Structural basis of {alpha}-scorpion toxin action on Nav channels

Fast inactivation of voltage-gated sodium (Nav) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Nav channel alone and in complex with a lethal α-scorpion toxin, AaH2, by electron microscopy, both at 3.5-angstrom resolution. AaH2 wedges into voltage-sensing domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular carboxyl-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a ~13-angstrom translation to unlatch the intracellular fast-inactivation gating machinery. Highlighting the polypharmacology of α-scorpion toxins, AaH2 also targets an unanticipated receptor site on VSD1 and a pore glycan adjacent to VSD4. Overall, this work provides key insights into fast inactivation, electromechanical coupling, and pathogenic mutations in Nav channels.

Source: ScienceNOW - March 20, 2019 Category: Science Authors: Clairfeuille, T., Cloake, A., Infield, D. T., Llongueras, J. P., Arthur, C. P., Li, Z. R., Jian, Y., Martin-Eauclaire, M.-F., Bougis, P. E., Ciferri, C., Ahern, C. A., Bosmans, F., Hackos, D. H., Rohou, A., Payandeh, J. Tags: Biochemistry, Online Only, Physiology r-articles Source Type: news