A general mechanism of KCNE1 modulation of KCNQ1 channels involving non-canonical VSD-PD coupling

Xiaoan Wu,Marta E Perez,H Peter Larsson,Sergei Yu Noskov

doi:10.1038/s42003-021-02418-1

Xiaoan Wu, Marta E Perez + Show 2 more

Open Access

https://doi.org/10.1038/s42003-021-02418-1

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Journal: Communications Biology	Publication Date: Jul 20, 2021
Citations: 4	License type: open-access

Affiliation: University of Miami, University of Calgary

Abstract

Voltage-gated KCNQ1 channels contain four separate voltage-sensing domains (VSDs) and a pore domain (PD). KCNQ1 expressed alone opens when the VSDs are in an intermediate state. In cardiomyocytes, KCNQ1 co-expressed with KCNE1 opens mainly when the VSDs are in a fully activated state. KCNE1 also drastically slows the opening of KCNQ1 channels and shifts the voltage dependence of opening by >40 mV. We here show that mutations of conserved residues at the VSD–PD interface alter the VSD–PD coupling so that the mutant KCNQ1/KCNE1 channels open in the intermediate VSD state. Using recent structures of KCNQ1 and KCNE beta subunits in different states, we present a mechanism by which KCNE1 rotates the VSD relative to the PD and affects the VSD–PD coupling of KCNQ1 channels in a non-canonical way, forcing KCNQ1/KCNE1 channels to open in the fully-activated VSD state. This would explain many of the KCNE1-induced effects on KCNQ1 channels.

Highlights

Voltage-gated KCNQ1 channels contain four separate voltage-sensing domains (VSDs) and a pore domain (PD)
A canonical mechanism proposed for Kv channels is generally based on that the interactions between the S4–S5 linker and the cytoplasmic end of the PD form the VSD–PD coupling and that the outward displacement of S4 segment pulls on the S4–S5 linker, which moves the lower end of S6 and opens the channel[17,18]
Utilizing mutant cycle analysis (MCA), we find that functional interactions at the interface between S4 and S5 are formed in KCNQ1 channels only in the presence of KCNE1, suggesting that KCNE1 modifies the KCNQ1 channel by altering VSD–PD interactions

Summary

Introduction

Voltage-gated KCNQ1 channels contain four separate voltage-sensing domains (VSDs) and a pore domain (PD). Using recent structures of KCNQ1 and KCNE beta subunits in different states, we present a mechanism by which KCNE1 rotates the VSD relative to the PD and affects the VSD–PD coupling of KCNQ1 channels in a non-canonical way, forcing KCNQ1/KCNE1 channels to open in the fully-activated VSD state. KCNE1 association induces a larger current amplitude and singlechannel conductance, as well as the elimination of the inactivation in the KCNQ1 channel[10,11] In sharp contrast, another auxiliary beta-subunit KCNE3 removes the voltage dependence of KCNQ1 current activation, locking the channel open in the physiological voltage range[12]. One possible explanation could be that KCNE1 suppresses the intermediate-open (IO) state of KCNQ1 such that KCNQ1/

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