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Protein

Volume-regulated anion channel subunit LRRC8A

Gene

LRRC8A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731, PubMed:29769723). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731). Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (PubMed:28193731). LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471). Required for in vivo channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24790029, PubMed:26824658, PubMed:28193731). Can form functional channels by itself (in vitro) (PubMed:26824658). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746). Also required for T-cell development (By similarity).By similarity7 Publications

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • volume-sensitive anion channel activity Source: UniProtKB

GO - Biological processi

  • anion transport Source: UniProtKB
  • cell volume homeostasis Source: UniProtKB
  • pre-B cell differentiation Source: UniProtKB
  • response to osmotic stress Source: UniProtKB
  • signal transduction Source: GO_Central
  • transmembrane transport Source: Reactome

Keywordsi

Molecular functionIon channel
Biological processDifferentiation, Ion transport, Transport

Enzyme and pathway databases

ReactomeiR-HSA-5223345 Miscellaneous transport and binding events

Protein family/group databases

TCDBi1.A.25.3.1 the gap junction-forming innexin (innexin) family

Names & Taxonomyi

Protein namesi
Recommended name:
Volume-regulated anion channel subunit LRRC8A
Alternative name(s):
Leucine-rich repeat-containing protein 8A
Swelling protein 1
Gene namesi
Name:LRRC8A
Synonyms:KIAA1437, LRRC8, SWELL11 Publication
ORF Names:UNQ221/PRO247
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 9

Organism-specific databases

EuPathDBiHostDB:ENSG00000136802.11
HGNCiHGNC:19027 LRRC8A
MIMi608360 gene
neXtProtiNX_Q8IWT6

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 22CytoplasmicSequence analysisAdd BLAST22
Transmembranei23 – 43HelicalSequence analysisAdd BLAST21
Topological domaini44 – 123ExtracellularSequence analysisAdd BLAST80
Transmembranei124 – 146HelicalSequence analysisAdd BLAST23
Topological domaini147 – 262CytoplasmicSequence analysisAdd BLAST116
Transmembranei263 – 285HelicalSequence analysisAdd BLAST23
Topological domaini286 – 319ExtracellularSequence analysisAdd BLAST34
Transmembranei320 – 342HelicalSequence analysisAdd BLAST23
Topological domaini343 – 810Cytoplasmic1 PublicationAdd BLAST468

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Agammaglobulinemia 5, autosomal dominant (AGM5)1 Publication
The disease is caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving LRRC8 has been found in a patient with congenital agammaglobulinemia. Translocation t(9;20)(q33.2;q12). The translocation truncates the LRRC8 gene, resulting in deletion of the eighth, ninth, and half of the seventh LRR domains.
Disease descriptionA primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.
See also OMIM:613506

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi44T → A or C: Altered anion selectivity. 1 Publication1
Mutagenesisi66N → A: Abolishes N-glycosylation; when associated with A-83. 1 Publication1
Mutagenesisi83N → A: Abolishes N-glycosylation; when associated with A-66. 1 Publication1

Organism-specific databases

DisGeNETi56262
MalaCardsiLRRC8A
MIMi613506 phenotype
OpenTargetsiENSG00000136802
Orphaneti33110 Autosomal agammaglobulinemia
PharmGKBiPA134909315

Polymorphism and mutation databases

BioMutaiLRRC8A
DMDMi37537912

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000844991 – 810Volume-regulated anion channel subunit LRRC8AAdd BLAST810

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineCombined sources1 Publication1
Disulfide bondi54 ↔ 310By similarity
Disulfide bondi57 ↔ 65By similarity
Glycosylationi66N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi83N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi113 ↔ 295By similarity
Modified residuei200PhosphothreonineBy similarity1
Modified residuei202PhosphoserineBy similarity1
Modified residuei215PhosphothreonineCombined sources1
Modified residuei217PhosphoserineCombined sources1

Post-translational modificationi

N-glycosylated.1 Publication

Keywords - PTMi

Acetylation, Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

EPDiQ8IWT6
MaxQBiQ8IWT6
PaxDbiQ8IWT6
PeptideAtlasiQ8IWT6
PRIDEiQ8IWT6
ProteomicsDBi70893

