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Structural insights into anion selectivity and activation mechanism of LRRC8 volume-regulated anion channels

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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., Polovitskaya, M.M., Yang, L., Li, M., Li, H., Han, Z., Wu, J., Zhang, Q., 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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