Two-stage electro–mechanical coupling of a KV channel in voltage-dependent activation

Panpan Hou, Po Wei Kang, Audrey Deyawe Kongmeneck, Nien-Du Yang, Yongfeng Liu, Jingyi Shi, Xianjin Xu, Kelli McFarland White, Mark A. Zaydman, Marina A. Kasimova, Guiscard Seebohm, Ling Zhong, Xiaoqin Zou, Mounir Tarek () and Jianmin Cui ()
Additional contact information
Panpan Hou: Washington University in St. Louis
Po Wei Kang: Washington University in St. Louis
Audrey Deyawe Kongmeneck: Université de Lorraine, CNRS, LPCT
Nien-Du Yang: Washington University in St. Louis
Yongfeng Liu: Washington University in St. Louis
Jingyi Shi: Washington University in St. Louis
Xianjin Xu: University of Missouri – Columbia
Kelli McFarland White: Washington University in St. Louis
Mark A. Zaydman: Washington University School of Medicine
Marina A. Kasimova: Université de Lorraine, CNRS, LPCT
Guiscard Seebohm: University Hospital Münster
Ling Zhong: Washington University in St. Louis
Xiaoqin Zou: University of Missouri – Columbia
Mounir Tarek: Université de Lorraine, CNRS, LPCT
Jianmin Cui: Washington University in St. Louis

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract In voltage-gated potassium (KV) channels, the voltage-sensing domain (VSD) undergoes sequential activation from the resting state to the intermediate state and activated state to trigger pore opening via electro–mechanical (E–M) coupling. However, the spatial and temporal details underlying E–M coupling remain elusive. Here, utilizing KV7.1’s unique two open states, we report a two-stage E–M coupling mechanism in voltage-dependent gating of KV7.1 as triggered by VSD activations to the intermediate and then activated state. When the S4 segment transitions to the intermediate state, the hand-like C-terminus of the VSD-pore linker (S4-S5L) interacts with the pore in the same subunit. When S4 then proceeds to the fully-activated state, the elbow-like hinge between S4 and S4-S5L engages with the pore of the neighboring subunit to activate conductance. This two-stage hand-and-elbow gating mechanism elucidates distinct tissue-specific modulations, pharmacology, and disease pathogenesis of KV7.1, and likely applies to numerous domain-swapped KV channels.

Date: 2020
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DOI: 10.1038/s41467-020-14406-w

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