TY - JOUR
T1 - Two-stage electro–mechanical coupling of a KV channel in voltage-dependent activation
AU - Hou, Panpan
AU - Kang, Po Wei
AU - Kongmeneck, Audrey Deyawe
AU - Yang, Nien Du
AU - Liu, Yongfeng
AU - Shi, Jingyi
AU - Xu, Xianjin
AU - White, Kelli Mc Farland
AU - Zaydman, Mark A.
AU - Kasimova, Marina A.
AU - Seebohm, Guiscard
AU - Zhong, Ling
AU - Zou, Xiaoqin
AU - Tarek, Mounir
AU - Cui, Jianmin
N1 - Funding Information:
The authors thank Prof. Jeanne Nerbonne for helpful discussion. This work was supported by R01 NS092570 and R01 HL126774 to J.C., by R01 GM109980 to X.Z., and by AHA 18POST34030203 to P.H.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078943579&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14406-w
DO - 10.1038/s41467-020-14406-w
M3 - Article
C2 - 32015334
AN - SCOPUS:85078943579
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 676
ER -