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Structure of a volume-regulated heteromeric LRRC8A/C channel.

<div class='caption-title'>a, Schematic of the possible distribution of subunits in heteromeric LRRC8A/C channels. Subunits in hexameric channels are represented by circles of different colors. The red box encloses all channel populations containing at least one copy of each subunit. b, Determination of the ratio of LRRC8A to LRRC8C in isolated complexes using LC-MS/MS. Pairwise ratios of LRRC8A peptides relative to LRRC8C peptides were either generated for endogenous LRRC8 protein obtained from HEK293 or LRRC8B,D,E−/− cells or overexpressed protein expressed after transfection with different ratios of DNA coding for LRRC8A and C subunits (that is, at A:C DNA ratios of 1:1 and 1:3). Absolute peptide amounts calculated by spiking each sample with known amounts of stable isotope-labeled peptides were used for ratio determination. Boxplots cover the first and third quartiles from bottom to top, and the whiskers extend to largest/smallest value but no further than 1.5 × IQR (interquartile range). The median ratio is indicated by a black solid line.</div>
<div class='caption-title'>LRRC8C structure.</div>
<div class='caption-title'>Structure of the LRRC8A/C1:1/Sb1 complex.</div>
Rutz S, Deneka D, Dittmann A, Sawicka M, Dutzler R
OpenAccess logo Nat Struct Mol Biol (2022)
Related entries: 8b40, 8b41, 8ben

Cited: 15 times
EuropePMC logo PMID: 36522427

Abstract

Volume-regulated anion channels (VRACs) participate in the cellular response to osmotic swelling. These membrane proteins consist of heteromeric assemblies of LRRC8 subunits, whose compositions determine permeation properties. Although structures of the obligatory LRRC8A, also referred to as SWELL1, have previously defined the architecture of VRACs, the organization of heteromeric channels has remained elusive. Here we have addressed this question by the structural characterization of murine LRRC8A/C channels. Like LRRC8A, these proteins assemble as hexamers. Despite 12 possible arrangements, we find a predominant organization with an A:C ratio of two. In this assembly, four LRRC8A subunits cluster in their preferred conformation observed in homomers, as pairs of closely interacting proteins that stabilize a closed state of the channel. In contrast, the two interacting LRRC8C subunits show a larger flexibility, underlining their role in the destabilization of the tightly packed A subunits, thereby enhancing the activation properties of the protein.

Articles - 8b42 mentioned but not cited (1)

  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)


Reviews citing this publication (2)

  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)
  2. 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 (12)

  1. 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 30 841-852 (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. 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)
  4. Applications of the Microscale Thermophoresis Binding Assay in COVID-19 Research. Nydegger DT, Pujol-Giménez J, Kandasamy P, Vogt B, Hediger MA. Viruses 15 1432 (2023)
  5. Interactomic exploration of LRRC8A in volume-regulated anion channels. Carpanese V, Festa M, Prosdocimi E, Bachmann M, Sadeghi S, Bertelli S, Stein F, Velle A, Abdel-Salam MAL, Romualdi C, Pusch M, Checchetto V. Cell Death Discov 10 299 (2024)
  6. Osmotically Activated Anion Current of Phycomyces Blakesleeanus-Filamentous Fungi Counterpart to Vertebrate Volume Regulated Anion Current. Stevanović KS, Čepkenović B, Križak S, Živić MŽ, Todorović NV. J Fungi (Basel) 9 637 (2023)
  7. Physiological Functions of the Volume-Regulated Anion Channel VRAC/LRRC8 and the Proton-Activated Chloride Channel ASOR/TMEM206. Kostritskaia Y, Klüssendorf M, Pan YE, Hassani Nia F, Kostova S, Stauber T. Handb Exp Pharmacol 283 181-218 (2024)
  8. 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)
  9. Exploring the influence of pore shape on conductance and permeation. Seiferth D, Biggin PC. Biophys J 123 3107-3119 (2024)
  10. 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)
  11. LRRC8/VRAC volume-regulated anion channels are crucial for hearing. Knecht DA, Zeziulia M, Bhavsar MB, Puchkov D, Maier H, Jentsch TJ. J Biol Chem 300 107436 (2024)
  12. Structural features of heteromeric channels composed of CALHM2 and CALHM4 paralogs. Drożdżyk K, Peter M, Dutzler R. Elife 13 RP96138 (2024)


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