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- EMDB-50073: Cryo-EM structure of a homomeric LRRC8C truncation disease mutant... -

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Basic information

Entry
Database: EMDB / ID: EMD-50073
TitleCryo-EM structure of a homomeric LRRC8C truncation disease mutant, with C1 symmetry
Map data
Sample
  • Complex: Homomeric LRRC8C truncation disease mutant
    • Protein or peptide: Homomeric LRRC8C truncation disease mutant
KeywordsAnion channel / Volume regulation / disease mutant / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 7.32 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 11, 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_50073.png

Downloads & links

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Map

FileDownload / File: emd_50073.map.gz / Format: CCP4 / Size: 18.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
2.6 Å/pix.
x 168 pix.
= 437.472 Å		2.6 Å/pix.
x 168 pix.
= 437.472 Å		2.6 Å/pix.
x 168 pix.
= 437.472 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 2.604 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.36
Minimum - Maximum-1.1954787 - 3.4356067
Average (Standard dev.)-0.0027221981 (±0.14050491)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions168168168
Spacing168168168
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_50073_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_50073_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Homomeric LRRC8C truncation disease mutant

EntireName: Homomeric LRRC8C truncation disease mutant
Components
  • Complex: Homomeric LRRC8C truncation disease mutant
    • Protein or peptide: Homomeric LRRC8C truncation disease mutant

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Supramolecule #1: Homomeric LRRC8C truncation disease mutant

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

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Macromolecule #1: Homomeric LRRC8C truncation disease mutant

MacromoleculeName: Homomeric LRRC8C truncation disease mutant / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
SequenceString: MSIPVTEFRQ FSEQQPAFRV LKPWWDVFTD YLSVAMLMIG VFGCTLQVMQ DKIICLPKRV QPAQNHSSLS NVSQAVASTT PLPPPKPSPA NPITVEMKGL KTDLDLQQYS FINQMCYERA LHWYAKYFPY LVLIHTLVFM LCSNFWFKFP GSSSKIEHFI SILGKCFDSP ...String:
MSIPVTEFRQ FSEQQPAFRV LKPWWDVFTD YLSVAMLMIG VFGCTLQVMQ DKIICLPKRV QPAQNHSSLS NVSQAVASTT PLPPPKPSPA NPITVEMKGL KTDLDLQQYS FINQMCYERA LHWYAKYFPY LVLIHTLVFM LCSNFWFKFP GSSSKIEHFI SILGKCFDSP WTTRALSEVS GEDSEEKDNR KNNMNRSNTI QSGPEGSLVN SQSLKSIPEK FVVDKSTAGA LDKKEGEQAK ALFEKVKKFR LHVEEGDILY AMYVRQTVLK VIKFLIIIAY NSALVSKVQF TVDCNVDIQD MTGYKNFSCN HTMAHLFSKL SFCYLCFVSI YGLTCLYTLY WLFYRSLREY SFEYVRQETG IDDIPDVKND FAFMLHMIDQ YDPLYSKRFA VFLSEVSENK IKAAELKALE VLFQ

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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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 7.32 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 224687
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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