Independent Origins of Scorpion Toxins Affecting Potassium and Sodium Channels

Abstract

Peptide neurotoxins targeting sodium (Na +) and potassium (K +) channels are two major components of scorpion venom for capturing prey (e.g., insects) and deterring competitors (e.g., small mammals). Although a great amount of information in terms of their sequences, structures and pharmacological functions is available currently, the origin of these toxins remains unsolved. Based on the genomic organization and three-dimensional structure similarities together with close functional relatedness, it has been proposed that these two types of molecules could arise from a common ancestor. However, recent studies have provided convincing experimental evidence in favor of their independent origins, in which an ancestral K + channel toxin firstly evolved from an antibacterial insect defensin-like molecule via a small deletion of the amino-terminal loop (n-loop) to remove steric hindrance between peptide-channel interaction whereas scorpion Na + channel toxins originated from an antifungal drosomycin-like ancestor through the insertion of a small amino-terminal turn and the extension of a carboxyl-terminal tail to reach a new receptor region on the channels, in line with the discovery that drosomycin can bind to the Drosophila's own Na + channels. These studies highlight the importance of insertion/deletion (indel) mutations in toxic origin from ancestral scaffolds of physiological functions.