PTM databases

iPTMnetiQ8IWT6
PhosphoSitePlusiQ8IWT6

Expressioni

Tissue specificityi

Expressed in brain, kidney, ovary, lung, liver, heart, and fetal brain and liver. Found at high levels in bone marrow; lower levels are detected in peripheral blood cells. Expressed on T-cells as well as on B-lineage cells.2 Publications

Gene expression databases

BgeeiENSG00000136802
CleanExiHS_LRRC8A
ExpressionAtlasiQ8IWT6 baseline and differential
GenevisibleiQ8IWT6 HS

Interactioni

Subunit structurei

Hexamer (By similarity). Heterohexamer; oligomerizes with other LRRC8 proteins (LRRC8B, LRRC8C, LRRC8D and/or LRRC8E) to form a heterohexamer (PubMed:24782309, PubMed:24790029, PubMed:26824658). Can form homohexamers in vitro, but these have lower conductance than heterohexamers (PubMed:26824658). Detected in a channel complex that contains LRRC8A, LRRC8C and LRRC8E (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).By similarityCurated4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct

Protein-protein interaction databases

BioGridi121126, 31 interactors
CORUMiQ8IWT6
DIPiDIP-61360N
IntActiQ8IWT6, 8 interactors
MINTiQ8IWT6
STRINGi9606.ENSP00000259324

Structurei

3D structure databases

ProteinModelPortaliQ8IWT6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati399 – 422LRR 1Sequence analysisAdd BLAST24
Repeati423 – 445LRR 2Sequence analysisAdd BLAST23
Repeati447 – 468LRR 3Sequence analysisAdd BLAST22
Repeati469 – 492LRR 4Sequence analysisAdd BLAST24
Repeati493 – 515LRR 5Sequence analysisAdd BLAST23
Repeati518 – 542LRR 6Sequence analysisAdd BLAST25
Repeati543 – 565LRR 7Sequence analysisAdd BLAST23
Repeati567 – 589LRR 8Sequence analysisAdd BLAST23
Repeati590 – 613LRR 9Sequence analysisAdd BLAST24
Repeati615 – 637LRR 10Sequence analysisAdd BLAST23
Repeati639 – 661LRR 11Sequence analysisAdd BLAST23
Repeati662 – 684LRR 12Sequence analysisAdd BLAST23
Repeati686 – 707LRR 13Sequence analysisAdd BLAST22
Repeati708 – 730LRR 14Sequence analysisAdd BLAST23
Repeati732 – 753LRR 15Sequence analysisAdd BLAST22
Repeati754 – 776LRR 16Sequence analysisAdd BLAST23
Repeati778 – 801LRR 17Sequence analysisAdd BLAST24

Sequence similaritiesi

Belongs to the LRRC8 family.Curated

Keywords - Domaini

Leucine-rich repeat, Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0619 Eukaryota
COG4886 LUCA
GeneTreeiENSGT00920000148937
HOGENOMiHOG000231806
HOVERGENiHBG052360
InParanoidiQ8IWT6
KOiK22038
OMAiVDTQPAY
OrthoDBiEOG091G01ER
PhylomeDBiQ8IWT6
TreeFamiTF331443

Family and domain databases

Gene3Di3.80.10.10, 2 hits
InterProiView protein in InterPro
IPR001611 Leu-rich_rpt
IPR003591 Leu-rich_rpt_typical-subtyp
IPR032675 LRR_dom_sf
IPR038960 LRRC8
IPR021040 LRRC8_Pannexin-like
PANTHERiPTHR43945 PTHR43945, 1 hit
PfamiView protein in Pfam
PF13855 LRR_8, 3 hits
PF12534 Pannexin_like, 1 hit
SMARTiView protein in SMART
SM00369 LRR_TYP, 8 hits
PROSITEiView protein in PROSITE
PS51450 LRR, 11 hits

Sequencei

Sequence statusi: Complete.

