Two-stage “Hand-and-Elbow” Gating Mechanism of a KV Channel

Abstract

During voltage-dependent activation, the voltage-sensing domain (VSD) of voltage-gated potassium (KV) channels activates in a stepwise manner from the resting state to the intermediate state and activated state, which then trigger pore opening via electro-mechanical (E-M) coupling. However, the spatial and temporal details underlying E-M coupling remain elusive. Leveraging the unique two open states of the KV7.1 channel that are associated with the VSD adopting the intermediate and activated conformations, here we report a two-stage E-M coupling mechanism in KV7.1 as triggered by the two-steps VSD activation. 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 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.