Molecular basis of ClC-6 function and its impairment in human disease

Zhang, Bing1; Zhang, Sensen2; Polovitskaya, Maya M.3,4; Yi, Jingbo2; Ye, Binglu1; Li, Ruochong2; Huang, Xueying1; Yin, Jian2; Neuens, Sebastian5; Balfroid, Tom6; Soblet, Julie5,7,8; Vens, Daphne9; Aeby, Alec6; Li, Xiaoling10; Cai, Jinjin11; Song, Yingcai1; Li, Yuanxi12; Tartaglia, Marco13; Li, Yang11,14; Jentsch, Thomas J.3,4,15; Yang, Maojun2,16; Liu, Zhiqiang1

2023-10-13

10.1126/sciadv.adg4479

SCIENCE ADVANCES   影响因子和分区

2375-2548

ClC-6 is a late endosomal voltage-gated chloride-proton exchanger that is predominantly expressed in the nervous system. Mutated forms of ClC-6 are associated with severe neurological disease. However, the mechanistic role of ClC-6 in normal and pathological states remains largely unknown. Here, we present cryo-EM structures of ClC-6 that guided subsequent functional studies. Previously unrecognized ATP binding to cytosolic ClC-6 domains enhanced ion transport activity. Guided by a disease-causing mutation (p.Y553C), we identified an interaction network formed by Y553/F317/T520 as potential hotspot for disease-causing mutations. This was validated by the identification of a patient with a de novo pathogenic variant p.T520A. Extending these findings, we found contacts between intramembrane helices and connecting loops that modulate the voltage dependence of ClC-6 gating and constitute additional candidate regions for disease-associated gain-of-function mutations. Besides providing insights into the structure, function, and regulation of ClC-6, our work correctly predicts hotspots for CLCN6 mutations in neurodegenerative disorders.

SCI ; EI

英语

通讯

National Key R&D Program of China[2022YFA1302701] ; National Natural Science Foundation of China["32030056","31671049","81771188","81901376","82271582"] ; Tsinghua-Foshan Innovation Special Fund[TFISF-2022THFS6122] ; King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR)[OSR-2020-CRG9-4352] ; National Key New Drug Creation Program of China[2018ZX09711002-002-012] ; Science and Technology Commission of Shanghai Municipality["184319071000","19140903102"] ; Natural Science Foundation of Shanghai[22ZR1449300] ; Program of Shanghai Academic/Technology Research Leader[22XD1402400] ; Deutsche Forschungsgemeinschaft (DFG)[JE164/14-2 (FOR2625)] ; Italian Ministry of Health[EXC-20149-39068087] ; Belgian Kids' Fund for Pediatric Research["RCR-2021-23671215","RCR-2022-23682289"] ; null[23S11900600]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001086506900013

AMER ASSOC ADVANCEMENT SCIENCE

20240715532871

Neurodegenerative diseases

Medicine and Pharmacology:461.6

Web of Science

1.Tongji Univ, Shanghai Matern & Infant Hosp 1, Clin & Translat Res Ctr, Sch Med,Dept Anesthesiol,Shanghai Key Lab Maternal, Shanghai 201204, Peoples R China
2.Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Sch Life Sci, Minist Educ,Key Lab Prot Sci,Beijing Adv Innovat C, Beijing 100084, Peoples R China
3.Leibniz Forschungsinst Mol Pharmakol FMP, D-13125 Berlin, Germany
4.Max Delbruck Ctr Mol Med MDC, D-13125 Berlin, Germany
5.Univ Libre Bruxelles ULB, Hop Univ Enfants Reine Fabiola, Dept Genet, Brussels, Belgium
6.Univ Libre Bruxelles ULB, Hop Univ Enfants Reine Fabiola, Dept Pediat Neurol, Brussels, Belgium
7.Univ Libre Bruxelles ULB, Hop Erasme, Dept Genet, Brussels, Belgium
8.Univ Libre Bruxelles ULB, Interuniv Inst Bioinformat Brussels, Brussels, Belgium
9.Univ Libre Bruxelles ULB, Hop Univ Enfants Reine Fabiola, Pediat Intens Care Unit, Brussels, Belgium
10.Shenyang Pharmaceut Univ, Wuya Coll Innovat, Shenyang 110016, Peoples R China
11.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China
12.East China Univ Sci & Technol, Sch Math, Inst Cognit Neurodynam, Shanghai 200237, Peoples R China
13.IRCCS, Osped Pediat Bambino Gesu, Mol Genet & Funct Genom, I-00146 Rome, Italy
14.Fudan Univ, Huashan Hosp, Natl Clin Res Ctr Aging & Med, Shanghai 200040, Peoples R China
15.Charite Univ Med Berlin, Cluster Excellence, NeuroCure, D-10117 Berlin, Germany
16.Southern Univ Sci & Technol, Cryo Em Facil Ctr, Shenzhen 518055, Guangdong, Peoples R China

Zhang, Bing,Zhang, Sensen,Polovitskaya, Maya M.,et al. Molecular basis of ClC-6 function and its impairment in human disease[J]. SCIENCE ADVANCES,2023,9(41).

Zhang, Bing.,Zhang, Sensen.,Polovitskaya, Maya M..,Yi, Jingbo.,Ye, Binglu.,...&Liu, Zhiqiang.(2023).Molecular basis of ClC-6 function and its impairment in human disease.SCIENCE ADVANCES,9(41).

Zhang, Bing,et al."Molecular basis of ClC-6 function and its impairment in human disease".SCIENCE ADVANCES 9.41(2023).