Kartik Sunagar

Marie Curie Fellow


The fascinating world of animal venoms

Venom in Reptiles

Three-fingered PerVERTs in Snake Venoms

         Three-finger toxins (3FTx) represent one of the most abundantly secreted and potently toxic components of Colubridae, Elapidae and Psammophiinae snake venoms. Despite their conserved structural similarity, they exhibit a diversity of biological activities. Although they are theorized to undergo adaptive evolution, the underlying diversification mechanisms remained elusive.

          In our studies on 3FTx, we theorized a correlation between the rapid diversification of 3FTx and the evolution of advanced venom delivery systems (VDS) in Caenophidia, following the evolution of a high pressure, hollow-fanged VDS in Elapidae. We show that Type I, II and III α-neurotoxins have evolved with extreme rapidity under the influence of positive selection. We also show that novel Oxyuranus/Pseudonaja Type II forms lacking the apotypic (ancestral) loop-2 stabilizing cysteine doublet characteristic of Type II forms, are not phylogenetically basal in relation to other Type IIs as previously thought, but are the result of secondary loss of these apotypic cysteines on at least three separate occasions. Not all 3FTxs have evolved rapidly: κ-neurotoxins, which form non-covalently associated heterodimers, have experienced a relatively weaker influence of diversifying selection; while cytotoxic 3FTx, with their functional sites, dispersed over 40% of the molecular surface, have been extremely constrained by negative selection. We show that the a previous theory of 3FTx molecular evolution (termed ASSET) is implausible and cannot account for the considerable variation observed in very short segments of 3FTx. Instead, we proposed a theory of Rapid Accumulation of Variations in Exposed Residues (RAVER; we originally named it PerVERTs for Periodic Variation in Exposed Residues of Toxins, but the term was not approved by the editor :P) to illustrate the significance of point mutations and focal mutagenesis in the evolution and diversification of 3FTx.