EMD-27678

Single-particle
4.12 Å
EMD-27678 Deposition: 21/07/2022
Map released: 08/03/2023
Last modified: 12/06/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-27678

LRRC8A:C conformation 1 (round) LRR focus 1

EMD-27678

Single-particle
4.12 Å
EMD-27678 Deposition: 21/07/2022
Map released: 08/03/2023
Last modified: 12/06/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Mus musculus
Sample: LRRC8A:C
Fitted models: 8drn (Avg. Q-score: 0.258)
Raw data: EMPIAR-11283

Deposition Authors: Kern DM , Brohawn SG
Structural basis for assembly and lipid-mediated gating of LRRC8A:C volume-regulated anion channels.
Kern DM , Bleier J , Mukherjee S , Hill JM , Kossiakoff AA , Isacoff EY , Brohawn SG
(2023) Nat Struct Mol Biol , 30 , 841 - 852
PUBMED: 36928458
DOI: doi:10.1038/s41594-023-00944-6
ISSN: 1545-9985
Abstract:
Leucine-rich repeat-containing protein 8 (LRRC8) family members form volume-regulated anion channels activated by hypoosmotic cell swelling. LRRC8 channels are ubiquitously expressed in vertebrate cells as heteromeric assemblies of LRRC8A (SWELL1) and LRRC8B-E subunits. Channels of different subunit composition have distinct properties that explain the functional diversity of LRRC8 currents across cell types. However, the basis for heteromeric LRRC8 channel assembly and function is unknown. Here we leverage a fiducial-tagging strategy to determine single-particle cryo-EM structures of heterohexameric LRRC8A:C channels in multiple conformations. Compared to homomers, LRRC8A:C channels show pronounced differences in architecture due to heterotypic LRR interactions that displace subunits away from the conduction axis and poise the channel for activation. Structures and functional studies further reveal that lipids embedded in the channel pore block ion conduction in the closed state. These results provide insight into determinants for heteromeric LRRC8 channel assembly, activity and gating by lipids.