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| Item Type: | Article |
|---|---|
| Title: | Molecular basis of ClC-6 function and its impairment in human disease |
| Creators Name: | Zhang, B., Zhang, S., Polovitskaya, M.M., Yi, J., Ye, B., Li, R., Huang, X., Yin, J., Neuens, S., Balfroid, T., Soblet, J., Vens, D., Aeby, A., Li, X., Cai, J., Song, Y., Li, Y., Tartaglia, M., Li, Y., Jentsch, T.J., 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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