Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Article numbere57680
Pages (from-to)1-30
Number of pages30
JournaleLife
Volume9
DOIs
StatePublished - Oct 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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