Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation.

Georg Kuenze,Kathryn R Brewer,Carlos G Vanoye,Eli F Mcdonald,Hope Woods,Jens Meiler,Charles R Sanders,Reshma R Desai,Alfred L George,Sneha Adusumilli

doi:10.7554/elife.57680

Georg Kuenze, Kathryn R Brewer + Show 8 more

Open Access

https://doi.org/10.7554/elife.57680

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Abstract

The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3.

Highlights

Voltage-gated K+ (KV) channels facilitate the movement of K+ ions across the lipid bilayer in response to membrane depolarization and are essential for signaling in electrically excitable tissues (Jan and Jan, 2012)
Most restraints were available for the region N-terminal to the KCNE1 TMD (S37-A44) whereas a smaller number of restraints fell within the TMD (L45-L71)
We focused our structural studies on the isolated KCNE1 TMD (including a short stretch of the N-terminal TMD-flanking region (S37-A44)) because previous studies had demonstrated that this domain alone is sufficient to produce the slow activation kinetics and increased current amplitude expected for KCNQ1-KCNE1 channels (Melman et al, 2001)

Summary

Introduction

Voltage-gated K+ (KV) channels facilitate the movement of K+ ions across the lipid bilayer in response to membrane depolarization and are essential for signaling in electrically excitable tissues (Jan and Jan, 2012). Different mechanisms have been proposed to explain how KCNE1 modulates KCNQ1 function including alteration of S4 movement (Nakajo and Kubo, 2007; Rocheleau and Kobertz, 2008; Osteen et al, 2010; Ruscic et al, 2013; Barro-Soria et al, 2014), perturbation of gate opening (Tapper and George, 2001; Melman et al, 2004; Panaghie et al, 2006), changes in VSD-PD coupling (Zaydman et al, 2014; Westhoff et al, 2019), or a combination of these effects Comparison of independently constructed KCNQ1-KCNE1 models with the recently determined structures of the KCNQ1-KCNE3 complex (Sun and MacKinnon, 2020) shows a conserved TMD-binding mode for KCNE1 and KCNE3, but reveals specific differences in the interaction of the activation motif with the channel, consistent with the different effects of these KCNE proteins on channel gating (Barro-Soria et al, 2017). Our results provide more precise information on the state-specific structural requirements and specificity of KCNE subunit interactions with KCNQ1

Results

Discussion

Materials and methods

Funding Funder National Institutes of Health