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Structure of a volume-regulated anion channel of the LRRC8 family.

Deneka D, Sawicka M, Lam AKM, Paulino C, Dutzler R
Nature 558 254-259 (2018)
Related entries: 6fnw, 6g8z, 6g9l

Cited: 99 times
EuropePMC logo PMID: 29769723

Abstract

Volume-regulated anion channels are activated in response to hypotonic stress. These channels are composed of closely related paralogues of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. Here, using cryo-electron microscopy and X-ray crystallography, we determine the structure of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is structurally related to connexin proteins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction. Our work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.

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  7. Beta-Cell Ion Channels and Their Role in Regulating Insulin Secretion. Thompson B, Satin LS. Compr Physiol 11 1-21 (2021)
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  13. Recent Advances in Chemical Biology Using Benzophenones and Diazirines as Radical Precursors. Hassan MM, Olaoye OO. Molecules 25 E2285 (2020)
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  17. 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)
  18. Effects of curcumin on ion channels and pumps: A review. Tabeshpour J, Banaeeyeh S, Eisvand F, Sathyapalan T, Hashemzaei M, Sahebkar A. IUBMB Life 71 812-820 (2019)
  19. The Relationship Between Actin Cytoskeleton and Membrane Transporters in Cisplatin Resistance of Cancer Cells. Shimizu T, Fujii T, Sakai H. Front Cell Dev Biol 8 597835 (2020)
  20. Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson's Disease. Tang T, Jian B, Liu Z. Biomolecules 13 802 (2023)
  21. The Homeostasis of Cartilage Matrix Remodeling and the Regulation of Volume-Sensitive Ion Channel. Deng Z, Chen X, Lin Z, Alahdal M, Wang D, Liu J, Li W. Aging Dis 13 787-800 (2022)
  22. 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)
  23. 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)
  24. 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)
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Articles citing this publication (67)



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