TY - JOUR
T1 - Closing In on the Resting State of the Shaker K+ Channel
AU - Pathak, Medha M.
AU - Yarov-Yarovoy, Vladimir
AU - Agarwal, Gautam
AU - Roux, Benoît
AU - Barth, Patrick
AU - Kohout, Susy
AU - Tombola, Francesco
AU - Isacoff, Ehud Y.
N1 - Funding Information:
We gratefully acknowledge Lisa Kurtz for invaluable help with molecular biology and preliminary data collection; Sandra Wiese for excellent molecular biology assistance; Chris Gandhi, David Baker, Jacqui Gulbis, and William A. Catterall for many helpful discussions; and Laura Gonzalez for making the movies. This work was supported by NIH Grant R01NS035549 (to E.Y.I.), NIMH Career Development Research Grant K01 MH67625 (to V.Y.-Y.), an American Heart Association postdoctoral fellowship (to F.T.), and NIH Grant GM-62342 (to B.R.). In addition, V.Y.-Y.'s work was supported in part by NIH Grant R01 NS15751 (to William A. Catterall).
PY - 2007/10/4
Y1 - 2007/10/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2007.09.023
DO - 10.1016/j.neuron.2007.09.023
M3 - Article
C2 - 17920020
AN - SCOPUS:34748848687
SN - 0896-6273
VL - 56
SP - 124
EP - 140
JO - Neuron
JF - Neuron
IS - 1
ER -