|Entry||Database: PDB / ID: 8dxr|
|Title||Structure of LRRC8C-LRRC8A(IL125) Chimera, Class 5|
|Components||Volume-regulated anion channel subunit LRRC8C,Volume-regulated anion channel subunit LRRC8A|
|Keywords||TRANSPORT PROTEIN / LRRC8C / LRRC8A / SWELL / VRAC / Chimera|
|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 transmembrane transport / monoatomic ion channel complex / monoatomic anion transport ...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 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 / endoplasmic reticulum membrane / cell surface / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / BspA type Leucine rich repeat region / BspA type Leucine rich repeat region (6 copies) / Leucine-rich repeat, SDS22-like subfamily / 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
Volume-regulated anion channel subunit LRRC8A / Volume-regulated anion channel subunit LRRC8C
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å|
|Authors||Takahashi, H. / Yamada, T. / Denton, J.S. / Strange, K. / Karakas, E.|
|Funding support|| United States, 1items |
|Citation||Journal: Elife / Year: 2023|
Title: Cryo-EM structures of an LRRC8 chimera with native functional properties reveal heptameric assembly.
Authors: Hirohide Takahashi / Toshiki Yamada / Jerod S Denton / Kevin Strange / Erkan Karakas /
Abstract: Volume-regulated anion channels (VRACs) mediate volume regulatory Cl and organic solute efflux from vertebrate cells. VRACs are heteromeric assemblies of LRRC8A-E proteins with unknown ...Volume-regulated anion channels (VRACs) mediate volume regulatory Cl and organic solute efflux from vertebrate cells. VRACs are heteromeric assemblies of LRRC8A-E proteins with unknown stoichiometries. Homomeric LRRC8A and LRRC8D channels have a small pore, hexameric structure. However, these channels are either non-functional or exhibit abnormal regulation and pharmacology, limiting their utility for structure-function analyses. We circumvented these limitations by developing novel homomeric LRRC8 chimeric channels with functional properties consistent with those of native VRAC/LRRC8 channels. We demonstrate here that the LRRC8C-LRRC8A(IL1) chimera comprising LRRC8C and 25 amino acids unique to the first intracellular loop (IL1) of LRRC8A has a heptameric structure like that of homologous pannexin channels. Unlike homomeric LRRC8A and LRRC8D channels, heptameric LRRC8C-LRRC8A(IL1) channels have a large-diameter pore similar to that estimated for native VRACs, exhibit normal DCPIB pharmacology, and have higher permeability to large organic anions. Lipid-like densities are located between LRRC8C-LRRC8A(IL1) subunits and occlude the channel pore. Our findings provide new insights into VRAC/LRRC8 channel structure and suggest that lipids may play important roles in channel gating and regulation.
|Structure viewer||Molecule: |
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|PDBx/mmCIF format||8dxr.cif.gz||364.8 KB||Display||PDBx/mmCIF format|
|PDB format||pdb8dxr.ent.gz||236.4 KB||Display||PDB format|
|PDBx/mmJSON format||8dxr.json.gz||Tree view||PDBx/mmJSON format|
|Summary document||8dxr_validation.pdf.gz||1.3 MB||Display||wwPDB validaton report|
|Full document||8dxr_full_validation.pdf.gz||1.3 MB||Display|
|Data in XML||8dxr_validation.xml.gz||58.9 KB||Display|
|Data in CIF||8dxr_validation.cif.gz||92.7 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 LRRC8C,Volume-regulated anion channel subunit LRRC8A
B: Volume-regulated anion channel subunit LRRC8C,Volume-regulated anion channel subunit LRRC8A
C: Volume-regulated anion channel subunit LRRC8C,Volume-regulated anion channel subunit LRRC8A
D: Volume-regulated anion channel subunit LRRC8C,Volume-regulated anion channel subunit LRRC8A
E: Volume-regulated anion channel subunit LRRC8C,Volume-regulated anion channel subunit LRRC8A
F: Volume-regulated anion channel subunit LRRC8C,Volume-regulated anion channel subunit LRRC8A
G: Volume-regulated anion channel subunit LRRC8C,Volume-regulated anion channel subunit LRRC8A
Mass: 94747.695 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: LRRC8C, AD158, FAD158, LRRC8A, KIAA1437, LRRC8, SWELL1, UNQ221/PRO247
Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8TDW0, UniProt: Q8IWT6
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: LRRC8C-LRRC8A(IL125) chimera / Type: COMPLEX / Details: Heptameric LRRC8C-LRRC8A(IL125) chimera. / Entity ID: all / Source: RECOMBINANT|
|Molecular weight||Value: 0.7 MDa / Experimental value: NO|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Spodoptera frugiperda (fall armyworm) / Strain: Sf9|
|Buffer solution||pH: 8|
|Specimen||Conc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN 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: 2200 nm / Nominal defocus min: 800 nm|
|Image recording||Electron dose: 54 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 3198|
|CTF correction||Type: PHASE FLIPPING ONLY|
|Particle selection||Num. of particles selected: 846122|
|Symmetry||Point symmetry: C1 (asymmetric)|
|3D reconstruction||Resolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85591 / Num. of class averages: 1 / Symmetry type: POINT|
|Atomic model building||Protocol: FLEXIBLE FIT / Space: REAL|
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