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- EMDB-50123: Structure of a homomeric LRRC8C point mutation disease mutant -

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Basic information

Entry
Database: EMDB / ID: EMD-50123
TitleStructure of a homomeric LRRC8C point mutation disease mutant
Map data
Sample
  • Complex: LRRC8C point mutation disease mutant
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8C
KeywordsAnion channel / Volume regulation / disease mutant / MEMBRANE PROTEIN
Function / homology
Function and homology information


Miscellaneous transport and binding events / volume-sensitive anion channel activity / aspartate transmembrane transport / taurine transmembrane transport / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion transmembrane transport / protein hexamerization / cellular response to osmotic stress / fat cell differentiation / monoatomic ion channel complex ...Miscellaneous transport and binding events / volume-sensitive anion channel activity / aspartate transmembrane transport / taurine transmembrane transport / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion transmembrane transport / protein hexamerization / cellular response to osmotic stress / fat cell differentiation / monoatomic ion channel complex / intracellular signal transduction / endoplasmic reticulum membrane / membrane / plasma membrane / cytoplasm
Similarity search - Function
LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / : / 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 LRRC8C
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsRutz S / Quinodoz M / Peter V / Garavelli L / Innes MA / Kellenberger S / Peng Z / Barone A / Campos-Xavier B / Unger S ...Rutz S / Quinodoz M / Peter V / Garavelli L / Innes MA / Kellenberger S / Peng Z / Barone A / Campos-Xavier B / Unger S / Rivolta C / Dutzler R / Superti-Furga A
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science FoundationNo. 310030_204373 Switzerland
CitationJournal: EMBO J / Year: 2025
Title: De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder.
Authors: Mathieu Quinodoz / Sonja Rutz / Virginie Peter / Livia Garavelli / A Micheil Innes / Elena F Lehmann / Stephan Kellenberger / Zhong Peng / Angelica Barone / Belinda Campos-Xavier / Sheila ...Authors: Mathieu Quinodoz / Sonja Rutz / Virginie Peter / Livia Garavelli / A Micheil Innes / Elena F Lehmann / Stephan Kellenberger / Zhong Peng / Angelica Barone / Belinda Campos-Xavier / Sheila Unger / Carlo Rivolta / Raimund Dutzler / Andrea Superti-Furga /
Abstract: Volume-regulated anion channels (VRACs) are multimeric proteins composed of different paralogs of the LRRC8 family. They are activated in response to hypotonic swelling, but little is known about ...Volume-regulated anion channels (VRACs) are multimeric proteins composed of different paralogs of the LRRC8 family. They are activated in response to hypotonic swelling, but little is known about their specific functions. We studied two human individuals with the same congenital syndrome affecting blood vessels, brain, eyes, and bones. The LRRC8C gene harbored de novo variants in both patients, located in a region of the gene encoding the boundary between the pore and a cytoplasmic domain, which is depleted of sequence variations in control subjects. When studied by cryo-EM, both LRRC8C mutant proteins assembled as their wild-type counterparts, but showed increased flexibility, suggesting a destabilization of subunit interactions. When co-expressed with the obligatory LRRC8A subunit, the mutants exhibited enhanced activation, resulting in channel activity even at isotonic conditions in which wild-type channels are closed. We conclude that structural perturbations of LRRC8C impair channel gating and constitute the mechanistic basis of the dominant gain-of-function effect of these pathogenic variants. The pleiotropic phenotype of this novel clinical entity associated with monoallelic LRRC8C variants indicates the fundamental roles of VRACs in different tissues and organs.
History
DepositionApr 18, 2024-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50123.png

Downloads & links

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Map

FileDownload / File: emd_50123.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
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

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.302 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.811
Minimum - Maximum-1.5568835 - 2.6761684
Average (Standard dev.)0.0021052293 (±0.064744204)
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: #1

Fileemd_50123_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_50123_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : LRRC8C point mutation disease mutant

EntireName: LRRC8C point mutation disease mutant
Components
  • Complex: LRRC8C point mutation disease mutant
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8C

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Supramolecule #1: LRRC8C point mutation disease mutant

SupramoleculeName: LRRC8C point mutation disease mutant / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Volume-regulated anion channel subunit LRRC8C

MacromoleculeName: Volume-regulated anion channel subunit LRRC8C / type: protein_or_peptide / ID: 1 / Number of copies: 7 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.362305 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSIPVTEFRQ FSEQQPAFRV LKPWWDVFTD YLSVAMLMIG VFGCTLQVMQ DKIICLPKRV QPAQNHSSLS NVSQAVASTT PLPPPKPSP ANPITVEMKG LKTDLDLQQY SFINQMCYER ALHWYAKYFP YLVLIHTLVF MLCSNFWFKF PGSSSKIEHF I SILGKCFD ...String:
MSIPVTEFRQ FSEQQPAFRV LKPWWDVFTD YLSVAMLMIG VFGCTLQVMQ DKIICLPKRV QPAQNHSSLS NVSQAVASTT PLPPPKPSP ANPITVEMKG LKTDLDLQQY SFINQMCYER ALHWYAKYFP YLVLIHTLVF MLCSNFWFKF PGSSSKIEHF I SILGKCFD SPWTTRALSE VSGEDSEEKD NRKNNMNRSN TIQSGPEGSL VNSQSLKSIP EKFVVDKSTA GALDKKEGEQ AK ALFEKVK KFRLHVEEGD ILYAMYVRQT VLKVIKFLII IAYNSALVSK VQFTVDCNVD IQDMTGYKNF SCNHTMAHLF SKL SFCYLC FVSIYGLTCL YTLYWLFYRS LREYSFEYVR QETGIDDIPD VKNDFAFMLH MIDQYDPLYS KRFALFLSEV SENK LKQLN LNNEWTPDKL RQKLQTNAHN RLELPLIMLS GLPDTVFEIT ELQSLKLEII KNVMIPATIA QLDNLQELSL HQCSV KIHS AALSFLKENL KVLSVKFDDM RELPPWMYGL RNLEELYLVG SLSHDISRNV TLESLRDLKS LKILSIKSNV SKIPQA VVD VSSHLQKMCI HNDGTKLVML NNLKKMTNLT ELELVHCDLE RIPHAVFSLL SLQELDLKEN NLKSIEEIVS FQHLRKL TV LKLWHNSITY IPEHIKKLTS LERLSFSHNK IEVLPSHLFL CNKIRYLDLS YNDIRFIPPE IGVLQSLQYF SITCNKVE S LPDELYFCKK LKTLKIGKNS LSVLSPKIGN LLFLSYLDVK GNHFEILPPE LGDCRALKRA GLVVEDALFE 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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 65.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 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:

8b41

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 180735
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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