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Cryo-EM structure of the volume-regulated anion channel LRRC8D isoform identifies features important for substrate permeation.

<div class='caption-title'>Overall structure and subunit interactions of the HsLRRC8D hexamer.</div>
<div class='caption-title'>Comparisons of the HsLRRC8D and HsLRRC8A structures.</div>
<div class='caption-title'>Role of pore constriction in anion selectivity.</div>
Nakamura R, Numata T, Kasuya G, Yokoyama T, Nishizawa T, Kusakizako T, Kato T, Hagino T, Dohmae N, Inoue M, Watanabe K, Ichijo H, Kikkawa M, Shirouzu M, Jentsch TJ, Ishitani R, Okada Y, Nureki O
OpenAccess logo Commun Biol 3 240 (2020)
Cited: 27 times
EuropePMC logo PMID: 32415200

Abstract

Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of the five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC). LRRC8A and at least one of the other LRRC8 isoforms assemble into heteromers to generate VRAC transport activities. Despite the availability of the LRRC8A structures, the structural basis of how LRRC8 isoforms other than LRRC8A contribute to the functional diversity of VRAC has remained elusive. Here, we present the structure of the human LRRC8D isoform, which enables the permeation of organic substrates through VRAC. The LRRC8D homo-hexamer structure displays a two-fold symmetric arrangement, and together with a structure-based electrophysiological analysis, revealed two key features. The pore constriction on the extracellular side is wider than that in the LRRC8A structures, which may explain the increased permeability of organic substrates. Furthermore, an N-terminal helix protrudes into the pore from the intracellular side and may be critical for gating.

Reviews - 6m04 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 - 6m04 mentioned but not cited (3)



Reviews citing this publication (9)

  1. 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)
  2. 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)
  3. 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)
  4. cGAMP the travelling messenger. Blest HTW, Chauveau L. Front Immunol 14 1150705 (2023)
  5. 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)
  6. 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)
  7. 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)
  8. 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)
  9. 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 (13)



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