Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs Journal Article
| Authors: | Kern, D. M.; Oh, S.; Hite, R. K.; Brohawn, S. G. |
| Article Title: | Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs |
| 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. © 2019, Kern et al. |
| Keywords: | mouse; neuroscience; molecular biophysics; cryo-em; ion channel; structural biology; lrrc8; volume regulation; vrac |
| Journal Title: | eLife |
| Volume: | 8 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2019-02-18 |
| Start Page: | e42636 |
| Language: | English |
| DOI: | 10.7554/eLife.42636 |
| PUBMED: | 30775971 |
| PROVIDER: | scopus |
| PMCID: | PMC6395065 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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