Molecular requirements for recognition of brain voltage-gated sodium channels by scorpion α-toxins

Roy Kahn, Izhar Karbat, Nitza Ilan, Lior Cohen, Stanislav Sokolov, William A. Catterall, Dalia Gordon, Michael Gurevitz

Research output: Contribution to journalArticlepeer-review

Abstract

The scorpion α-toxin Lqh2 (firqm Leiurus quinquestriatus hebraeus) is active at various mammalian voltage-gated sodium channels (Navs) and is inactive it insect Navs. To resolve the molecular basis of this preference we used the following strategy: 1) Lqh2 was expressed in recombinant form and key residues important for activity at the rat brain channel rNav1.2a were identified by mutagenesis. These residues form a bipartite functional surface made of a conserved "core domain" (residues of the loops connecting the secondary structure elements of the molecule core), and a variable "NC domain" (five-residue turn and the C-tail) as was reported for other scorpion α-toxins. 2) The functional role of the two domains was validated by their stepwise construction on the similar scaffold of the anti-insect toxin LqhαIT. Analysis of the activity of the intermediate constructs highlighted the critical role of Phe15 of the core domain in toxin potency at rNav1.2a, and has suggested that the shape of the NC-domain is important for toxin efficacy. 3) Based on these findings and by comparison with other scorpion α-toxins we were able to eliminate the activity of Lqh2 at rNav1.4 (skeletal muscle), hNav1.5 (cardiac), and rNav1.6 channels, with no hindrance of its activity at Nav.1.1-1.3. These results suggest that by employing a similar approach the design of further target-selective sodium channel modifiers is imminent.

Original languageEnglish
Pages (from-to)20684-20691
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number31
DOIs
StatePublished - 31 Jul 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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