Q8IWT6-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD
60 70 80 90 100
KMICLPCKWV TKDSCNDSFR GWAAPGPEPT YPNSTILPTP DTGPTGIKYD
110 120 130 140 150
LDRHQYNYVD AVCYENRLHW FAKYFPYLVL LHTLIFLACS NFWFKFPRTS
160 170 180 190 200
SKLEHFVSIL LKCFDSPWTT RALSETVVEE SDPKPAFSKM NGSMDKKSST
210 220 230 240 250
VSEDVEATVP MLQRTKSRIE QGIVDRSETG VLDKKEGEQA KALFEKVKKF
260 270 280 290 300
RTHVEEGDIV YRLYMRQTII KVIKFILIIC YTVYYVHNIK FDVDCTVDIE
310 320 330 340 350
SLTGYRTYRC AHPLATLFKI LASFYISLVI FYGLICMYTL WWMLRRSLKK
360 370 380 390 400
YSFESIREES SYSDIPDVKN DFAFMLHLID QYDPLYSKRF AVFLSEVSEN
410 420 430 440 450
KLRQLNLNNE WTLDKLRQRL TKNAQDKLEL HLFMLSGIPD TVFDLVELEV
460 470 480 490 500
LKLELIPDVT IPPSIAQLTG LKELWLYHTA AKIEAPALAF LRENLRALHI
510 520 530 540 550
KFTDIKEIPL WIYSLKTLEE LHLTGNLSAE NNRYIVIDGL RELKRLKVLR
560 570 580 590 600
LKSNLSKLPQ VVTDVGVHLQ KLSINNEGTK LIVLNSLKKM ANLTELELIR
610 620 630 640 650
CDLERIPHSI FSLHNLQEID LKDNNLKTIE EIISFQHLHR LTCLKLWYNH
660 670 680 690 700
IAYIPIQIGN LTNLERLYLN RNKIEKIPTQ LFYCRKLRYL DLSHNNLTFL
710 720 730 740 750
PADIGLLQNL QNLAITANRI ETLPPELFQC RKLRALHLGN NVLQSLPSRV
760 770 780 790 800
GELTNLTQIE LRGNRLECLP VELGECPLLK RSGLVVEEDL FNTLPPEVKE
810
RLWRADKEQA
Length:810
Mass (Da):94,199
Last modified:March 1, 2003 - v1
Checksum:iE0C5E6EBEE8275E8
GO

Sequence cautioni

The sequence AAQ88653 differs from that shown. Reason: Erroneous initiation.Curated
The sequence BAA92675 differs from that shown. Reason: Erroneous initiation.Curated
The sequence BAC11161 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti323S → P in BAC11161 (PubMed:14702039).Curated1
Sequence conflicti744Q → R in BAC11161 (PubMed:14702039).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY143166 mRNA Translation: AAN18279.1
AB037858 mRNA Translation: BAA92675.1 Different initiation.
AL672142 Genomic DNA No translation available.
BC051322 mRNA Translation: AAH51322.1
AY358286 mRNA Translation: AAQ88653.1 Different initiation.
AK074723 mRNA Translation: BAC11161.1 Different initiation.
CCDSiCCDS35155.1
RefSeqiNP_001120716.1, NM_001127244.1
NP_001120717.1, NM_001127245.1
NP_062540.2, NM_019594.3
XP_005252152.1, XM_005252095.2
XP_005252153.1, XM_005252096.3
XP_006717249.1, XM_006717186.2
XP_011517165.1, XM_011518863.1
XP_011517166.1, XM_011518864.2
XP_011517167.1, XM_011518865.2
UniGeneiHs.643600

Genome annotation databases

EnsembliENST00000259324; ENSP00000259324; ENSG00000136802
ENST00000372599; ENSP00000361680; ENSG00000136802
ENST00000372600; ENSP00000361682; ENSG00000136802
GeneIDi56262
KEGGihsa:56262
UCSCiuc004bwl.5 human

Keywords - Coding sequence diversityi

Chromosomal rearrangement

Similar proteinsi

Entry informationi

Entry nameiLRC8A_HUMAN
AccessioniPrimary (citable) accession number: Q8IWT6
Secondary accession number(s): Q6UXM2, Q8NCI0, Q9P2B1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 3, 2003
Last sequence update: March 1, 2003
Last modified: July 18, 2018
This is version 156 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 9
    Human chromosome 9: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

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