Protein Structure and Folding
Substitution of the Gla Domain in Factor X with That of Protein C Impairs Its Interaction with Factor VIIa/Tissue Factor: LACK OF COMPARABLE EFFECT BY SIMILAR SUBSTITUTION IN FACTOR IX*

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We previously reported that the first epidermal growth factor-like (EGF1) domain in factor X (FX) or factor IX (FIX) plays an important role in the factor VIIa/tissue factor (FVIIa/TF)-induced coagulation. To assess the role of γ-carboxyglutamic acid (Gla) domains of FX and FIX in FVIIa/TF induced coagulation, we studied four new and two previously described replacement mutants: FXPCGla and FIXPCGla (Gla domain replaced with that of protein C), FXPCEGF1 and FIXPCEGF1 (EGF1 domain replaced with that of protein C), as well as FXPCGla/EGF1 and FIXPCGla/EGF1 (both Gla and EGF1 domains replaced with those of protein C). FVIIa/TF activation of each FX mutant and the corresponding reciprocal activation of FVII/TF by each FXa mutant were impaired. In contrast, FVIIa/TF activation of FIXPCGla was minimally affected, and the reciprocal activation of FVII/TF by FIXaPCGla was normal; however, both reactions were impaired for the FIXPCEGF1 and FIXPCGla/EGF1 mutants. Predictably, FXIa activation of FIXPCEGF1 was normal, whereas it was impaired for the FIXPCGla and FIXPCGla/EGF1 mutants. Molecular models reveal that alternate interactions exist for the Gla domain of protein C such that it is comparable with FIX but not FX in its binding to FVIIa/TF. Further, additional interactions exist for the EGF1 domain of FX, which are not possible for FIX. Importantly, a seven-residue insertion in the EGF1 domain of protein C prevents its interaction with FVIIa/TF. Cumulatively, our data provide a molecular framework demonstrating that the Gla and EGF1 domains of FX interact more strongly with FVIIa/TF than the corresponding domains in FIX.

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This work was supported by National Institutes of Health Grants HL 36365 and HL 70369 (to S. P. B.) and HL 34462 (to G. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.