气候变化领域集成服务门户(CCPortal): Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies

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DOI	10.1073/PNAS.2100066118
	Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies
	Pan X.; Li Z.; Jin X.; Zhao Y.; Huang G.; Huang X.; Shen Z.; Cao Y.; Dong M.; Lei J.; Yan N.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Among the nine subtypes of human voltage-gated sodium (Nav) channels, the brain and cardiac isoforms, Nav1.1 and Nav1.5, each carry more than 400 missense mutations respectively associated with epilepsy and cardiac disorders. High-resolution structures are required for structure-function relationship dissection of the disease variants. We report the cryo-EM structures of the full-length human Nav1.1-β4 complex at 3.3 Å resolution here and the Nav1.5- E1784K variant in the accompanying paper. Up to 341 and 261 disease-related missense mutations in Nav1.1 and Nav1.5, respectively, are resolved. Comparative structural analysis reveals several clusters of disease mutations that are common to both Nav1.1 and Nav1.5. Among these, the majority of mutations on the extracellular loops above the pore domain and the supporting segments for the selectivity filter may impair structural integrity, while those on the pore domain and the voltage-sensing domains mostly interfere with electromechanical coupling and fast inactivation. Our systematic structural delineation of these mutations provides important insight into their pathogenic mechanism, which will facilitate the development of precise therapeutic interventions against various sodium channelopathies. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cryo-EM structure; Dravet syndrome; Epileptic seizure; Fast inactivation; Nav1.1
语种	英语
scopus关键词	sodium channel Nav1.1; sodium channel Nav1.1 subunit beta 4; sodium channel Nav1.5; unclassified drug; Article; comparative study; cryoelectron microscopy; excitation contraction coupling; gene cluster; gene mutation; genetic variability; HEK293T cell line; human; human cell; missense mutation; mutational analysis; priority journal; seizure; severe myoclonic epilepsy in infancy; sodium channelopathy; structure analysis
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/181175
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; Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, 310024, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, 310024, China; National Institute of Biological Sciences, Beijing, 102206, 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	Pan X.,Li Z.,Jin X.,et al. Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies[J],2021,118(11).
APA	Pan X..,Li Z..,Jin X..,Zhao Y..,Huang G..,...&Yan N..(2021).Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Pan X.,et al."Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).