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Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5

文献类型：期刊论文

作者Yang, Zhenni2,12,13; Zheng, Yueming2,10,11,13; Ma, Demin2,13; Wang, Long; Zhang, Jiatong2,12,13; Song, Tiefeng2,3,13; Wang, Yong2,3,13; Zhang, Yan2,12,13; Nan, Fajun10,11; Su, Nannan4
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2025-04-08
卷号122期号:14页码:11
关键词KCNQ PIP2 ligand activation structure mechanism
ISSN号0027-8424
DOI10.1073/pnas.2416738122
英文摘要The human voltage-gated potassium channels KCNQ2, KCNQ3, and KCNQ5 can form homo-and heterotetrameric channels that are responsible for generating the neuronal M current and maintaining the membrane potential stable. Activation of KCNQ channels requires both the depolarization of membrane potential and phosphatidylinositol 4,5-bisphosphate (PIP2). Here, we report cryoelectron microscopy structures of the human KCNQ5-calmodulin (CaM) complex in the apo, PIP2-bound, and both PIP2-and the activator HN37-bound states in either a closed or an open conformation. In the closed conformation, a PIP2 molecule binds in the middle of the groove between two adjacent voltage-sensing domains (VSDs), whereas in the open conformation, one additional PIP2 binds to the interface of VSD and the pore domain, accompanying structural rearrangement of the cytosolic domain of KCNQ and CaM. The structures, along with electrophysiology analyses, reveal the two different binding modes of PIP2 and elucidate the PIP2 activation mechanism of KCNQ5.
WOS关键词POTASSIUM CHANNEL GENE ; VOLTAGE-SENSOR ; INOSITOL TRISPHOSPHATE ; PIP2 ; MODULATION ; MEMBRANE ; ANTICONVULSANT ; EXCITABILITY ; CYTOSKELETON ; CONTRIBUTE
资助项目National Key Research and Development Program of China[2020YFA0908501] ; National Natural Science Foundation of China[32371204] ; National Science Fund for Distinguished Young Scholars[81825021] ; National Science and Technology Innovation 2030 Major Program[2021ZD0200900] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2020284] ; Ministry of Education Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University ; Fundamental Research Funds for the Central Universities ; K.C. Wong Education Foundation ; [92169202]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001466171200001
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/317410]  
专题新药研究国家重点实验室
通讯作者Su, Nannan; Gao, Zhaobing; Guo, Jiangtao
作者单位1.Zhejiang Univ, Frontier Sci Ctr Brain Sci & Brain Machine Integra, Sch Brain Sci & Brain Med, Chinese Acad Med Sci,Key Lab Med Neurobiol,Minist, Hangzhou 310058, Zhejiang, Peoples R China
2.Zhejiang Univ, Affiliated Hosp 4, Sch Med, Dept Biophys, Hangzhou 310058, Zhejiang, Peoples R China
3.Zhejiang Univ, Coll Life Sci, Hangzhou 310058, Zhejiang, Peoples R China
4.Zhejiang Univ, Affiliated Hosp 4, Int Inst Med, Sch Med, Yiwu 322000, Zhejiang, Peoples R China
5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Guangdong, Peoples R China
6.Zhejiang Univ, Med Ctr, Liangzhu Lab, Hangzhou 311121, Zhejiang, Peoples R China
7.Zhejiang Univ, Sch Brain Sci & Brain Med, Natl Hlth Commiss, Hangzhou 310058, Zhejiang, Peoples R China
8.Zhejiang Univ, Coll Life Sci, State Key Lab Plant Environm Resilience, Hangzhou 310058, Zhejiang, Peoples R China
9.Zhejiang Univ, Canc Ctr, Hangzhou 310058, Zhejiang, Peoples R China
10.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Zhenni,Zheng, Yueming,Ma, Demin,et al. Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2025,122(14):11.
APA Yang, Zhenni.,Zheng, Yueming.,Ma, Demin.,Wang, Long.,Zhang, Jiatong.,...&Guo, Jiangtao.(2025).Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,122(14),11.
MLA Yang, Zhenni,et al."Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 122.14(2025):11.

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来源：上海药物研究所

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