Q7L1W4 · LRC8D_HUMAN
- ProteinVolume-regulated anion channel subunit LRRC8D
- GeneLRRC8D
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids858 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes (PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731, PubMed:32415200).
The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24790029, PubMed:26824658, PubMed:28193731).
Plays a redundant role in the efflux of amino acids, such as aspartate, in response to osmotic stress (PubMed:28193731).
LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471).
Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24782309, PubMed:24790029, PubMed:26824658, PubMed:28193731).
Also acts as a regulator of glucose-sensing in pancreatic beta cells: VRAC currents, generated in response to hypotonicity- or glucose-induced beta cell swelling, depolarize cells, thereby causing electrical excitation, leading to increase glucose sensitivity and insulin secretion (By similarity).
VRAC channels containing LRRC8D inhibit transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (PubMed:33171122).
Mediates the import of the antibiotic blasticidin-S into the cell (PubMed:24782309).
The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24790029, PubMed:26824658, PubMed:28193731).
Plays a redundant role in the efflux of amino acids, such as aspartate, in response to osmotic stress (PubMed:28193731).
LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471).
Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24782309, PubMed:24790029, PubMed:26824658, PubMed:28193731).
Also acts as a regulator of glucose-sensing in pancreatic beta cells: VRAC currents, generated in response to hypotonicity- or glucose-induced beta cell swelling, depolarize cells, thereby causing electrical excitation, leading to increase glucose sensitivity and insulin secretion (By similarity).
VRAC channels containing LRRC8D inhibit transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (PubMed:33171122).
Mediates the import of the antibiotic blasticidin-S into the cell (PubMed:24782309).
Catalytic activity
- chloride(in) = chloride(out)
- iodide(out) = iodide(in)
- taurine(out) = taurine(in)
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytoplasm | |
Cellular Component | endoplasmic reticulum membrane | |
Cellular Component | membrane | |
Cellular Component | monoatomic ion channel complex | |
Cellular Component | plasma membrane | |
Molecular Function | volume-sensitive anion channel activity | |
Biological Process | aspartate transmembrane transport | |
Biological Process | cellular response to osmotic stress | |
Biological Process | intracellular glucose homeostasis | |
Biological Process | monoatomic anion transmembrane transport | |
Biological Process | protein hexamerization | |
Biological Process | taurine transmembrane transport |
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameVolume-regulated anion channel subunit LRRC8D
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ7L1W4
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Multi-pass membrane protein
Endoplasmic reticulum membrane ; Multi-pass membrane protein
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-22 | Cytoplasmic | ||||
Sequence: MFTLAEVASLNDIQPTYRILKP | ||||||
Transmembrane | 23-48 | Helical | ||||
Sequence: WWDVFMDYLAVVMLMVAIFAGTMQLT | ||||||
Topological domain | 49-163 | Extracellular | ||||
Sequence: KDQVVCLPVLPSPVNSKAHTPPGNAEVTTNIPKMEAATNQDQDGRTTNDISFGTSAVTPDIPLRATYPRTDFALPNQEAKKEKKDPTGRKTNLDFQQYVFINQMCYHLALPWYSK | ||||||
Transmembrane | 164-182 | Helical | ||||
Sequence: YFPYLALIHTIILMVSSNF | ||||||
