|Entry||Database: PDB / ID: 8drn|
|Title||LRRC8A:C conformation 1 (round) LRR focus 1|
|Keywords||MEMBRANE PROTEIN / ION CHANNEL / VOLUME-REGULATION|
|Function / homology|
Function and homology information
Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / taurine transport / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion channel activity / monoatomic anion transmembrane transport / monoatomic ion channel complex ...Miscellaneous transport and binding events / pre-B cell differentiation / volume-sensitive anion channel activity / taurine transport / aspartate transmembrane transport / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / monoatomic anion channel activity / monoatomic anion transmembrane transport / monoatomic ion channel complex / monoatomic anion transport / cell volume homeostasis / cellular response to osmotic stress / protein hexamerization / response to osmotic stress / fat cell differentiation / intracellular glucose homeostasis / positive regulation of myoblast differentiation / chloride transmembrane transport / positive regulation of insulin secretion / spermatogenesis / lysosomal membrane / electron transfer activity / periplasmic space / iron ion binding / heme binding / endoplasmic reticulum membrane / cell surface / endoplasmic reticulum / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / Leucine-rich repeat, SDS22-like subfamily / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine rich repeat / Leucine-rich repeat profile. ...LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / Leucine-rich repeat, SDS22-like subfamily / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine rich repeat / 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 LRRC8C
Similarity search - Component
|Biological species||Mus musculus (house mouse)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.12 Å|
|Authors||Kern, D.M. / Brohawn, S.G.|
|Funding support|| United States, 1items |
|Citation||Journal: Nat Struct Mol Biol / Year: 2023|
Title: Structural basis for assembly and lipid-mediated gating of LRRC8A:C volume-regulated anion channels.
Authors: David M Kern / Julia Bleier / Somnath Mukherjee / Jennifer M Hill / Anthony A Kossiakoff / Ehud Y Isacoff / Stephen G Brohawn /
Abstract: Leucine-rich repeat-containing protein 8 (LRRC8) family members form volume-regulated anion channels activated by hypoosmotic cell swelling. LRRC8 channels are ubiquitously expressed in vertebrate ...Leucine-rich repeat-containing protein 8 (LRRC8) family members form volume-regulated anion channels activated by hypoosmotic cell swelling. LRRC8 channels are ubiquitously expressed in vertebrate cells as heteromeric assemblies of LRRC8A (SWELL1) and LRRC8B-E subunits. Channels of different subunit composition have distinct properties that explain the functional diversity of LRRC8 currents across cell types. However, the basis for heteromeric LRRC8 channel assembly and function is unknown. Here we leverage a fiducial-tagging strategy to determine single-particle cryo-EM structures of heterohexameric LRRC8A:C channels in multiple conformations. Compared to homomers, LRRC8A:C channels show pronounced differences in architecture due to heterotypic LRR interactions that displace subunits away from the conduction axis and poise the channel for activation. Structures and functional studies further reveal that lipids embedded in the channel pore block ion conduction in the closed state. These results provide insight into determinants for heteromeric LRRC8 channel assembly, activity and gating by lipids.
|Structure viewer||Molecule: |
-Downloads & links
|PDBx/mmCIF format||8drn.cif.gz||202 KB||Display||PDBx/mmCIF format|
|PDB format||pdb8drn.ent.gz||139 KB||Display||PDB format|
|PDBx/mmJSON format||8drn.json.gz||Tree view||PDBx/mmJSON format|
|Summary document||8drn_validation.pdf.gz||1.2 MB||Display||wwPDB validaton report|
|Full document||8drn_full_validation.pdf.gz||1.2 MB||Display|
|Data in XML||8drn_validation.xml.gz||39.8 KB||Display|
|Data in CIF||8drn_validation.cif.gz||55.9 KB||Display|
-Related structure data
|Related structure data|
C: citing same article (ref.)
M: map data used to model this data
|Similar structure data|
Similarity search - Function & homologyF&H Search
Similarity search - FunctionF&H Search
Similarity search - HomologyF&H Search
|PDB pages||PDBj / wwPDB / NCBI|
|Related items in Molecule of the Month|
A: Volume-regulated anion channel subunit LRRC8A,Soluble cytochrome b562
F: Volume-regulated anion channel subunit LRRC8C
|#1: Protein|| |
Mass: 105530.102 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Lrrc8a, Lrrc8, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q80WG5, UniProt: P0ABE7
|#2: Protein|| |
Mass: 93624.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Lrrc8c, Ad158, Fad158 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8R502
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: LRRC8A:C / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT|
|Molecular weight||Value: 0.620 MDa / Experimental value: NO|
|Source (natural)||Organism: Mus musculus (house mouse)|
|Source (recombinant)||Organism: Spodoptera frugiperda (fall armyworm)|
|Buffer solution||pH: 7.4|
|Specimen||Conc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: TFS KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: -2 nm / Nominal defocus min: -0.6 nm|
|Image recording||Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|3D reconstruction||Resolution: 4.12 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 110018 / Symmetry type: POINT|
|Refinement||Cross valid method: NONE|
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