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

被引:218
作者
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
机构
[1] Max Planck Inst Biochem, Abt Strukturforsch, D-82152 Martinsried, Germany
[2] Duke Univ, Med Ctr, Dept Med, Div Hematol, Durham, NC 27710 USA
[3] DESY, MPG ASMB, Prot Dynam Grp, Max Planck Res Unit Struct Mol Biol, D-22603 Hamburg, Germany
[4] Univ Marburg, Inst Pharmazeut Chem, D-35032 Marburg, Germany
关键词
D O I
10.1038/46594
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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(1). 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(2). 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(3,4), 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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页码:434 / 439
页数:6
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