Structure and physiological function of the human KCNQ1 channel voltage sensor intermediate state
- Vanderbilt University, United States
- Washington University in St Louis, United States
- Northwestern University, United States
- University of Alabama in Huntsville, United States
Abstract
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 laevis oocytes 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.
Data availability
The structures determined in this work have been deposited into the Protein Databank (PDB ID 6MIE).NMR data assignments and structural restraints have been deposited in the BioMagResBank (BMRB ID 30517).All electrophysiology and voltage-clamp fluorometry data generated or analysed during this study are included in the manuscript, supporting files, and source data file.
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NMR structure of the KCNQ1 voltage-sensing domainProtein Data Base, 6MIE.
Article and author information
Author details
Funding
National Institutes of Health (R01 HL122010)
- Alfred L George
- Jens Meiler
- Charles R Sanders
National Institutes of Health (R01 NS092570)
- Jianmin Cui
National Institutes of Health (R01 HL126774)
- Jianmin Cui
National Institutes of Health (F32 GM117770)
- Keenan C Taylor
American Heart Association (18POST34030203)
- Panpan Hou
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Merritt Maduke, Stanford University School of Medicine, United States
Ethics
Animal experimentation: Oocytes from Xenopus laevis (frogs) were employed in this work (at Washington University) and the frogs were cared for in accordance with the protocol approved by the Washington University Animal Studies Committee (Protocol # 20190030).
Version history
- Received: November 23, 2019
- Accepted: February 24, 2020
- Accepted Manuscript published: February 25, 2020 (version 1)
- Version of Record published: March 13, 2020 (version 2)
Copyright
© 2020, Taylor et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure and physiological function of the human KCNQ1 channel voltage sensor intermediate state
eLife 9:e53901.
https://doi.org/10.7554/eLife.53901
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