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- PDB-9dxa: LRRC8A:D Conformation 2 -

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Basic information

Entry
Database: PDB / ID: 9dxa
TitleLRRC8A:D Conformation 2
Components
  • Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562
  • Volume-regulated anion channel subunit LRRC8D
KeywordsMEMBRANE PROTEIN / ION CHANNEL / VOLUME-REGULATION
Function / homology
Function and homology information


Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / taurine transmembrane transport / monoatomic anion transmembrane transport / protein hexamerization / cell volume homeostasis ...Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / taurine transmembrane transport / monoatomic anion transmembrane transport / protein hexamerization / cell volume homeostasis / cellular response to osmotic stress / monoatomic anion transport / response to osmotic stress / intracellular glucose homeostasis / monoatomic ion channel complex / positive regulation of myoblast differentiation / chloride transmembrane transport / electron transport chain / positive regulation of insulin secretion / spermatogenesis / electron transfer activity / periplasmic space / iron ion binding / lysosomal membrane / heme binding / endoplasmic reticulum membrane / cell surface / identical protein binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / : / : / Leucine-rich repeat region / Leucine-rich repeat, SDS22-like subfamily / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Leucine rich repeat ...LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / : / : / Leucine-rich repeat region / Leucine-rich repeat, SDS22-like subfamily / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / Soluble cytochrome b562 / Volume-regulated anion channel subunit LRRC8A / Volume-regulated anion channel subunit LRRC8D
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLurie, A. / Brohawn, S.G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)128263 United States
CitationJournal: Nat Commun / Year: 2025
Title: Assembly and lipid-gating of LRRC8A:D volume-regulated anion channels.
Authors: Antony Lurie / Christina A Stephens / David M Kern / Katharine M Henn / Naomi R Latorraca / Stephen G Brohawn /
Abstract: Volume-regulated anion channels (VRACs) are ubiquitously expressed vertebrate ion channels that open in response to hypotonic swelling. VRACs assemble as heteromers of LRRC8A and LRRC8B-E subunits, ...Volume-regulated anion channels (VRACs) are ubiquitously expressed vertebrate ion channels that open in response to hypotonic swelling. VRACs assemble as heteromers of LRRC8A and LRRC8B-E subunits, with different subunit combinations resulting in channels with different properties. Recent studies have described the structures of LRRC8A:C VRACs, but how other VRACs assemble, and which structural features are conserved or variant across channel assemblies remains unknown. Herein, we used cryo-EM to determine structures of a LRRC8A:D VRAC with a 4:2 subunit stoichiometry, which we captured in two conformations. The presence of LRRC8D subunits widens and increases hydrophobicity of the selectivity filter, which may contribute to the unique substrate selectivity of LRRC8D-containing VRACs. The structures reveal lipids bound inside the channel pore, similar to those observed in LRRC8A:C VRACs. We observe that LRRC8D subunit incorporation disrupts packing of the cytoplasmic LRR domains, increasing channel dynamics and opening lateral intersubunit gaps, which we speculate are necessary for pore lipid evacuation and channel activation. Molecular dynamics simulations show that lipids can reside stably within the pore to close the channel. Using electrophysiological experiments, we confirmed that pore lipids block conduction in the closed state, demonstrating that lipid-gating is a general property of VRACs.
History
DepositionOct 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562
B: Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562
C: Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562
D: Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562
E: Volume-regulated anion channel subunit LRRC8D
F: Volume-regulated anion channel subunit LRRC8D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)634,14924
Polymers620,7566
Non-polymers13,39318
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562 / Leucine-rich repeat-containing protein 8A / Protein ebouriffe / ebo / Cytochrome b-562


Mass: 105530.102 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: LRRC8A(BRIL),LRRC8A(BRIL),LRRC8A(BRIL) / Source: (gene. exp.) Mus musculus (house mouse) / Gene: Lrrc8a, Lrrc8, cybC, Z5846, ECs5213 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q80WG5, UniProt: P0ABE8
#2: Protein Volume-regulated anion channel subunit LRRC8D / Leucine-rich repeat-containing protein 5 / Leucine-rich repeat-containing protein 8D


Mass: 99317.867 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Lrrc8d, Lrrc5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8BGR2
#3: Chemical
ChemComp-PEE / 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE


Mass: 744.034 Da / Num. of mol.: 18 / Source method: obtained synthetically / Formula: C41H78NO8P / Comment: DOPE, phospholipid*YM
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: LRRC8A:D channel / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.620 MDa / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 18000 nm / Nominal defocus min: 6000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 46893 / Symmetry type: POINT

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