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- Title
A general mechanism of KCNE1 modulation of KCNQ1 channels involving non-canonical VSD-PD coupling.
- Authors
Wu, Xiaoan; Perez, Marta E.; Noskov, Sergei Yu; Larsson, H. Peter
- 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. Wu et al. demonstrate that KCNE1 exerts its effects on potassium channel KCNQ1 function by regulating the coupling between the voltage-sensing domain and pore domain via KCNE1-induced rotation. As a consequence of this rotation, residue clashes occur that prohibit the formation of a conductive intermediate state conformation of the voltage sensor.
- Subjects
HEART cells; GENETIC mutation; POTASSIUM channels; VOLTAGE-sensitive dyes; ION channels
- Publication
Communications Biology, 2021, Vol 4, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-021-02418-1