气候变化领域集成服务门户(CCPortal): Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome

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DOI	10.1073/PNAS.2100069118
	Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome
	Li Z.; Jin X.; Wu T.; Zhao X.; Wang W.; Lei J.; Pan X.; Yan N.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Nav1.5 is the primary voltage-gated Na+ (Nav) channel in the heart. Mutations of Nav1.5 are associated with various cardiac disorders exemplified by the type 3 long QT syndrome (LQT3) and Brugada syndrome (BrS). E1784K is a common mutation that has been found in both LQT3 and BrS patients. Here we present the cryo-EM structure of the human Nav1.5-E1784K variant at an overall resolution of 3.3 Å. The structure is nearly identical to that of the wild-type human Nav1.5 bound to quinidine. Structural mapping of 91- and 178-point mutations that are respectively associated with LQT3 and BrS reveals a unique distribution pattern for LQT3 mutations. Whereas the BrS mutations spread evenly on the structure, LQT3 mutations are clustered mainly to the segments in repeats III and IV that are involved in gating, voltage-sensing, and particularly inactivation. A mutational hotspot involving the fast inactivation segments is identified and can be mechanistically interpreted by our “door wedge” model for fast inactivation. The structural analysis presented here, with a focus on the impact of mutations on inactivation and late sodium current, establishes a structure-function relationship for the mechanistic understanding of Nav1.5 channelopathies. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Brugada syndrome; Fast inactivation; Long QT syndrome; Nav1.5; Structure-function relationship
语种	英语
scopus关键词	mutant protein; sodium channel Nav1.5; Article; Brugada syndrome; channel gating; controlled study; human; long QT syndrome 3; point mutation; priority journal; protein structure; sodium channelopathy; structure activity relation; structure analysis; wild type
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181174
作者单位	State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China; Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, United States
推荐引用方式 GB/T 7714	Li Z.,Jin X.,Wu T.,et al. Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome[J],2021,118(11).
APA	Li Z..,Jin X..,Wu T..,Zhao X..,Wang W..,...&Yan N..(2021).Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Li Z.,et al."Structure of human Nav1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).