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| Item Type: | Article |
|---|---|
| Title: | Molecular basis of ClC-6 function and its impairment in human disease |
| Creators Name: | Zhang, B. and Zhang, S. and Polovitskaya, M.M. and Yi, J. and Ye, B. and Li, R. and Huang, X. and Yin, J. and Neuens, S. and Balfroid, T. and Soblet, J. and Vens, D. and Aeby, A. and Li, X. and Cai, J. and Song, Y. and Li, Y. and Tartaglia, M. and Li, Y. and Jentsch, T.J. and Yang, M. and Liu, Z. |
| Abstract: | 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. |
| Keywords: | Chloride Channels, Ion Transport, Mutation, Protons |
| Source: | Science Advances |
| ISSN: | 2375-2548 |
| Publisher: | American Association for the Advancement of Science |
| Volume: | 9 |
| Number: | 41 |
| Page Range: | eadg4479 |
| Date: | 13 October 2023 |
| Official Publication: | https://doi.org/10.1126/sciadv.adg4479 |
| PubMed: | View item in PubMed |
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