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

• Published in: Nature (London) Vol. 402; no. 6760; pp. 434 - 439
• Main Authors: Bode, Wolfram, Macedo-Ribeiro, Sandra, Huber, Robert, Quinn-Allen, Mary Ann, Kim, Suhng Wook, Ortel, Thomas L, Bourenkov, Gleb P, Bartunik, Hans D, Stubbs, Milton T, Kane, William H, Fuentes-Prior, Pablo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 25.11.1999; Nature Publishing Group
• Subjects: Amino Acid Sequence; Binding Sites; Biological and medical sciences; Blood coagulation. Blood cells; Cells; Circulatory system; Coagulation; Coagulation factors; Crystallography, X-Ray; Crystals; Factor Va - chemistry; Factor Va - metabolism; Factor VIIIa - metabolism; Fundamental and applied biological sciences. Psychology; Human factors; Humans; Membranes; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Sequence Alignment; Stereoisomerism; Human; Factor V; Domain structure; Molecular structure; Molecular interaction; Activation; Cofactor; Coagulation factor; Conformation; Crystalline structure
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/46594

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.