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

Commun Biol

Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA.

Published: July 2021

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292421PMC
http://dx.doi.org/10.1038/s42003-021-02418-1DOI Listing

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