Journal of thrombosis and haemostasis : JTH · 2026
Pseudonaja textilis venom factor Va circumvents natural regulatory mechanisms via a unique A2 domain region.
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Schreuder Mark, Cheung Ka Lei, Kruijsdijk Lynn, Reitsma Pieter H, Bos Mettine H A
Аннотация
BACKGROUND: The coagulation factor (F)V variant derived from the venom of the Australian snake Pseudonaja(P)textilis (ptFV) has several unique procoagulant adaptations that circumvent normal regulatory mechanisms. Notably, ptFV has a significantly extended A2 domain C-terminus (A2T), a region whose role in human FV biology is poorly understood.
OBJECTIVES: In this study, we generated chimeric FV variants to elucidate the functional relevance of this extended structural region.
METHODS: The ptFV A2T was exchanged for the homologous human FV region and vice versa, generating ptFV-hA2T and hFV-ptA2T.
RESULTS: Surprisingly, our findings showed that the enhanced procoagulant activity of ptFV is mediated by A2T. Using this structural element, ptFV bypassed the need for membrane binding by facilitating productive interactions with venom-derived P textilis FXa and prothrombin in solution. Substituting the human A2T for the corresponding region in ptFV enabled human FVa to function in the absence of membranes, in a similar fashion to P textilis FVa (ptFVa), although this required complex formation with venom-derived P textilis FXa, suggesting the presence of an essential element in the venom protease. In addition, we observed that the ptFV A2T region significantly contributed to functional activated protein C resistance. Unlike mammalian FVa, a ptFVa variant of the human FV A2T retained structural integrity despite loss of cofactor function.
CONCLUSION: Taken together, ptFV A2T is an exceptional structural element that drives the enhanced procoagulant functions underlying the snake venom's extreme toxicity.
OBJECTIVES: In this study, we generated chimeric FV variants to elucidate the functional relevance of this extended structural region.
METHODS: The ptFV A2T was exchanged for the homologous human FV region and vice versa, generating ptFV-hA2T and hFV-ptA2T.
RESULTS: Surprisingly, our findings showed that the enhanced procoagulant activity of ptFV is mediated by A2T. Using this structural element, ptFV bypassed the need for membrane binding by facilitating productive interactions with venom-derived P textilis FXa and prothrombin in solution. Substituting the human A2T for the corresponding region in ptFV enabled human FVa to function in the absence of membranes, in a similar fashion to P textilis FVa (ptFVa), although this required complex formation with venom-derived P textilis FXa, suggesting the presence of an essential element in the venom protease. In addition, we observed that the ptFV A2T region significantly contributed to functional activated protein C resistance. Unlike mammalian FVa, a ptFVa variant of the human FV A2T retained structural integrity despite loss of cofactor function.
CONCLUSION: Taken together, ptFV A2T is an exceptional structural element that drives the enhanced procoagulant functions underlying the snake venom's extreme toxicity.