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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
Nat Struct Mol Biol (2023)
Related entries: 8dr8, 8dra, 8dre, 8drk, 8dro, 8drq, 8ds3, 8ds9, 8dsa, 8f74, 8f75, 8f77, 8f79, 8f7b, 8f7d, 8f7e, 8f7j

Cited: 7 times
EuropePMC logo PMID: 36928458

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.

Reviews citing this publication (1)

  1. 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)

Articles citing this publication (6)

  1. Structure of a volume-regulated heteromeric LRRC8A/C channel. Rutz S, Deneka D, Dittmann A, Sawicka M, Dutzler R. Nat Struct Mol Biol 30 52-61 (2023)
  2. Cryo-EM structures of an LRRC8 chimera with native functional properties reveal heptameric assembly. Takahashi H, Yamada T, Denton JS, Strange K, Karakas E. Elife 12 e82431 (2023)
  3. Insights into stoichiometry and gating of heteromeric LRRC8A-LRRC8C volume-regulated anion channels. Hagino T, Qiu Z. Nat Struct Mol Biol 30 714-716 (2023)
  4. Mechanically-primed voltage-gated proton channels from angiosperm plants. Zhao C, Webster PD, De Angeli A, Tombola F. Nat Commun 14 7515 (2023)
  5. Structural insights into anion selectivity and activation mechanism of LRRC8 volume-regulated anion channels. Liu H, Polovitskaya MM, Yang L, Li M, Li H, Han Z, Wu J, Zhang Q, Jentsch TJ, Liao J. Cell Rep 42 112926 (2023)
  6. Trends in volume-regulated anion channel (VRAC) research: visualization and bibliometric analysis from 2014 to 2022. Liu T, Li Y, Wang D, Stauber T, Zhao J. Front Pharmacol 14 1234885 (2023)


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