Crystal structures of the membrane-binding C2 domain of human coagulation factor V.
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.
Macedo-Ribeiro
S
S
Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Martinsried, Germany.
Bode
W
W
Huber
R
R
Quinn-Allen
M A
MA
Kim
S W
SW
Ortel
T L
TL
Bourenkov
G P
GP
Bartunik
H D
HD
Stubbs
M T
MT
Kane
W H
WH
Fuentes-Prior
P
P
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015944:Factor VIIIa / Q000378:metabolism; D015943:Factor Va / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013237:Stereoisomerism
D015943:Factor Va; D015944:Factor VIIIa