title: Structural basis for gating charge movement in the voltage sensor of a sodium channel.
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 3(10)-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.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.forename: Paul G
authors.initials: PG
authors.lastname: DeCaen
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Westenbroek
authors.forename: Chien-Yuan
authors.initials: CY
authors.lastname: Pan
authors.forename: Todd
authors.initials: T
authors.lastname: Scheuer
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D003461:Crystallography; D004574:Electromagnetic Fields; D004594:Electrophysiology; D006860:Hydrogen Bonding; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015222:Sodium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C443666:NaChBac protein, bacteria; D015222:Sodium Channels; D001120:Arginine