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

Journal Article (Journal Article)

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 beta-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.

Full Text

Duke Authors

Cited Authors

  • Macedo-Ribeiro, S; Bode, W; Huber, R; Quinn-Allen, MA; Kim, SW; Ortel, TL; Bourenkov, GP; Bartunik, HD; Stubbs, MT; Kane, WH; Fuentes-Prior, P

Published Date

  • November 25, 1999

Published In

Volume / Issue

  • 402 / 6760

Start / End Page

  • 434 - 439

PubMed ID

  • 10586886

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/46594


  • eng

Conference Location

  • England