Structure and function of the voltage sensor of sodium channels probed by a beta-scorpion toxin.: Voltage Sensor of Sodium Channels Probed by a β-Scorpion Toxin

Sandrine Cestèle 1 Vladimir Yarov-Yarovoy 1 Yusheng Qu 1 François Sampieri 2 Todd Scheuer 1 William Catterall 1, *
* Auteur correspondant
1 Department of Pharmacology
2 IP - Ingénierie des protéines
Abstract : Voltage sensing by voltage-gated sodium channels determines the electrical excitability of cells, but the molecular mechanism is unknown. beta-Scorpion toxins bind specifically to neurotoxin receptor site 4 and induce a negative shift in the voltage dependence of activation through a voltage sensor-trapping mechanism. Kinetic analysis showed that beta-scorpion toxin binds to the resting state, and subsequently the bound toxin traps the voltage sensor in the activated state in a voltage-dependent but concentration-independent manner. The rate of voltage sensor trapping can be fit by a two-step model, in which the first step is voltage-dependent and correlates with the outward gating movement of the IIS4 segment, whereas the second step is voltage-independent and results in shifted voltage dependence of activation of the channel. Mutations of Glu(779) in extracellular loop IIS1-S2 and both Glu(837) and Leu(840) in extracellular loop IIS3-S4 reduce the binding affinity of beta-scorpion toxin. Mutations of positively charged and hydrophobic amino acid residues in the IIS4 segment do not affect beta-scorpion toxin binding but alter voltage dependence of activation and enhance beta-scorpion toxin action. Structural modeling with the Rosetta algorithm yielded a three-dimensional model of the toxin-receptor complex with the IIS4 voltage sensor at the extracellular surface. Our results provide mechanistic and structural insight into the voltage sensor-trapping mode of scorpion toxin action, define the position of the voltage sensor in the resting state of the sodium channel, and favor voltage-sensing models in which the S4 segment spans the membrane in both resting and activated states.
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Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2006, 281 (30), pp.21332-44. 〈10.1074/jbc.M603814200〉
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Sandrine Cestèle, Vladimir Yarov-Yarovoy, Yusheng Qu, François Sampieri, Todd Scheuer, et al.. Structure and function of the voltage sensor of sodium channels probed by a beta-scorpion toxin.: Voltage Sensor of Sodium Channels Probed by a β-Scorpion Toxin. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2006, 281 (30), pp.21332-44. 〈10.1074/jbc.M603814200〉. 〈inserm-00381701〉

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