9EZC

Structure of the extracellular subdomain of a homomeric LRRC8C truncation disease mutant

9EZC の概要

• エントリーDOI: 10.2210/pdb9ezc/pdb
• EMDBエントリー: 50072
• 分子名称: Volume-regulated anion channel subunit LRRC8C (1 entity in total)
• 機能のキーワード: anion channel, volume regulation, disease mutation, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 334039.59

構造登録者

Rutz, S.,Quinodoz, M.,Peter, V.,Garavelli, L.,Innes, M.A.,Kellenberger, S.,Peng, Z.,Barone, A.,Campos-Xavier, B.,Unger, S.,Rivolta, C.,Dutzler, R.,Superti-Furga, A. (登録日: 2024-04-11, 公開日: 2024-11-13, 最終更新日: 2025-06-04)

主引用文献

Quinodoz, M.,Rutz, S.,Peter, V.,Garavelli, L.,Innes, A.M.,Lehmann, E.F.,Kellenberger, S.,Peng, Z.,Barone, A.,Campos-Xavier, B.,Unger, S.,Rivolta, C.,Dutzler, R.,Superti-Furga, A.
De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder.
Embo J., 44:413-436, 2025

PubMed Abstract: Volume-regulated anion channels (VRACs) are multimeric proteins composed of different paralogs of the LRRC8 family. They are activated in response to hypotonic swelling, but little is known about their specific functions. We studied two human individuals with the same congenital syndrome affecting blood vessels, brain, eyes, and bones. The LRRC8C gene harbored de novo variants in both patients, located in a region of the gene encoding the boundary between the pore and a cytoplasmic domain, which is depleted of sequence variations in control subjects. When studied by cryo-EM, both LRRC8C mutant proteins assembled as their wild-type counterparts, but showed increased flexibility, suggesting a destabilization of subunit interactions. When co-expressed with the obligatory LRRC8A subunit, the mutants exhibited enhanced activation, resulting in channel activity even at isotonic conditions in which wild-type channels are closed. We conclude that structural perturbations of LRRC8C impair channel gating and constitute the mechanistic basis of the dominant gain-of-function effect of these pathogenic variants. The pleiotropic phenotype of this novel clinical entity associated with monoallelic LRRC8C variants indicates the fundamental roles of VRACs in different tissues and organs.

PubMed: 39623139
DOI: 10.1038/s44318-024-00322-y

実験手法

ELECTRON MICROSCOPY (3.41 Å)