Center for Structural Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United States; Institute for Drug Discovery, Leipzig University, Leipzig, Germany
Carlos G Vanoye
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States
Reshma R Desai
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States
Sneha Adusumilli
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States
Kathryn R Brewer
Center for Structural Biology, Vanderbilt University, Nashville, United States; Department of Biochemistry, Vanderbilt University, Nashville, United States
Hope Woods
Center for Structural Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United States
Center for Structural Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United States
Center for Structural Biology, Vanderbilt University, Nashville, United States; Department of Biochemistry, Vanderbilt University, Nashville, United States
Alfred L George Jr
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States
Jens Meiler
Center for Structural Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United States; Institute for Drug Discovery, Leipzig University, Leipzig, Germany; Department of Pharmacology, Vanderbilt University, Nashville, United States
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.
