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. Bourenkov, Hans D. Bartunik, Milton T. Stubbs, William H. Kane and Pablo Fuentes-Prior
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Sandra Macedo-Ribeiro: Max-Planck-Institut für Biochemie
Wolfram Bode: Max-Planck-Institut für Biochemie
Robert Huber: Max-Planck-Institut für Biochemie
Mary Ann Quinn-Allen: Duke University Medical Center
Suhng Wook Kim: Duke University Medical Center
Thomas L. Ortel: Duke University Medical Center
Gleb P. Bourenkov: Max-Planck Research Unit for Structural Molecular Biology, Protein Dynamics Group, MPG-ASMB c/o DESY
Hans D. Bartunik: Max-Planck Research Unit for Structural Molecular Biology, Protein Dynamics Group, MPG-ASMB c/o DESY
Milton T. Stubbs: Institut für Pharmazeutische Chemie, Philipps Universität Marburg
William H. Kane: Duke University Medical Center
Pablo Fuentes-Prior: Max-Planck-Institut für Biochemie

Nature, 1999, vol. 402, issue 6760, 434-439

Abstract: 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.

Date: 1999
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DOI: 10.1038/46594

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