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

<div class='caption-title'>Structure of an LRRC8A-DCPIB complex in lipid nanodiscs.</div>
<div class='caption-title'>Complex purification and reconstitution.</div>
<div class='caption-title'>Representative micrographs from LRRC8A preparations in MSP1E3D1 nanodiscs with DCPIB, digitonin, and MSP2N2 nanodiscs.</div>
Kern DM, Oh S, Hite RK, Brohawn SG
OpenAccess logo Elife 8 (2019)
Related entries: 6nzw, 6nzz

Cited: 57 times
EuropePMC logo PMID: 30775971

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.

Reviews - 6o00 mentioned but not cited (2)

  1. On the molecular nature of large-pore channels. Syrjanen J, Michalski K, Kawate T, Furukawa H. J Mol Biol 433 166994 (2021)
  2. Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8. Kasuya G, Nureki O. Front Pharmacol 13 896532 (2022)

Articles - 6o00 mentioned but not cited (1)



Reviews citing this publication (19)

  1. Biophysics and Structure-Function Relationships of LRRC8-Formed Volume-Regulated Anion Channels. König B, Stauber T. Biophys J 116 1185-1193 (2019)
  2. Chloride Channels in Astrocytes: Structure, Roles in Brain Homeostasis and Implications in Disease. Elorza-Vidal X, Gaitán-Peñas H, Estévez R. Int J Mol Sci 20 E1034 (2019)
  3. Cell Death Induction and Protection by Activation of Ubiquitously Expressed Anion/Cation Channels. Part 1: Roles of VSOR/VRAC in Cell Volume Regulation, Release of Double-Edged Signals and Apoptotic/Necrotic Cell Death. Okada Y, Sabirov RZ, Sato-Numata K, Numata T. Front Cell Dev Biol 8 614040 (2020)
  4. Chloride transport modulators as drug candidates. Verkman AS, Galietta LJV. Am J Physiol Cell Physiol 321 C932-C946 (2021)
  5. Ion Channel Involvement in Tumor Drug Resistance. Altamura C, Gavazzo P, Pusch M, Desaphy JF. J Pers Med 12 210 (2022)
  6. Large Nanodiscs: A Potential Game Changer in Structural Biology of Membrane Protein Complexes and Virus Entry. Padmanabha Das KM, Shih WM, Wagner G, Nasr ML. Front Bioeng Biotechnol 8 539 (2020)
  7. SWELL signalling in adipocytes: can fat 'feel' fat? Gunasekar SK, Xie L, Sah R. Adipocyte 8 223-228 (2019)
  8. The Volume-Regulated Anion Channel in Glioblastoma. Caramia M, Sforna L, Franciolini F, Catacuzzeno L. Cancers (Basel) 11 E307 (2019)
  9. A SWELL time to develop the molecular pharmacology of the volume-regulated anion channel (VRAC). Figueroa EE, Denton JS. Channels (Austin) 16 27-36 (2022)
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  11. Targeting purinergic receptors to suppress the cytokine storm induced by SARS-CoV-2 infection in pulmonary tissue. Leão Batista Simões J, Fornari Basso H, Cristine Kosvoski G, Gavioli J, Marafon F, Elias Assmann C, Barbosa Carvalho F, Dulce Bagatini M. Int Immunopharmacol 100 108150 (2021)
  12. Physiology of the volume-sensitive/regulatory anion channel VSOR/VRAC. Part 1: from its discovery and phenotype characterization to the molecular entity identification. Okada Y. J Physiol Sci 74 3 (2024)
  13. Properties, Structures, and Physiological Roles of Three Types of Anion Channels Molecularly Identified in the 2010's. Okada Y, Sabirov RZ, Merzlyak PG, Numata T, Sato-Numata K. Front Physiol 12 805148 (2021)
  14. Structure-function relationships of the LRRC8 subunits and subdomains of the volume-regulated anion channel (VRAC). Ghouli MR, Fiacco TA, Binder DK. Front Cell Neurosci 16 962714 (2022)
  15. To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say. Chen GL, Li J, Zhang J, Zeng B. Cells 12 1870 (2023)
  16. Molecular Biophysics of Class A G Protein Coupled Receptors-Lipids Interactome at a Glance-Highlights from the A2A Adenosine Receptor. Tzortzini E, Kolocouris A. Biomolecules 13 957 (2023)
  17. Novel Perspective of Cardiovascular Diseases: Volume-Regulatory Anion Channels in the Cell Membrane. Hou L, Liu Y, Sun C, Xu R, Cao G, Wang X. Membranes (Basel) 12 644 (2022)
  18. DNA-nanostructure-templated assembly of planar and curved lipid-bilayer membranes. Elbahnasawy MA, Nasr ML. Front Chem 10 1047874 (2022)
  19. Physiology of the volume-sensitive/regulatory anion channel VSOR/VRAC: part 2: its activation mechanisms and essential roles in organic signal release. Okada Y. J Physiol Sci 74 34 (2024)

Articles citing this publication (35)



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