TY - JOUR
T1 - Crystal structures of the membrane-binding C2 domain of human coagulation factor V
AU - Macedo-Ribeiro, Sandra
AU - Bode, Wolfram
AU - Huber, Robert
AU - Quinn-Allen, Mary Ann
AU - Kim, Suhng Wook
AU - Ortel, Thomas L.
AU - Bourenkow, Gleb P.
AU - Bartunik, Hans D.
AU - Stubbs, Milton T.
AU - Kane, William H.
AU - Fuentes-Prior, Pablo
PY - 1999/11/25
Y1 - 1999/11/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033604610&partnerID=8YFLogxK
U2 - 10.1038/46594
DO - 10.1038/46594
M3 - Article
C2 - 10586886
AN - SCOPUS:0033604610
SN - 0028-0836
VL - 402
SP - 434
EP - 439
JO - Nature
JF - Nature
IS - 6760
ER -