Activated Protein C (APC) is an anticoagulant serine protease that proteolytically inactivates the coagulation cofactors, factors (F) Va and VIIIa. FVIIIa is a non-covalent heterotrimer consisting of A1, A2 and A3-C1-C2 subunits. APC-catalyzed inactivation of FVIIIa results from proteolysis at the P1 residues Arg336 and Arg562 within the A1 and A2 subunits, respectively, with cleavage at Arg336 representing the dominant reaction. We recently showed that replacement of the P4-P3′ residues surrounding the Arg336 site with the corresponding residues flanking Arg562 resulted in an ∼100-fold reduction in cleavage rate at Arg336 (
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