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- PDB-9ezc: Structure of the extracellular subdomain of a homomeric LRRC8C tr... -

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Basic information

Entry
Database: PDB / ID: 9ezc
TitleStructure of the extracellular subdomain of a homomeric LRRC8C truncation disease mutant
ComponentsVolume-regulated anion channel subunit LRRC8C
KeywordsMEMBRANE PROTEIN / Anion channel / Volume regulation / disease mutation
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsRutz, S. / Quinodoz, M. / Peter, V. / Garavelli, L. / Innes, M.A. / Kellenberger, S. / Peng, Z. / Barone, A. / Campos-Xavier, B. / Unger, S. ...Rutz, S. / Quinodoz, M. / Peter, V. / Garavelli, L. / Innes, M.A. / Kellenberger, S. / Peng, Z. / Barone, A. / Campos-Xavier, B. / Unger, S. / Rivolta, C. / Dutzler, R. / Superti-Furga, A.
Funding support Switzerland, 1items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 13, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.2Jun 4, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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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 LRRC8C
B: Volume-regulated anion channel subunit LRRC8C
C: Volume-regulated anion channel subunit LRRC8C
D: Volume-regulated anion channel subunit LRRC8C
E: Volume-regulated anion channel subunit LRRC8C
F: Volume-regulated anion channel subunit LRRC8C
G: Volume-regulated anion channel subunit LRRC8C


Theoretical massNumber of molelcules
Total (without water)334,0407
Polymers334,0407
Non-polymers00
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 LRRC8C / Factor for adipocyte differentiation 158 / Leucine-rich repeat-containing protein 8C


Mass: 47719.941 Da / Num. of mol.: 7 / Mutation: Leu400IlefsTer8
Source method: isolated from a genetically manipulated source
Details: The compound only shows the extracellular subdomain (ESD) of the channel
Source: (gene. exp.) Homo sapiens (human) / Gene: LRRC8C, AD158, FAD158 / Production host: Homo sapiens (human) / References: UniProt: Q8TDW0
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: Homomeric LRRC8C truncation disease mutant / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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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: 2400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 65 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 224687 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 50.47 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00325894
ELECTRON MICROSCOPYf_angle_d0.87347945
ELECTRON MICROSCOPYf_chiral_restr0.0519875
ELECTRON MICROSCOPYf_plane_restr0.0042973
ELECTRON MICROSCOPYf_dihedral_angle_d4.9954749

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