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.
| Original language | English (US) |
|---|---|
| Article number | e57680 |
| Pages (from-to) | 1-30 |
| Number of pages | 30 |
| Journal | eLife |
| Volume | 9 |
| DOIs | |
| State | Published - Oct 2020 |
Funding
This work was supported by NIH grants R01 HL122010 and R01 GM080403. GK was supported by fellowships from the German Research Foundation (KU 3510/1–1) and the American Heart Association (18POST34080422). EFM was supported by NIH training grant T32 GM065086. KRB was supported by NIH training grant T32 GM008320. This work was conducted using the resources of the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University. JM further acknowledges the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through SFB1423, project number 421152132.
ASJC Scopus subject areas
- General Neuroscience
- General Biochemistry, Genetics and Molecular Biology
- General Immunology and Microbiology