Abstract
Rapid and controlled clot formation is achieved through sequential activation of circulating serine proteinase precursors on phosphatidylserine-rich procoagulant membranes of activated platelets and endothelial cells1. 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 same A1-A2-B-A3-C1-C2 architecture2. Membrane binding is mediated by the C2 domains of both cofactors. Here we report two crystal structures of the C2 domain of human factor Va. The conserved β-barrel framework provides a scaffold for three protruding loops, one of which adopts markedly different conformations in the two crystal forms. We propose a mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa to phospholipid membranes3,4, on the basis of (1) immersion of hydrophobic residues at the apices of these loops in the apolar membrane core; (2) specific interactions with phosphatidylserine head groups in the groove enclosed by these loops; and (3) favourable electrostatic contacts of basic side chains with negatively charged membrane phosphate groups.
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Acknowledgements
We thank D. Grosse and M. Renatus for initial crystallization trials. W.B. is supported by the Biomed. and Training and Mobility Programs of the EU, by the HFSP and by the SFB469; M.A.Q.-A. and W.H.K. by the NIH; T.L.O., a Pew Scholar, by the March of Dimes Birth Defects Foundation; and S.M.-R. by PraxisXXI, FCT, Portugal.
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Macedo-Ribeiro, S., Bode, W., Huber, R. et al. Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature 402, 434–439 (1999). https://doi.org/10.1038/46594
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DOI: https://doi.org/10.1038/46594
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