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

Hou, P.; Kang, P. W.; Deyawe Kongmeneck, A.; Yang, N.-D.; Liu, Y.; Shi, J.; Xu, X.; White, K. M.; Zaydman, M. A.; Kasimova, M. A.; Seebohm, G.; Zhong, L.; Zou, X.; Tarek, M.; Cui, J.

doi:10.1101/798207

bioRxiv · 10.1101/798207

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

Hou, P.·Kang, P. W.·Deyawe Kongmeneck, A.·Yang, N.-D.·Liu, Y.·Shi, J.·Xu, X.·White, K. M.·Zaydman, M. A.·Kasimova, M. A.·Seebohm, G.·Zhong, L.·Zou, X.·Tarek, M.·Cui, J.

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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, we leverage KV7.1s unique two open states associated with the VSD adopting the intermediate and activated conformations to 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 on to the fully-activated state, the elbow-like hinge between S4 and S4-S5L engages with the pore 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 KV channels.

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Hou, P., Kang, P. W., Deyawe Kongmeneck, A., Yang, N.-D., Liu, Y., Shi, J., Xu, X., White, K. M., Zaydman, M. A., Kasimova, M. A., Seebohm, G., Zhong, L., Zou, X., Tarek, M., Cui, J.. 2019-10-09. Two-stage electro-mechanical coupling of a Kv channel in voltage-dependent activation. https://doi.org/10.1101/798207

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