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| Item Type: | Article |
|---|---|
| Title: | Structural insights into anion selectivity and activation mechanism of LRRC8 volume-regulated anion channels |
| Creators Name: | Liu, H. and Polovitskaya, M.M. and Yang, L. and Li, M. and Li, H. and Han, Z. and Wu, J. and Zhang, Q. and Jentsch, T.J. and Liao, J. |
| Abstract: | Volume-regulated anion channels (VRACs) are hexamers of LRRC8 proteins that are crucial for cell volume regulation. N termini (NTs) of the obligatory LRRC8A subunit modulate VRACs activation and ion selectivity, but the underlying mechanisms remain poorly understood. Here, we report a 2.8-Å cryo-electron microscopy structure of human LRRC8A that displays well-resolved NTs. Amino-terminal halves of NTs fold back into the pore and constrict the permeation path, thereby determining ion selectivity together with an extracellular selectivity filter with which it works in series. They also interact with pore-surrounding helices and support their compact arrangement. The C-terminal halves of NTs interact with intracellular loops that are crucial for channel activation. Molecular dynamics simulations indicate that low ionic strength increases NT mobility and expands the radial distance between pore-surrounding helices. Our work suggests an unusual pore architecture with two selectivity filters in series and a mechanism for VRAC activation by cell swelling. |
| Keywords: | VSOR, SWELL1, Chloride Channel, N Terminus, Large Pore Channel |
| Source: | Cell Reports |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press / Elsevier |
| Volume: | 42 |
| Number: | 8 |
| Page Range: | 112926 |
| Date: | 29 August 2023 |
| Official Publication: | https://doi.org/10.1016/j.celrep.2023.112926 |
| PubMed: | View item in PubMed |
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