Activation of Factor v by Venom Proteases

Abstract

Blood coagulation factor V is the nonenzymatic protein cofactor essential to the formation of thrombin. Activated factor V, FVa, is a cofactor of FXa in the socalled prothrombinase complex. Inclusion of FVa in this complex results in a more than 1,000-fold enhancement of the rate of prothrombin activation. Several animal venoms contain activities that have the capacity to activate human factor V. Besides activators of factor V, inactivating enzymes are also found in animal venoms. Of those venom proteases that affect FV activity, snake venoms of different families, including those of the Viperidae, Crotalidae, and Elapidae, have been most widely studied. Venom factor V activators have proven to be excellent tools in studying the structure-function relationship of factor V(a). In particular, one of the proteases of the Viperidae family, the factor V activator from the venom of Russell's viper (RVV-V) has been very helpful, because it is also used in diagnostic tests for quantification of plasma factor V levels and for the screening of defects in the protein C pathway.In this paper, we present an up-to-date overview of those venom proteases that possess the capacity to activate or inactivate coagulation factor V and, where possible, summarize structural and functional properties of these proteases. Furthermore, we provide a novel detailed three-dimensional homology model for RVV-V, the factor V activator from Russell's viper venom. This model will be helpful to explain the remarkable substrate specificity of RVV-V on the basis of its threedimensional structure.

Translational Venomics: Third-Generation Antivenomics of Anti-Siamese Russell’s Viper, Daboia siamensis, Antivenom Manufactured in Taiwan CDC’s Vaccine Center

“…RVV-X (8.5% of Taiwanese D. siamensis venom proteome) specifically, activates coagulation Stuart factor (factor X, FX) by cleaving the same Arg-Ile bond that is cleaved by factors IXa and VIIa during physiological coagulation [ 43 , 44 ]. Thrombin-like serine protease RVV-V (14% of D. siamensis (Taiwan) venom proteins), specifically activates factor V by the selective single cleavage at site III (Arg1545-Ser1546) [ 45 ]. The structural basis of this narrow substrate specificity has been solved by X-ray crystallography [ 46 ].…”