Journal article
Structural basis of α-scorpion toxin action on Na v channels
Science (American Association for the Advancement of Science), Vol.363(6433), p.1302
03/22/2019
DOI: 10.1126/science.aav8573
PMID: 30733386
Abstract
Fast inactivation of voltage-gated sodium (Na
) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Na
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 Na
channels.
Details
- Title: Subtitle
- Structural basis of α-scorpion toxin action on Na v channels
- Creators
- Thomas Clairfeuille - Department of Structural Biology, Genentech Inc., South San Francisco, CA, USAAlexander Cloake - Department of Physics, University of Oxford, Oxford OX1 3PU, UKDaniel T Infield - Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, USAJosé P Llongueras - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USAChristopher P Arthur - Department of Structural Biology, Genentech Inc., South San Francisco, CA, USAZhong Rong Li - Department of Biomolecular Resources, Genentech Inc., South San Francisco, CA, USAYuwen Jian - Department of Neuroscience, Genentech Inc., South San Francisco, CA, USAMarie-France Martin-Eauclaire - Aix Marseille Université, CNRS, LNC, UMR 7291, 13003 Marseille, FrancePierre E Bougis - Aix Marseille Université, CNRS, LNC, UMR 7291, 13003 Marseille, FranceClaudio Ciferri - Department of Structural Biology, Genentech Inc., South San Francisco, CA, USAChristopher A Ahern - Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, USA. christopher-ahern@uiowa.edu frank.bosmans@ugent.be hackos.david@gene.com rohou.alexis@gene.com payandeh.jian@gene.comFrank Bosmans - Department of Basic and Applied Medical Sciences, Ghent University, 9000 Ghent, Belgium. christopher-ahern@uiowa.edu frank.bosmans@ugent.be hackos.david@gene.com rohou.alexis@gene.com payandeh.jian@gene.comDavid H Hackos - Department of Neuroscience, Genentech Inc., South San Francisco, CA, USA. christopher-ahern@uiowa.edu frank.bosmans@ugent.be hackos.david@gene.com rohou.alexis@gene.com payandeh.jian@gene.comAlexis Rohou - Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA. christopher-ahern@uiowa.edu frank.bosmans@ugent.be hackos.david@gene.com rohou.alexis@gene.com payandeh.jian@gene.comJian Payandeh - Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA. christopher-ahern@uiowa.edu frank.bosmans@ugent.be hackos.david@gene.com rohou.alexis@gene.com payandeh.jian@gene.com
- Resource Type
- Journal article
- Publication Details
- Science (American Association for the Advancement of Science), Vol.363(6433), p.1302
- Publisher
- United States
- DOI
- 10.1126/science.aav8573
- PMID
- 30733386
- ISSN
- 0036-8075
- eISSN
- 1095-9203
- Grant note
- R01 GM122420 / NIGMS NIH HHS Howard Hughes Medical Institute. R01 NS091352 / NINDS NIH HHS
- Language
- English
- Date published
- 03/22/2019
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984070673802771
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