Positively selected sites of scorpion depressant toxins: Possible roles in toxin functional divergence

Scorpion depressant toxins represent a distinct pharmacological group of sodium channel neurotoxins, identified by their preferential ability in induction of depressant and flaccid paralysis of insects. However, recent observations that some members in this group exhibit anti-mammal activity raise an interesting evolutionary question of whether it is a consequence of adaptive evolution to the early radiation of mammals on earth. By employing the maximum likelihood method, we provided convincing statistical evidence in favor of positive selection driving the evolution of the depressant toxins, and found that two of three positively selected sites are located on the functional surface of the toxins. A complex model of the scorpion depressant toxin LqhIT2 binding to insect sodium channel α-subunit (DmNav1) was constructed by structural bioinformatics approaches which highlights a possible direct interaction between these two sites and insect sodium channels. Our work presented here thus suggests that accelerated substitutions in these site residues could offer an evolutionary advantage for these toxins to adapt different channels from diverse origins.