Molecular Characterization of an Extended Binding Site for Coagulation Factor Va in the Positive Exosite of Activated Protein C
Copyright policy )Molecular Characterization of an Extended Binding Site for Coagulation Factor Va in the Positive Exosite of Activated Protein C
The anticoagulant human plasma serine protease, activated protein C (APC), inhibits blood coagulation by specific inactivation of the coagulation cofactors factor Va (FVa) and factor VIIIa. Site-directed mutagenesis of residues in three surface loops of a positive exosite located on APC was used to identify residues that play a significant role in binding to FVa. Eighteen different residues were mutated to alanine singly, in pairs, or in triple mutation combinations. Mutant APC proteins were purified and characterized for their inactivation of FVa. Three APC residues were identified that provide major contributions to FVa interactions: Lys(193), Arg(229), and Arg(230). In addition, four residues made significant minor contributions to FVa interactions: Lys(191), Lys(192), Asp(214), and Glu(215). All of these residues primarily contribute to APC cleavage at Arg(506) in FVa and play a small role in the interaction of APC with the Arg(306) cleavage site. In conjunction with previously published work, these results define an extensive FVa binding site in the positive exosite of APC that is primarily involved in binding and cleaving at Arg(506) on FVa.
- Scripps Research Institute United States
Models, Molecular, Alanine, Binding Sites, Time Factors, Lysine, DNA Mutational Analysis, Glutamic Acid, Arginine, Recombinant Proteins, Kinetics, Fibrinolytic Agents, Factor Va, Mutation, Mutagenesis, Site-Directed, Humans, Protein Binding, Protein C
Models, Molecular, Alanine, Binding Sites, Time Factors, Lysine, DNA Mutational Analysis, Glutamic Acid, Arginine, Recombinant Proteins, Kinetics, Fibrinolytic Agents, Factor Va, Mutation, Mutagenesis, Site-Directed, Humans, Protein Binding, Protein C
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