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

Sandra Macedo-Ribeiro, Wolfram Bode, Robert Huber, Mary Ann Quinn-Allen, Suhng Wook Kim, Thomas L. Ortel, Gleb P. Bourenkow, Hans D. Bartunik, Milton T. Stubbs, William H. Kane, Pablo Fuentes-Prior

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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 cells. 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 architecture. 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 membranes 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.

Original languageEnglish
Pages (from-to)434-439
Number of pages6
JournalNature
Volume402
Issue number6760
DOIs
Publication statusPublished - 1999 Nov 25
Externally publishedYes

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Macedo-Ribeiro, S., Bode, W., Huber, R., Quinn-Allen, M. A., Kim, S. W., Ortel, T. L., Bourenkow, G. P., Bartunik, H. D., Stubbs, M. T., Kane, W. H., & Fuentes-Prior, P. (1999). Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature, 402(6760), 434-439. https://doi.org/10.1038/46594