Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating

The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (I<sub>Ks</sub>) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5-3.4 Å) structures of human KCNQ1<sub>APO</sub>, and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4-S5 linker, maintaining a loop conformation during I<sub>Ks</sub> gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during I<sub>Ks</sub> gating. These structural rearrangements: (1) stabilize the closed pore and the conformation of the intermediate state voltage-sensing domain, thereby determining channel gating, ion permeation, and single-channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4-S5 linker, KCNE1, and the adjacent S6', stabilizing channel opening; (3) create a fenestration capable of binding compounds specific for KCNQ1 + KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes I<sub>Ks</sub> function and provides a foundation for developing targeted LQTS therapy.

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Journal
Cell Research
Published
2025-10-02
DOI
https://doi.org/10.1038/s41422-025-01182-9
Citations
5
Primary Topic
Cardiac electrophysiology and arrhythmias
Type
article
Field-Weighted Citation Impact
6.94

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Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating

Fengjiao Liu, Vincent Kam Wai Wong, Bing Shen, Xinyu Cheng et al.
5 citations
Cell Research
Cardiac electrophysiology and arrhythmias
6.94
article

Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating

Fengjiao Liu, Vincent Kam Wai Wong, Bing Shen, Xinyu Cheng, Zhuo Zhou, Panpan Hou, Xiaoqing Lin, Erwin Neher, Zhi‐Hong Jiang, Weiwei Nan, Zhenzhen Yan, Bin Hu, Wandi Zhu, Frank Noé, Dexiang Jiang, Chen Huang, Yi Mou, Qiansen Zhang, Huaiyu Yang, Zihan Zhou, Jin Zhang, Haijie Yu, Ling Zhong, Shuangyan Wan, Lijuan Ma, Sookja Kim Chung, Hangyu Zhang, Chenxin Xiao, Xiangjun Peng, Yaoguang Hua
article en
5 citations

Abstract

The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (I<sub>Ks</sub>) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5-3.4 Å) structures of human KCNQ1<sub>APO</sub>, and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4-S5 linker, maintaining a loop conformation during I<sub>Ks</sub> gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during I<sub>Ks</sub> gating. These structural rearrangements: (1) stabilize the closed pore and the conformation of the intermediate state voltage-sensing domain, thereby determining channel gating, ion permeation, and single-channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4-S5 linker, KCNE1, and the adjacent S6', stabilizing channel opening; (3) create a fenestration capable of binding compounds specific for KCNQ1 + KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes I<sub>Ks</sub> function and provides a foundation for developing targeted LQTS therapy.

Cell ResearchVol. 35(11)
Macau University of Science and Technology (MO), University of Macau (MO), State Administration of Traditional Chinese Medicine of the People's Republic of China (CN), Jiangxi Provincial Academy of Medical Sciences (CN), First Affiliated Hospital of Jiangxi Medical College (CN), Gannan Medical University (CN), Drug Discovery Laboratory (Norway) (NO), The Ohio State University (US), East China Normal University (CN), Freie Universität Berlin (DE), University of Hong Kong (HK), Tsinghua University (CN)
American Heart Association, National Natural Science Foundation of China, Natural Science Foundation of Jiangxi Province, Education Department of Jiangxi Province, Macau University of Science and Technology
Openalex Percentile: Top 3%
Cardiac electrophysiology and arrhythmias
6.94
DOIOpen Access PDFOpenAlex
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