Molecular basis of the high insecticidal potency of scorpion α-toxins

Izhar Karbat, Felix Frolow, Oren Froy, Nicolas Gilles, Lior Cohen, Michael Turkov, Dalia Gordon, Michael Gurevitz

Research output: Contribution to journalArticlepeer-review

Abstract

Scorpion α-toxins are similar in their mode of action and three-dimensional structure but differ considerably in affinity for various voltage-gated sodium channels (NaChs). To clarify the molecular basis of the high potency of the α-toxin LqhαIT (from Leiurus quinquestriatus hebraeus) for insect NaChs, we identified by mutagenesis the key residues important for activity. We have found that the functional surface is composed of two distinct domains: a conserved "Core-domain" formed by residues of the loops connecting the secondary structure elements of the molecule core and a variable "NC-domain" formed by a five-residue turn (residues 8-12) and a C-terminal segment (residues 56-64). We further analyzed the role of these domains in toxin activity on insects by their stepwise construction onto the scaffold of the anti-mammalian α-toxin, Aah2 (from Androctonus australis hector). The chimera harboring both domains, Aah2LqhαIT(face), was as active to insects as LqhαIT. Structure determination of Aah2 LqhαIT(face) by x-ray crystallography revealed that the NC-domain deviates from that of Aah2 and forms an extended protrusion off the molecule core as appears in LqhαIT. Notably, such a protrusion is observed in all α-toxins active on insects. Altogether, the division of the functional surface into two domains and the unique configuration of the NC-domain illuminate the molecular basis of α-toxin specificity for insects and suggest a putative binding mechanism to insect NaChs.

Original languageEnglish
Pages (from-to)31679-31686
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number30
DOIs
StatePublished - 23 Jul 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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