Structural insights into anion selectivity and activation mechanism of LRRC8 volume-regulated anion channels.
CP: Molecular biology
N terminus
SWELL1
VSOR
chloride channel
large pore channel
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
29 08 2023
29 08 2023
Historique:
received:
29
12
2022
revised:
12
06
2023
accepted:
18
07
2023
medline:
4
9
2023
pubmed:
6
8
2023
entrez:
6
8
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37543949
pii: S2211-1247(23)00937-3
doi: 10.1016/j.celrep.2023.112926
pmc: PMC10480491
pii:
doi:
Substances chimiques
Membrane Proteins
0
Anions
0
LRRC8A protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
112926Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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