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Elife. 2019 Feb 18;8. pii: e42636. doi: 10.7554/eLife.42636.

Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs.

Author information

1
Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United States.
2
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States.
3
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.

Abstract

Hypoosmotic conditions activate volume-regulated anion channels in vertebrate cells. These channels are formed by leucine-rich repeat-containing protein 8 (LRRC8) family members and contain LRRC8A in homo- or hetero-hexameric assemblies. Here, we present single-particle cryo-electron microscopy structures of Mus musculus LRRC8A in complex with the inhibitor DCPIB reconstituted in lipid nanodiscs. DCPIB plugs the channel like a cork in a bottle - binding in the extracellular selectivity filter and sterically occluding ion conduction. Constricted and expanded structures reveal coupled dilation of cytoplasmic LRRs and the channel pore, suggesting a mechanism for channel gating by internal stimuli. Conformational and symmetry differences between LRRC8A structures determined in detergent micelles and lipid bilayers related to reorganization of intersubunit lipid binding sites demonstrate a critical role for the membrane in determining channel structure. These results provide insight into LRRC8 gating and inhibition and the role of lipids in the structure of an ionic-strength sensing ion channel.

KEYWORDS:

LRRC8; VRAC; cryo-EM; ion channel; molecular biophysics; mouse; neuroscience; structural biology; volume regulation

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