Abstract
The steep voltage dependence of gating of the voltage-gated Na channel (NaV) is essential for electrical excitability. However, the structural basis of voltage gating mechanisms remains uncertain because the resting state exists only at deeply negative membrane potentials. In the current study, Wisedchaisri et al (Cell 2019;178:993, PMID 31353218) stabilized the resting conformation by inserting voltage-shifting mutations and introduced a disulfide crosslink in the voltage-sensing module (VS) of the ancestral bacterial Na channel NaVAb. The investigators reported a cryo-EM structure of the resting state and a complete voltage-dependent gating mechanism. The S4 segment of the VS is found to be drawn intracellularly, with 3 gating charges passing through the transmembrane electric field. The movement connects S4 to the S4–S5 linker, tightens the collar around the S6 activation gate, and prevents its opening. The authors conclude that the findings support the “sliding helix” mechanism of voltage sensing and provides a gating mechanism for voltage sensor function, pore opening, and activation-gate closure.
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