二级结构转变和双PIP2结合定义心脏KCNQ1-KCNE1通道门控。

IF 25.9 1区 生物学 Q1 CELL BIOLOGY
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
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引用次数: 0

摘要

KCNQ1 + KCNE1钾通道复合物产生对心脏复极至关重要的缓慢延迟整流电流(IKs)。KCNQ1和KCNE1的功能缺失突变导致1型和5型(LQT1/LQT5)长QT综合征(LQTS),占临床LQTS病例的三分之一以上。尽管之前对KCNQ1和KCNQ1 + KCNE3的结构进行了研究,但KCNQ1 + KCNE1的结构基础仍未得到解决。利用低温电镜和电生理学,我们确定了人类KCNQ1APO和KCNQ1 + KCNE1在关闭和打开状态下的高分辨率(2.5-3.4 Å)结构。KCNE1在三个KCNQ1亚基的界面处占据关键位置,在KCNQ1跨膜片段中诱导6次螺旋到环的转变。其中三个发生在S4-S5连接体的两端,在IKs门控期间保持环构象,而另外三个,在S6和螺旋a中,在IKs门控期间经历动态的螺旋环转变。这些结构重排:(1)稳定封闭孔和中间态电压感应域的构象,从而决定通道门控、离子渗透和单通道电导;(2)启用双PIP2调制机制,其中一个PIP2占据规范位点,而第二个PIP2桥接S4-S5连接器KCNE1和相邻的S6',稳定通道开放;(3)创建一个能够结合KCNQ1 + KCNE1特异性化合物(例如AC-1)的开孔。总之,这些发现揭示了离子通道门控过程中以前未被认识到的大规模二级结构转变,微调IKs功能,并为开发靶向LQTS治疗提供了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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 (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.

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来源期刊
Cell Research
Cell Research 生物-细胞生物学
CiteScore
53.90
自引率
0.70%
发文量
2420
审稿时长
2.3 months
期刊介绍: Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.
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