tailieunhanh - Báo cáo khoa học: Selective modulation of protein C affinity for EPCR and phospholipids by Gla domain mutation

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. . | ềFEBS Journal Selective modulation of protein C affinity for EPCR and phospholipids by Gla domain mutation Roger J. S. Preston1 Ana Villegas-Mendez1 Yong-Hui Sun2 Jose Hermida1 Paolo Simioni3 Helen Philippou1 t Bjorn Dahlback2 and David A. Lane1 1 Department of Haematology Division of Investigative Science Hammersmith Campus Imperial college London UK 2 Department of Laboratory Medicine Division of ClinicalChemistry Lund University University Hospital Malmo Sweden 3 Department of Medicaland SurgicalSciences 2nd Chair of InternalMedicine University of Padua Medical School Italy Keywords protein C activated protein C endothelial cell protein C receptor Correspondence D. A. Lane Department of Haematology ImperialCollege London Hammersmith HospitalCampus London W12 ONN UK E-mail Present address Department of Haematology University of Navarra Pamplona Spain tPresent address Academic Unit of Molecular Vascular Medicine University of Leeds Schoolof Medicine UK Received 9 July 2004 revised 6 September 2004 accepted 9 September 2004 doi 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 X 105 M-1-s-1 a dissociation rate constant of X 10 2 s 1 and equilibrium binding constant KD of 147 nM. It was activated by thrombin over endothelial cells with a Km of 213 nM and once activated to APC rapidly inactivated FVa. Each of these interactions was .

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