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Molecular Description of Scorpion Toxin Interaction with Voltage-Gated Sodium Channels

  • Michael Gurevitz
  • Dalia Gordon
  • Maya Gur Barzilai
  • Roy Kahn
  • Lior Cohen
  • Yehu Moran
  • Noam Zilberberg
  • Oren Froy
  • Hagit Altman-Gueta
  • Michael Turkov
  • Ke Dong
  • Izhar Karbat
Living reference work entry

Abstract

Scorpion alpha and beta toxins interact with voltage-gated sodium channels (Navs) at two pharmacologically distinct sites. Alpha toxins bind at receptor site 3 and inhibit channel inactivation, whereas beta toxins bind at receptor site 4 and shift the voltage-dependent activation toward more hyperpolarizing potentials. The two toxin classes are subdivided to distinct pharmacological groups according to their binding preferences and competition for receptor sites at Nav subtypes. To elucidate the surface of interaction of the two toxin classes with Navs and clarify the molecular basis of varying toxin preferences, an efficient expression system was established. Mutagenesis accompanied by toxicity, binding, and electrophysiological assays, in parallel to determination of the three-dimensional structure using NMR and X-ray crystallography, uncovered the bioactive surfaces of toxin representatives of all pharmacological groups. Exchange of external loops between channels that exhibit marked differences in sensitivity to various toxins accompanied by point mutagenesis highlighted channel determinants that play a role in toxin selectivity. These data were used in further mapping of the brain channel rNav1.2a receptor sites for the beta-toxin Css4 (from Centruroides suffusus suffusus) and the alpha-toxin Lqh2 (from Leiurus quinquestriatus hebraeus). On the basis of channel mutations that affected Css4 activity, the known structure of the toxin and its bioactive surface, and using the structure of a potassium channel as template, a structural model of Css4 interaction with the gating module of domain II was constructed. This initial model was the first step in the identification of part of receptor site 4. In parallel, a swapping and a mutagenesis approach employing the rNav1.2a mammalian and DmNav1 insect Navs and the toxin Lqh2 as a probe were used to search for receptor site 3. The channel mapping along with toxin dissociation assays and double-mutant cycle analyses using toxin and channel mutants identified the gating module of domain IV as the site of interaction with the toxin core domain, thus describing the docking orientation of an alpha toxin at the channel surface.

Keywords

Receptor Site Scorpion Venom Scorpion Toxin Alpha Toxin Galanthus Nivalis Agglutinin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Michael Gurevitz
    • 1
  • Dalia Gordon
    • 1
  • Maya Gur Barzilai
    • 1
  • Roy Kahn
    • 1
  • Lior Cohen
    • 2
  • Yehu Moran
    • 3
  • Noam Zilberberg
    • 4
  • Oren Froy
    • 5
  • Hagit Altman-Gueta
    • 1
  • Michael Turkov
    • 1
  • Ke Dong
    • 6
  • Izhar Karbat
    • 1
  1. 1.Department of Plant Molecular Biology & Ecology, George S. Wise Faculty of Life SciencesTel-Aviv UniversityTel-AvivIsrael
  2. 2.Department of Neurobiology, Silberman Institute of Life SciencesHebrew University of JerusalemJerusalemIsrael
  3. 3.Department of Ecology, Evolution and Behavior, Silberman Institute of Life SciencesHebrew University of JerusalemJerusalemIsrael
  4. 4.Department of Life SciencesBen Gurion UniversityBeer ShevaIsrael
  5. 5.Institute of Biochemistry, Food Science and Nutrition, Faculty of AgricultureThe Hebrew University of JerusalemRehovotIsrael
  6. 6.Department of Entomology and the Genetics and Neuroscience ProgramsMichigan State UniversityEast LansingUSA

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