Topological domain | 183-308 | Cytoplasmic | ||||
Sequence: WFKYPKTCSKVEHFVSILGKCFESPWTTKALSETACEDSEENKQRITGAQTLPKHVSTSSDEGSPSASTPMINKTGFKFSAEKPVIEVPSMTILDKKDGEQAKALFEKVRKFRAHVEDSDLIYKLY | ||||||
Transmembrane | 309-328 | Helical | ||||
Sequence: VVQTVIKTAKFIFILCYTAN | ||||||
Topological domain | 329-360 | Extracellular | ||||
Sequence: FVNAISFEHVCKPKVEHLIGYEVFECTHNMAY | ||||||
Transmembrane | 361-386 | Helical | ||||
Sequence: MLKKLLISYISIICVYGFICLYTLFW | ||||||
Topological domain | 387-858 | Cytoplasmic | ||||
Sequence: LFRIPLKEYSFEKVREESSFSDIPDVKNDFAFLLHMVDQYDQLYSKRFGVFLSEVSENKLREISLNHEWTFEKLRQHISRNAQDKQELHLFMLSGVPDAVFDLTDLDVLKLELIPEAKIPAKISQMTNLQELHLCHCPAKVEQTAFSFLRDHLRCLHVKFTDVAEIPAWVYLLKNLRELYLIGNLNSENNKMIGLESLRELRHLKILHVKSNLTKVPSNITDVAPHLTKLVIHNDGTKLLVLNSLKKMMNVAELELQNCELERIPHAIFSLSNLQELDLKSNNIRTIEEIISFQHLKRLTCLKLWHNKIVTIPPSITHVKNLESLYFSNNKLESLPVAVFSLQKLRCLDVSYNNISMIPIEIGLLQNLQHLHITGNKVDILPKQLFKCIKLRTLNLGQNCITSLPEKVGQLSQLTQLELKGNCLDRLPAQLGQCRMLKKSGLVVEDHLFDTLPLEVKEALNQDINIPFANGI |
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 44 | Alters channel anion selectivity. | ||||
Sequence: T → C | ||||||
Mutagenesis | 143 | Affects ion selectivity of the channel. Reduced permeability to negatively charged glutamate and gluconate. | ||||
Sequence: F → R | ||||||
Natural variant | VAR_051132 | 371 | in dbSNP:rs11552246 | |||
Sequence: S → Y |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 760 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for chain, disulfide bond, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000084493 | 1-858 | UniProt | Volume-regulated anion channel subunit LRRC8D | |||
Sequence: MFTLAEVASLNDIQPTYRILKPWWDVFMDYLAVVMLMVAIFAGTMQLTKDQVVCLPVLPSPVNSKAHTPPGNAEVTTNIPKMEAATNQDQDGRTTNDISFGTSAVTPDIPLRATYPRTDFALPNQEAKKEKKDPTGRKTNLDFQQYVFINQMCYHLALPWYSKYFPYLALIHTIILMVSSNFWFKYPKTCSKVEHFVSILGKCFESPWTTKALSETACEDSEENKQRITGAQTLPKHVSTSSDEGSPSASTPMINKTGFKFSAEKPVIEVPSMTILDKKDGEQAKALFEKVRKFRAHVEDSDLIYKLYVVQTVIKTAKFIFILCYTANFVNAISFEHVCKPKVEHLIGYEVFECTHNMAYMLKKLLISYISIICVYGFICLYTLFWLFRIPLKEYSFEKVREESSFSDIPDVKNDFAFLLHMVDQYDQLYSKRFGVFLSEVSENKLREISLNHEWTFEKLRQHISRNAQDKQELHLFMLSGVPDAVFDLTDLDVLKLELIPEAKIPAKISQMTNLQELHLCHCPAKVEQTAFSFLRDHLRCLHVKFTDVAEIPAWVYLLKNLRELYLIGNLNSENNKMIGLESLRELRHLKILHVKSNLTKVPSNITDVAPHLTKLVIHNDGTKLLVLNSLKKMMNVAELELQNCELERIPHAIFSLSNLQELDLKSNNIRTIEEIISFQHLKRLTCLKLWHNKIVTIPPSITHVKNLESLYFSNNKLESLPVAVFSLQKLRCLDVSYNNISMIPIEIGLLQNLQHLHITGNKVDILPKQLFKCIKLRTLNLGQNCITSLPEKVGQLSQLTQLELKGNCLDRLPAQLGQCRMLKKSGLVVEDHLFDTLPLEVKEALNQDINIPFANGI | |||||||
Disulfide bond | 54↔354 | UniProt | |||||
Sequence: CLPVLPSPVNSKAHTPPGNAEVTTNIPKMEAATNQDQDGRTTNDISFGTSAVTPDIPLRATYPRTDFALPNQEAKKEKKDPTGRKTNLDFQQYVFINQMCYHLALPWYSKYFPYLALIHTIILMVSSNFWFKYPKTCSKVEHFVSILGKCFESPWTTKALSETACEDSEENKQRITGAQTLPKHVSTSSDEGSPSASTPMINKTGFKFSAEKPVIEVPSMTILDKKDGEQAKALFEKVRKFRAHVEDSDLIYKLYVVQTVIKTAKFIFILCYTANFVNAISFEHVCKPKVEHLIGYEVFEC | |||||||
Modified residue (large scale data) | 221 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 233 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 239 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 241 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 242 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 246 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 246 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 248 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 251 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 604 | PRIDE | Phosphoserine | ||||
Sequence: S |
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Interaction
Subunit
Heterohexamer (PubMed:32415200).
Oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8B, LRRC8C and/or LRRC8E) to form a heterohexamer (PubMed:24782309, PubMed:26530471, PubMed:26824658, PubMed:28193731).
In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist (Probable)
Oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8B, LRRC8C and/or LRRC8E) to form a heterohexamer (PubMed:24782309, PubMed:26530471, PubMed:26824658, PubMed:28193731).
In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist (Probable)
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q7L1W4 | LRRC8A Q8IWT6 | 2 | EBI-861997, EBI-10970086 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias, repeat.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 221-251 | Disordered | ||||
Sequence: SEENKQRITGAQTLPKHVSTSSDEGSPSAST | ||||||
Compositional bias | 227-251 | Polar residues | ||||
Sequence: RITGAQTLPKHVSTSSDEGSPSAST | ||||||
Repeat | 514-534 | LRR 1 | ||||
Sequence: NLQELHLCHCPAKVEQTAFSF | ||||||
Repeat | 538-559 | LRR 2 | ||||
Sequence: HLRCLHVKFTDVAEIPAWVYLL | ||||||
Repeat | 561-582 | LRR 3 | ||||
Sequence: NLRELYLIGNLNSENNKMIGLE | ||||||
Repeat | 589-609 | LRR 4 | ||||
Sequence: HLKILHVKSNLTKVPSNITDV | ||||||
Repeat | 612-632 | LRR 5 | ||||
Sequence: HLTKLVIHNDGTKLLVLNSLK | ||||||
Repeat | 636-657 | LRR 6 | ||||
Sequence: NVAELELQNCELERIPHAIFSL | ||||||
Repeat | 659-680 | LRR 7 | ||||
Sequence: NLQELDLKSNNIRTIEEIISFQ | ||||||
Repeat | 684-705 | LRR 8 | ||||
Sequence: RLTCLKLWHNKIVTIPPSITHV | ||||||
Repeat | 707-728 | LRR 9 | ||||
Sequence: NLESLYFSNNKLESLPVAVFSL | ||||||
Repeat | 730-751 | LRR 10 | ||||
Sequence: KLRCLDVSYNNISMIPIEIGLL | ||||||
Repeat | 753-774 | LRR 11 | ||||
Sequence: NLQHLHITGNKVDILPKQLFKC | ||||||
Repeat | 776-797 | LRR 12 | ||||
Sequence: KLRTLNLGQNCITSLPEKVGQL | ||||||
Repeat | 799-820 | LRR 13 | ||||
Sequence: QLTQLELKGNCLDRLPAQLGQC |
Domain
The volume-regulated anion channel (VRAC) channel forms a trimer of dimers, with symmetry mismatch between the pore-forming domain and the cytosolic LRR repeats, a topology similar to gap junction proteins.
Sequence similarities
Belongs to the LRRC8 family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length858
- Mass (Da)98,201
- Last updated2004-07-05 v1
- Checksum52A8B6EEF6F0FE2B
Computationally mapped potential isoform sequences
There are 5 potential isoforms mapped to this entry
Sequence caution
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 227-251 | Polar residues | ||||
Sequence: RITGAQTLPKHVSTSSDEGSPSAST |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AL391497 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471097 EMBL· GenBank· DDBJ | EAW73130.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471097 EMBL· GenBank· DDBJ | EAW73131.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471097 EMBL· GenBank· DDBJ | EAW73132.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC024159 EMBL· GenBank· DDBJ | AAH24159.2 EMBL· GenBank· DDBJ | mRNA | ||
AK001332 EMBL· GenBank· DDBJ | BAA91631.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AY358874 EMBL· GenBank· DDBJ | AAQ89233.1 EMBL· GenBank· DDBJ | mRNA | Different initiation |