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- EMDB-47282: LRRC8A:D Conformation 1 -

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Basic information

Entry
Database: EMDB / ID: EMD-47282
TitleLRRC8A:D Conformation 1
Map dataSharpened map
Sample
  • Complex: LRRC8A:D channel
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8D
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
KeywordsION CHANNEL / VOLUME-REGULATION / MEMBRANE PROTEIN
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
Soluble cytochrome b562 / Volume-regulated anion channel subunit LRRC8A / Volume-regulated anion channel subunit LRRC8D
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLurie A / Brohawn SG
Funding support United States, 1 items
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 10, 2024-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateDec 24, 2025-
Current statusDec 24, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47282.png

Downloads & links

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Map

FileDownload / File: emd_47282.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 416 pix.
= 435.968 Å		1.05 Å/pix.
x 416 pix.
= 435.968 Å		1.05 Å/pix.
x 416 pix.
= 435.968 Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.048 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.7938673 - 1.5999641
Average (Standard dev.)0.0006359089 (±0.026051298)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 435.968 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Unsharpened map

Fileemd_47282_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

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Half map: Half map B

Fileemd_47282_half_map_1.map
AnnotationHalf map B
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Half map: Half map A

Fileemd_47282_half_map_2.map
AnnotationHalf map A
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Sample components

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Entire : LRRC8A:D channel

EntireName: LRRC8A:D channel
Components
  • Complex: LRRC8A:D channel
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8D
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

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Supramolecule #1: LRRC8A:D channel

SupramoleculeName: LRRC8A:D channel / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 620 KDa

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Macromolecule #1: Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562

MacromoleculeName: Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562
type: protein_or_peptide / ID: 1 / Details: LRRC8A(BRIL),LRRC8A(BRIL),LRRC8A(BRIL) / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 105.530102 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD KMICLPCKWV TKDSCNDSFR GWAASSADLE DNWETLNDN LKVIEKADNA AQVKDALTKM RAAALDAQKA TPPKLEDKSP DSPEMKDFRH GFDILVGQID DALKLANEGK V KEAQAAAE ...String:
MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD KMICLPCKWV TKDSCNDSFR GWAASSADLE DNWETLNDN LKVIEKADNA AQVKDALTKM RAAALDAQKA TPPKLEDKSP DSPEMKDFRH GFDILVGQID DALKLANEGK V KEAQAAAE QLKTTRNAYI QKYLDTGPTG IKYDLDRHQY NYVDAVCYEN RLHWFAKYFP YLVLLHTLIF LACSNFWFKF PR TSSKLEH FVSILLKCFD SPWTTRALSE TVVEESDPKP AFSKMNGSMD KKSSTVSEDV EATVPMLQRT KSRIEQGIVD RSE TGVLDK KEGEQAKALF EKVKKFRTHV EEGDIVYRLY MRQTIIKVIK FALIICYTVY YVHNIKFDVD CTVDIESLTG YRTY RCAHP LATLFKILAS FYISLVIFYG LICMYTLWWM LRRSLKKYSF ESIREESSYS DIPDVKNDFA FMLHLIDQYD PLYSK RFAV FLSEVSENKL RQLNLNNEWT LDKLRQRLTK NAQDKLELHL FMLSGIPDTV FDLVELEVLK LELIPDVTIP PSIAQL TGL KELWLYHTAA KIEAPALAFL RENLRALHIK FTDIKEIPLW IYSLKTLEEL HLTGNLSAEN NRYIVIDGLR ELKRLKV LR LKSNLSKLPQ VVTDVGVHLQ KLSINNEGTK LIVLNSLKKM VNLTELELIR CDLERIPHSI FSLHNLQEID LKDNNLKT I EEIISFQHLH RLTCLKLWYN HIAYIPIQIG NLTNLERLYL NRNKIEKIPT QLFYCRKLRY LDLSHNNLTF LPADIGLLQ NLQNLAVTAN RIEALPPELF QCRKLRALHL GNNVLQSLPS RVGELTNLTQ IELRGNRLEC LPVELGECPL LKRSGLVVEE DLFSTLPPE VKERLWRADK EQASNSLEVL FQ

UniProtKB: Volume-regulated anion channel subunit LRRC8A, Soluble cytochrome b562, Volume-regulated anion channel subunit LRRC8A

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Macromolecule #2: Volume-regulated anion channel subunit LRRC8D

MacromoleculeName: Volume-regulated anion channel subunit LRRC8D / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 99.317867 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MFTLAEVASL NDIQPTYRIL KPWWDVFMDY LAVVMLMVAI FAGTMQLTKD QVVCLPVLPS PANSKAHTPP GNADITTEVP RMETATHQD QNGQTTTNDV AFGTSAVTPD IPLQATHPHA ESTLPNQEAK KEKRDPTGRK TNLDFQQYVF INQMCYHLAL P WYSKYFPY ...String:
MFTLAEVASL NDIQPTYRIL KPWWDVFMDY LAVVMLMVAI FAGTMQLTKD QVVCLPVLPS PANSKAHTPP GNADITTEVP RMETATHQD QNGQTTTNDV AFGTSAVTPD IPLQATHPHA ESTLPNQEAK KEKRDPTGRK TNLDFQQYVF INQMCYHLAL P WYSKYFPY LALIHTIILM VSSNFWFKYP KTCSKVEHFV SILGKCFESP WTTKALSETA CEDSEENKQR ITGAQTLPKH VS TSSDEGS PSASTPMINK TGFKFSAEKP VIEVPSMTIL DKKDGEQAKA LFEKVRKFRA HVEDSDLIYK LYVVQTLIKT AKF IFILCY TANFVNAISF EHVCKPKVEH LTGYEVFECT HNMAYMLKKL LISYISIICV YGFICLYTLF WLFRIPLKEY SFEK VREES SFSDIPDVKN DFAFLLHMVD QYDQLYSKRF GVFLSEVSEN KLREISLNHE WTFEKLRQHV SRNAQDKQEL HLFML SGVP DAVFDLTDLD VLKLELIPEA KIPAKISQMT NLQELHLCHC PAKVEQTAFS FLRDHLRCLH VKFTDVAEIP AWVYLL KNL RELYLIGNLN SENNKMIGLE SLRELRHLKI LHVKSNLTKV PSNITDVAPH LTKLVIHNDG TKLLVLNSLK KMMNVAE LE LQNCELERIP HAIFSLSNLQ ELDLKSNNIR TIEEIISFQH LKRLTCLKLW HNKIVAIPPS ITHVKNLESL YFSNNKLE S LPTAVFSLQK LRCLDVSYNN ISTIPIEIGL LQNLQHLHIT GNKVDILPKQ LFKCVKLRTL NLGQNCIASL PEKISQLTQ LTQLELKGNC LDRLPAQLGQ CRMLKKSGLV VEDQLFDTLP LEVKEALNQD VNVPFANGIS NSENLYFQ

UniProtKB: Volume-regulated anion channel subunit LRRC8D

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Macromolecule #3: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

MacromoleculeName: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / type: ligand / ID: 3 / Number of copies: 18 / Formula: PEE
Molecular weightTheoretical: 744.034 Da
Chemical component information

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 18.0 µm / Nominal defocus min: 6.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8ds3

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 43907
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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