期刊
FEBS JOURNAL
卷 272, 期 1, 页码 97-108出版社
WILEY
DOI: 10.1111/j.1432-1033.2004.04401.x
关键词
protein C; activated protein C; endothelial cell protein C receptor
Uniquely amongst vitamin K-dependent coagulation proteins, protein C interacts via its Gla domain both with a receptor, the endothelial cell protein C receptor (EPCR), and with phospholipids. We have studied naturally occurring and recombinant protein C Gla domain variants for soluble (s)EPCR binding, cell surface activation to activated protein C (APC) by the thrombin-thrombomodulin complex, and phospholipid dependent factor Va (FVa) inactivation by APC, to establish if these functions are concordant. Wild-type protein C binding to sEPCR was characterized with surface plasmon resonance to have an association rate constant of 5.23x10(5) M-1.s(-1), a dissociation rate constant of 7.61x10(-2) s(-1) and equilibrium binding constant (K-D) of 147 nM. It was activated by thrombin over endothelial cells with a K-m of 213 nM and once activated to APC, rapidly inactivated FVa. Each of these interactions was dramatically reduced for variants causing gross Gla domain misfolding (R-1L, R-1C, E16D and E26K). Recombinant variants Q32A, V34A and D35A had essentially normal functions. However, R9H and H10Q/S11G/S12N/D23S/Q32E/N33D/H44Y (QGNSEDY) variants had slightly reduced (
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