Structure and physiological function of the human KCNQ1 channel voltage sensor intermediate state
Keenan C Taylor,
Po Wei Kang,
Panpan Hou,
Nien-Du Yang,
Georg Kuenze,
Jarrod A Smith,
Jingyi Shi,
Hui Huang,
Kelli McFarland White,
Dungeng Peng,
Alfred L George,
Jens Meiler,
Robert L McFeeters,
Jianmin Cui,
Charles R Sanders
Affiliations
Keenan C Taylor
Department of Biochemistry, Vanderbilt University, Nashville, United States; Center for Structural Biology, Vanderbilt University, Nashville, United States
Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity, and Arrhythmia Center, Washington University in St. Louis, St. Louis, United States
Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity, and Arrhythmia Center, Washington University in St. Louis, St. Louis, United States
Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity, and Arrhythmia Center, Washington University in St. Louis, St. Louis, United States
Georg Kuenze
Center for Structural Biology, Vanderbilt University, Nashville, United States; Departments of Chemistry and Pharmacology, Vanderbilt University, Nashville, United States
Jarrod A Smith
Department of Biochemistry, Vanderbilt University, Nashville, United States; Center for Structural Biology, Vanderbilt University, Nashville, United States
Jingyi Shi
Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity, and Arrhythmia Center, Washington University in St. Louis, St. Louis, United States
Hui Huang
Department of Biochemistry, Vanderbilt University, Nashville, United States; Center for Structural Biology, Vanderbilt University, Nashville, United States
Kelli McFarland White
Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity, and Arrhythmia Center, Washington University in St. Louis, St. Louis, United States
Dungeng Peng
Department of Biochemistry, Vanderbilt University, Nashville, United States; Center for Structural Biology, Vanderbilt University, Nashville, United States; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, United States
Alfred L George
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, United States
Jens Meiler
Center for Structural Biology, Vanderbilt University, Nashville, United States; Departments of Chemistry and Pharmacology, Vanderbilt University, Nashville, United States; Department of Bioinformatics, Vanderbilt University Medical Center, Nashville, United States
Robert L McFeeters
Department of Chemistry, University of Alabama in Huntsville, Huntsville, United States
Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity, and Arrhythmia Center, Washington University in St. Louis, St. Louis, United States
Department of Biochemistry, Vanderbilt University, Nashville, United States; Center for Structural Biology, Vanderbilt University, Nashville, United States; Department of Medicine, Vanderbilt University Medical Center, Nashville, United States
Voltage-gated ion channels feature voltage sensor domains (VSDs) that exist in three distinct conformations during activation: resting, intermediate, and activated. Experimental determination of the structure of a potassium channel VSD in the intermediate state has previously proven elusive. Here, we report and validate the experimental three-dimensional structure of the human KCNQ1 voltage-gated potassium channel VSD in the intermediate state. We also used mutagenesis and electrophysiology in Xenopus laevisoocytes to functionally map the determinants of S4 helix motion during voltage-dependent transition from the intermediate to the activated state. Finally, the physiological relevance of the intermediate state KCNQ1 conductance is demonstrated using voltage-clamp fluorometry. This work illuminates the structure of the VSD intermediate state and demonstrates that intermediate state conductivity contributes to the unusual versatility of KCNQ1, which can function either as the slow delayed rectifier current (IKs) of the cardiac action potential or as a constitutively active epithelial leak current.
