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- EMDB-15837: Cryo-EM structure of heteromeric LRRC8A/C Volume-Regulated Anion ... -

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Basic information

Entry
Database: EMDB / ID: EMD-15837
TitleCryo-EM structure of heteromeric LRRC8A/C Volume-Regulated Anion Channel
Map data
Sample
  • Complex: Heteromeric LRRC8A/C Volume-Regulated Anion Channel
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8A
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8C
KeywordsIon channel / Volume-regulated anion channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / taurine transmembrane transport / monoatomic anion transmembrane transport / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / cellular response to osmotic stress / monoatomic anion transport ...Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / taurine transmembrane transport / monoatomic anion transmembrane transport / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / cellular response to osmotic stress / monoatomic anion transport / cell volume homeostasis / protein hexamerization / response to osmotic stress / monoatomic ion channel complex / fat cell differentiation / intracellular glucose homeostasis / positive regulation of myoblast differentiation / chloride transmembrane transport / positive regulation of insulin secretion / spermatogenesis / lysosomal membrane / endoplasmic reticulum membrane / cell surface / endoplasmic reticulum / signal transduction / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / Leucine Rich Repeat / Leucine-rich repeat, SDS22-like subfamily / 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
Volume-regulated anion channel subunit LRRC8A / Volume-regulated anion channel subunit LRRC8C
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.6 Å
AuthorsSawicka M / Dutzler R
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: Structure of a volume-regulated heteromeric LRRC8A/C channel.
Authors: Sonja Rutz / Dawid Deneka / Antje Dittmann / Marta Sawicka / Raimund Dutzler /
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 ...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.
History
DepositionSep 19, 2022-
Header (metadata) releaseDec 14, 2022-
Map releaseDec 14, 2022-
UpdateJul 26, 2023-
Current statusJul 26, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15837.png

Downloads & links

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Map

FileDownload / File: emd_15837.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 336 pix.
= 437.472 Å		1.3 Å/pix.
x 336 pix.
= 437.472 Å		1.3 Å/pix.
x 336 pix.
= 437.472 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.302 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.016777424 - 0.04995145
Average (Standard dev.)0.00016644076 (±0.0015432108)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 437.47202 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_15837_half_map_1.map
Projections & Slices
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Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_15837_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Heteromeric LRRC8A/C Volume-Regulated Anion Channel

EntireName: Heteromeric LRRC8A/C Volume-Regulated Anion Channel
Components
  • Complex: Heteromeric LRRC8A/C Volume-Regulated Anion Channel
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8A
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8C

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Supramolecule #1: Heteromeric LRRC8A/C Volume-Regulated Anion Channel

SupramoleculeName: Heteromeric LRRC8A/C Volume-Regulated Anion Channel / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Volume-regulated anion channel subunit LRRC8A

