding is mediated by the C 2 domains of both cofactors, Here we report two crystal structures of the C 2 domain of human factor Va. The conserved beta-barrel framework provides a scaffold for three protruding loops, one of which adopts markedly differen t conformations in the two crystal forms. We propose a mechanism of calcium -independent, stereospecific binding of factors Va and VIIIa to phospholipi d membranes(3,4), on the basis of (1) immersion of hydrophobic residues at the apices of these loops in the apolar membrane core; (2) specific interac tions with phosphatidylserine head groups in the groove enclosed by these l oops; and (3) favourable electrostatic contacts of basic side chains with n egatively charged membrane phosphate groups.