Duplication of Coagulation Factor Genes and Evolution of Snake Venom Prothrombin Activators

Abstract

Snake venom is a complex mixture of pharmacologically active molecules which are responsible for immobilization, paralysis, death and digestion of prey organisms. This armory of toxins has evolved to target two key systems, namely the neuromuscular and circulatory systems, in order to induce rapid immobilization and death. So far, several hundreds of protein toxins from snake venoms have been purified and characterized. Most of these toxins have been documented to be structurally, and at times functionally, similar to proteins expressed in different tissues of the body. For example, elapid phospholipase A2 toxins are structurally and catalytically similar to mammalian pancreatic phospholipase A2 enzymes (Robin Doley et al. 2009). Similarly, sarafotoxins are structurally and functionally similar to endothelins produced primarily in endothelium (Landan et al. 1991a). Based on such structural and functional similarities, it is hypothesized that toxin proteins are “recruited” from body proteins by gene duplication (Fry 2005). Accordingly, the genes of body proteins are duplicated and modified to have differential and specific expression in venom glands. This phenomenon is broadly termed as “recruitment”. This “recruitment” process of body proteins has not only been observed in snakes but also in various other venomous animals, such as cone snails, spiders, scorpions and sea anemones as well as hematophagous animals (Fry et al. 2009). Although this overarching concept existed in the field of snake venom toxins for decades, there is not much direct molecular evidence for this process of “recruitment”. Our laboratory has extensively characterized prothrombin activators from Australian elapid snake venoms and documented their structural and functional similarity with mammalian plasma coagulation factors. Through systematic, detailed studies, we provided the molecular details of the “recruitment” of venom prothrombin activators from plasma coagulation factors after gene duplication. We also identified several key structural changes that make these prothrombin activators better toxins. In this chapter, we will describe the first molecular evidence for the “recruitment” process and the evolution of prothrombin activators in venoms of Australian elapid snakes.