Structural basis for gating charge movement in the voltage sensor of a sodium channel

Vladimir Yarov-Yarovoy, Paul G. DeCaen, Ruth E. Westenbroek, Chien Yuan Pan, Todd Scheuer, David Baker, William A. Catterall

Research output: Contribution to journalArticle

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Abstract

Voltage-dependent gating of ion channels is essential for electrical signaling in excitable cells, but the structural basis for voltage sensor function is unknown. We constructed high-resolution structural models of resting, intermediate, and activated states of the voltage-sensing domain of the bacterial sodium channel NaChBac using the Rosetta modeling method, crystal structures of related channels, and experimental data showing state-dependent interactions between the gating charge-carrying arginines in the S4 segment and negatively charged residues in neighboring transmembrane segments. The resulting structural models illustrate a network of ionic and hydrogen-bonding interactions that are made sequentially by the gating charges as they move out under the influence of the electric field. The S4 segment slides 6-8 Å outward through a narrow groove formed by the S1, S2, and S3 segments, rotates -30° , and tilts sideways at a pivot point formed by a highly conserved hydrophobic region near the middle of the voltage sensor. The S4 segment has a 310-helical conformation in the narrow inner gating pore, which allows linear movement of the gating charges across the inner one-half of the membrane. Conformational changes of the intracellular one-half of S4 during activation are rigidly coupled to lateral movement of the S4-S5 linker, which could induce movement of the S5 and S6 segments and open the intracellular gate of the pore. We confirmed the validity of these structural models by comparing with a high-resolution structure of a NaChBac homolog and showing predicted molecular interactions of hydrophobic residues in the S4 segment in disulfide-locking studies.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number2
DOIs
StatePublished - Jan 10 2012

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Sodium Channels
Structural Models
Ion Channel Gating
S 6
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Disulfides
Arginine
Membranes

ASJC Scopus subject areas

  • General

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Structural basis for gating charge movement in the voltage sensor of a sodium channel. / Yarov-Yarovoy, Vladimir; DeCaen, Paul G.; Westenbroek, Ruth E.; Pan, Chien Yuan; Scheuer, Todd; Baker, David; Catterall, William A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 2, 10.01.2012.

Research output: Contribution to journalArticle

Yarov-Yarovoy, Vladimir ; DeCaen, Paul G. ; Westenbroek, Ruth E. ; Pan, Chien Yuan ; Scheuer, Todd ; Baker, David ; Catterall, William A. / Structural basis for gating charge movement in the voltage sensor of a sodium channel. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 2.
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