Closing In on the Resting State of the Shaker K+ Channel

Medha M. Pathak, Vladimir Yarov-Yarovoy, Gautam Agarwal, Benoît Roux, Patrick Barth, Susy Kohout, Francesco Tombola, Ehud Y. Isacoff

Research output: Contribution to journalArticle

230 Scopus citations

Abstract

Membrane depolarization causes voltage-gated ion channels to transition from a resting/closed conformation to an activated/open conformation. We used voltage-clamp fluorometry to measure protein motion at specific regions of the Shaker Kv channel. This enabled us to construct new structural models of the resting/closed and activated/open states based on the Kv1.2 crystal structure using the Rosetta-Membrane method and molecular dynamics simulations. Our models account for the measured gating charge displacement and suggest a molecular mechanism of activation in which the primary voltage sensors, S4s, rotate by ∼180° as they move "outward" by 6-8 Å. A subsequent tilting motion of the S4s and the pore domain helices, S5s, of all four subunits induces a concerted movement of the channel's S4-S5 linkers and S6 helices, allowing ion conduction. Our models are compatible with a wide body of data and resolve apparent contradictions that previously led to several distinct models of voltage sensing.

Original languageEnglish (US)
Pages (from-to)124-140
Number of pages17
JournalNeuron
Volume56
Issue number1
DOIs
StatePublished - Oct 4 2007
Externally publishedYes

Keywords

  • MOLNEURO
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Neuroscience(all)

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    Pathak, M. M., Yarov-Yarovoy, V., Agarwal, G., Roux, B., Barth, P., Kohout, S., Tombola, F., & Isacoff, E. Y. (2007). Closing In on the Resting State of the Shaker K+ Channel. Neuron, 56(1), 124-140. https://doi.org/10.1016/j.neuron.2007.09.023