Molecular basis of ClC-6 function and its impairment in human disease
文献类型：期刊论文
| 作者 | Zhang, Bing16; Zhang, Sensen15; Polovitskaya, Maya M.13,14; Yi, Jingbo15; Ye, Binglu16; Li, Ruochong15; Huang, Xueying16; Yin, Jian15; Neuens, Sebastian12; Balfroid, Tom11 |
| 刊名 | SCIENCE ADVANCES
 |
| 出版日期 | 2023-10-13 |
| 卷号 | 9期号:41页码:15 |
| ISSN号 | 2375-2548 |
| DOI | 10.1126/sciadv.adg4479 |
| 通讯作者 | Tartaglia, Marco(marco.tartaglia@opbg.net) ; Li, Yang(liyang@simm.ac.cn) ; Jentsch, Thomas J.(jentsch@fmp-berlin.de) ; Yang, Maojun(maojunyang@tsinghua.edu.cn) ; Liu, Zhiqiang(liuzhiqiang@51mch.com) |
| 英文摘要 | 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. |
| WOS关键词 | CHLORIDE CHANNEL CLC-1 ; TEMPERATURE-DEPENDENCE ; CONFORMATIONAL-CHANGES ; VOLTAGE-DEPENDENCE ; TRANSPORT ; PROTEINS ; OSTEOPETROSIS ; MUTATIONS ; EXCHANGER ; ANION |
| 资助项目 | National Key R&D Program of China[2022YFA1302701] ; National Natural Science Foundation of China[32030056] ; National Natural Science Foundation of China[31671049] ; National Natural Science Foundation of China[81771188] ; National Natural Science Foundation of China[81901376] ; National Natural Science Foundation of China[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] ; Shanghai Municipal Science and Technology Major Project ; Science and Technology Commission of Shanghai Municipality[184319071000] ; Science and Technology Commission of Shanghai Municipality[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] ; Belgian Kids' Fund for Pediatric Research[RCR-2022-23682289] ; INNOVIRIS.brussels ; Biomedical Engineering Special Program of'Science and Technology Innovation Projects' from Shanghai Science and Technology Commission ; [23S11900600] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:001086506900013 |
| 出版者 | AMER ASSOC ADVANCEMENT SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/307575]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Tartaglia, Marco; Li, Yang; Jentsch, Thomas J.; Yang, Maojun; Liu, Zhiqiang |
| 作者单位 | 1.Southern Univ Sci & Technol, Cryo Em Facil Ctr, Shenzhen 518055, Guangdong, Peoples R China 2.Charite Univ Med Berlin, Cluster Excellence, NeuroCure, D-10117 Berlin, Germany 3.Fudan Univ, Huashan Hosp, Natl Clin Res Ctr Aging & Med, Shanghai 200040, Peoples R China 4.IRCCS, Osped Pediat Bambino Gesu, Mol Genet & Funct Genom, I-00146 Rome, Italy 5.East China Univ Sci & Technol, Sch Math, Inst Cognit Neurodynam, Shanghai 200237, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China 7.Shenyang Pharmaceut Univ, Wuya Coll Innovat, Shenyang 110016, Peoples R China 8.Univ Libre Bruxelles ULB, Hop Univ Enfants Reine Fabiola, Pediat Intens Care Unit, Brussels, Belgium 9.Univ Libre Bruxelles ULB, Interuniv Inst Bioinformat Brussels, Brussels, Belgium 10.Univ Libre Bruxelles ULB, Hop Erasme, Dept Genet, Brussels, Belgium |
| 推荐引用方式 GB/T 7714 | 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):15. |
| APA | 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),15. |
| MLA | Zhang, Bing,et al."Molecular basis of ClC-6 function and its impairment in human disease".SCIENCE ADVANCES 9.41(2023):15. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。