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<p>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 <i>KCNQ1</i> and <i>KCNE1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月2日

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

摘要

The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (IKs) 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 KCNQ1APO, 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 IKs gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during IKs 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 IKs function and provides a foundation for developing targeted LQTS therapy.