title: Target-Driven Positive Selection at Hot Spots of Scorpion Toxins Uncovers Their Potential in Design of Insecticides.
abstract: Positive selection sites (PSSs), a class of amino acid sites with an excess of nonsynonymous to synonymous substitutions, are indicators of adaptive molecular evolution and have been detected in many protein families involved in a diversity of biological processes by statistical approaches. However, few studies are conducted to evaluate their functional significance and the driving force behind the evolution (i.e., agent of selection). Scorpion α-toxins are a class of multigene family of peptide neurotoxins affecting voltage-gated Na(+ )(Nav) channels, whose members exhibit differential potency and preference for insect and mammalian Nav channels. In this study, we undertook a systematical molecular dissection of nearly all the PSSs newly characterized in the Mesobuthus α-toxin family and a two-residue insertion ((19)AlaPhe(20)) located within a positively selected loop via mutational analysis of α-like MeuNaTxα-5, one member affecting both insect and mammalian Nav channels. This allows to identify hot-spot residues on its functional face involved in interaction with the receptor site of Nav channels, which comprises two PSSs (Ile(40) and Leu(41)) and the small insertion, both located on two spatially separated functional loops. Mutations at these hot-spots resulted in a remarkably decreased anti-mammalian activity in MeuNaTxα-5 with partially impaired or enhanced insecticide activity, suggesting the potential of PSSs in designing promising candidate insecticides from scorpion α-like toxins. Based on an experiment-guided toxin-channel complex model and high evolutionary variability in the receptor site of predators and prey of scorpions, we provide new evidence for target-driven adaptive evolution of scorpion toxins to deal with their targets' diversity.
authors.affiliation: Group of Peptide Biology and Evolution, State Key Laboratory of Integrated Management of Pest Insects & Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Laboratory of Toxicology, University of Leuven, Leuven, Belgium.
authors.forename: Steve
authors.initials: S
authors.lastname: Peigneur
authors.affiliation: Group of Peptide Biology and Evolution, State Key Laboratory of Integrated Management of Pest Insects & Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Group of Peptide Biology and Evolution, State Key Laboratory of Integrated Management of Pest Insects & Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Shangfei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Laboratory of Toxicology, University of Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
authors.affiliation: Group of Peptide Biology and Evolution, State Key Laboratory of Integrated Management of Pest Insects & Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China zhusy@ioz.ac.cn.
authors.forename: Shunyi
authors.initials: S
authors.lastname: Zhu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D005075:Biological Evolution; D003062:Codon; D019143:Evolution, Molecular; D007313:Insecta; D007306:Insecticides / Q000737:chemistry*; D008958:Models, Molecular; D005810:Multigene Family; D010455:Peptides / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D012604:Scorpion Venoms / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D012605:Scorpions; D026941:Sodium Channel Blockers / Q000737:chemistry; D015222:Sodium Channels / Q000235:genetics
chemical_list: D003062:Codon; D007306:Insecticides; D010455:Peptides; D012604:Scorpion Venoms; D026941:Sodium Channel Blockers; D015222:Sodium Channels
keywords: electrophysiological recording; predation; prey; selective agent; sodium channel; toxin-channel complex.