MacromoleculeName: Volume-regulated anion channel subunit LRRC8A / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 95.056312 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSIPVTELRY FADTQPAYRI LKPWWDVFTD YISIVMLMIA VFGGTLQVTQ DKMICLPCKW VTKDSCNDSF RGWAASSPEP TYPNSTVLP TPDTGPTGIK YDLDRHQYNY VDAVCYENRL HWFAKYFPYL VLLHTLIFLA CSNFWFKFPR TSSKLEHFVS I LLKCFDSP ...String:
MSIPVTELRY FADTQPAYRI LKPWWDVFTD YISIVMLMIA VFGGTLQVTQ DKMICLPCKW VTKDSCNDSF RGWAASSPEP TYPNSTVLP TPDTGPTGIK YDLDRHQYNY VDAVCYENRL HWFAKYFPYL VLLHTLIFLA CSNFWFKFPR TSSKLEHFVS I LLKCFDSP WTTRALSETV VEESDPKPAF SKMNGSMDKK SSTVSEDVEA TVPMLQRTKS RIEQGIVDRS ETGVLDKKEG EQ AKALFEK VKKFRTHVEE GDIVYRLYMR QTIIKVIKFA LIICYTVYYV HNIKFDVDCT VDIESLTGYR TYRCAHPLAT LFK ILASFY ISLVIFYGLI CMYTLWWMLR RSLKKYSFES IREESSYSDI PDVKNDFAFM LHLIDQYDPL YSKRFAVFLS EVSE NKLRQ LNLNNEWTLD KLRQRLTKNA QDKLELHLFM LSGIPDTVFD LVELEVLKLE LIPDVTIPPS IAQLTGLKEL WLYHT AAKI EAPALAFLRE NLRALHIKFT DIKEIPLWIY SLKTLEELHL TGNLSAENNR YIVIDGLREL KRLKVLRLKS NLSKLP QVV TDVGVHLQKL SINNEGTKLI VLNSLKKMVN LTELELIRCD LERIPHSIFS LHNLQEIDLK DNNLKTIEEI ISFQHLH RL TCLKLWYNHI AYIPIQIGNL TNLERLYLNR NKIEKIPTQL FYCRKLRYLD LSHNNLTFLP ADIGLLQNLQ NLAVTANR I EALPPELFQC RKLRALHLGN NVLQSLPSRV GELTNLTQIE LRGNRLECLP VELGECPLLK RSGLVVEEDL FSTLPPEVK ERLWRADKEQ ALEVLFQ

UniProtKB: Volume-regulated anion channel subunit LRRC8A

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Macromolecule #2: Volume-regulated anion channel subunit LRRC8C

MacromoleculeName: Volume-regulated anion channel subunit LRRC8C / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 93.472594 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSIPVTEFRQ FSEQQPAFRV LKPWWDVFTD YLSVAMLMIG VFGCTLQVMQ DKIICLPKRV QPAQNHSSVP NVSQAVISTT PLPPPKPSP TNPATVEMKG LKTDLDLQQY SFINQMCYER ALHWYAKYFP YLVLIHTLVF MLCSNFWFKF PGSSSKIEHF I SILGKCFD ...String:
MSIPVTEFRQ FSEQQPAFRV LKPWWDVFTD YLSVAMLMIG VFGCTLQVMQ DKIICLPKRV QPAQNHSSVP NVSQAVISTT PLPPPKPSP TNPATVEMKG LKTDLDLQQY SFINQMCYER ALHWYAKYFP YLVLIHTLVF MLCSNFWFKF PGSSSKIEHF I SILGKCFD SPWTTRALSE VSGEDSEEKD NRKNNMNRSG TIQSGPEGNL VRSQSLKSIP EKFVVDKSAA GALDKKEGEQ AK ALFEKVK KFRLHVEEGD ILYAMYVRQT VLKVIKFLII IAYNSALVSK VQFTVDCNVD IQDMTGYKNF SCNHTMAHLF SKL SFCYLC FVSIYGLTCL YTLYWLFYRS LREYSFEYVR QETGIDDIPD VKNDFAFMLH MIDQYDPLYS KRFAVFLSEV SENK LKQLN LNNEWTPDKL RQKLQTNAHN RLELPLIMLS GLPDTVFEIT ELQSLKLEII KNVMIPATIA QLDNLQELCL HQCSV KIHS AALSFLKENL KVLSVKFDDM RELPPWMYGL RNLEELYLVG SLSHDISKNV TLESLRDLKS LKILSIKSNV SKIPQA VVD VSSHLQKMCV HNDGTKLVML NNLKKMTNLT ELELVHCDLE RIPHAVFSLL SLQELDLKEN NLKSIEEIVS FQHLRKL TV LKLWYNSIAY IPEHIKKLTS LERLFFSHNK VEVLPSHLFL CNKIRYLDLS YNDIRFIPPE IGVLQSLQYF SITCNKVE S LPDELYFCKK LKTLKIGKNS LSVLSPKIGN LLFLSYLDIK GNHFEVLPPE LGDCRALKRA RLVVEDALFE TLPSDVREQ MKADALEVLF Q

UniProtKB: Volume-regulated anion channel subunit LRRC8C

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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: 8.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 67.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 119006
FSC plot (resolution estimation)

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