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Science 336 (6078): 229-233

Copyright © 2012 by the American Association for the Advancement of Science

Mechanism of Voltage Gating in Potassium Channels

Morten Ø. Jensen1,*, Vishwanath Jogini1, David W. Borhani1, Abba E. Leffler1, Ron O. Dror1, and David E. Shaw1,2,*

1 D. E. Shaw Research, New York, NY 10036, USA.
2 Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.

Figure 1
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Fig. 1. VSD motion during gating. (A) Intracellular views of activated (+V, conducting) and resting (–V, nonconducting) states; dashed lines separate two subunits each of T1 and T1+ resting states. Decrease in pore cavity water molecules (red/blue graph; initially ~40) indicates dewetting and pore hydrophobic closure after ~20 μs at –V. Magnified views: water-filled and empty (closed) cavities; PVP (hydrophobic constriction) motif is purple. Increase of the R1(Q)–Ala351 distance (arrows) explains lack of resting-state interdomain cross-linking (47); both states are compatible with Shaker tryptophan tolerance mutagenesis data (48) (see fig. S3). (B) Sequential inward movement of the VSD S4 gating-charge residues; colored traces track R2 to K5 Cα positions. R2 translates ~15 Å (T1: 15.4 ± 2.5 Å, simulations 5 and 6; T1+: 14.3 ± 0.9 Å, simulation 9), in agreement with KvAP (11, 41) and Shaker (42) accessibility data and resting state-specific cross-linking of Shaker Ile230 (S2) and R1(Q) (49). (C) Local S4 helix rotation of R2 to R4 (simulations 5, 6, and 9). (D) VSD gating-charge displacements, Q(t) = {Sigma}i qi [f(zi,t) – f(zi,0)]. f(z) is the transmembrane fractional potential drop [colored background in (B)]. zi,t is the z position of VSD atom i at time t, qi, partial charge. The total gating charge, 13.3 ± 0.4 e, was estimated as the difference between the final displacements at +V and –V. (Inset) Fractional potential drop across the VSD (18) and gating-charge residue z positions. (E) Cα RMSDs for the entire channel (T1 and T1+), the pore domain, and a single VSD decomposed into S1 to S3a (loops omitted), S3b to S4, and S4 alone. (Inset) Schematic of the full channel.


Figure 2
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Fig. 2. Key steps of voltage-gated K+ channel activation. (A and B ) Deactivation (red), then early activation (blue; first ~120 μs). Paddle Cα RMSD relative to the initial structure, inward and outward S4 gating-charge residue movement, and total gating-charge transfer. (C to H) Late activation (final ~10 μs, after essentially complete gating-charge transfer). (C) Pore cavity rewetting, Leu331 (S5)–Pro405 (S6) side-chain interchange, and cumulative outward K+ permeation events. [(D) and (E)] K+ population of pore cavity and SF. (F) S4-S5 linker/S6 interaction energies. (Insets) S5 and S6 (ribbons), S4-S5 linker (spheres), and S6 (surface) before and after repacking. (G) S4-S5 linker/S6 contacts. (H) Upper gate (Ile402/SF site S5) lateral opening.


Figure 3
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Fig. 3. Mechanistic model for voltage gating. Subjecting the activated state (1) to hyperpolarizing voltage initiates S4 inward movement and VSD–pore loosening. Ion depletion of the pore cavity (2)—coupled to inward motion of a single S4—leads to pore hydrophobic collapse. Closure of upper (Ile402 in Kv1.2) and lower gates [PVP motif; Leu331 (S5)–Pro405 (S6) side-chain interchange (21)] halts conduction (3). S4 continues inward; as S4 completes its inward motion, the S4-S5 linker helix moves fully down and the VSDs loosen from the pore, consolidating the resting state (4). Subjecting the resting state to depolarizing voltage drives S4 outward. When all four S4 and S4-S5 linker helices are fully up (5) and all VSDs repack against the pore, the lower gate becomes destabilized; the 4 -> 5 transition constitutes the rate-limiting step in the activation process. Lower gate fluctuation triggers pore opening and partial pore rehydration (water molecules cooperatively enter the cavity) that allow ion entry and initial outward conduction (6); the 5 -> 6 transition is essentially voltage-independent. The presence of ions drives complete pore rehydration that pushes fully open the upper and lower gates, returning the channel to the activated state (1). The lateral position of the VSDs (circles) relative to the pore domain (squares) is shown schematically (extracellular view).


Figure 4
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Fig. 4. The omega pore. (A and C) Resting-state conformations of chimera and R2Ser mutant VSDs. Spheres in (A) mark residues accessible to chemical modification from the extracellular (yellow) and intracellular (purple) sides in the resting state (42), consistent with ~15 Å S4 inward motion (Fig. 2A). (B) Water and K+ (R2Ser) densities (arbitrary units). The R2Ser mutation increases hydration at Phe233 by ~50%, facilitating K+ permeation. The ion permeation pathway (the omega pore) in the R2Ser mutant is shown as a gray mesh in (C). The green surface and spheres indicate predominant K+ sites and actual positions from a single permeation event; the blue surfaces represent VSD hydration.


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