LRC8A_MOUSE
ID LRC8A_MOUSE Reviewed; 810 AA.
AC Q80WG5; A2AQZ0;
DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Volume-regulated anion channel subunit LRRC8A {ECO:0000305};
DE AltName: Full=Leucine-rich repeat-containing protein 8A {ECO:0000303|PubMed:24752297};
DE AltName: Full=Protein ebouriffe {ECO:0000303|PubMed:8828840};
DE Short=ebo {ECO:0000303|PubMed:8828840};
GN Name=Lrrc8a {ECO:0000303|PubMed:24752297, ECO:0000312|MGI:MGI:2652847};
GN Synonyms=Lrrc8 {ECO:0000303|PubMed:14660746};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP DISEASE.
RX PubMed=8828840; DOI=10.1095/biolreprod55.2.355;
RA Lalouette A., Lablack A., Guenet J.L., Montagutelli X., Segretain D.;
RT "Male sterility caused by sperm cell-specific structural abnormalities in
RT ebouriffe, a new mutation of the house mouse.";
RL Biol. Reprod. 55:355-363(1996).
RN [5]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=14660746; DOI=10.1172/jci200318937;
RA Sawada A., Takihara Y., Kim J.Y., Matsuda-Hashii Y., Tokimasa S.,
RA Fujisaki H., Kubota K., Endo H., Onodera T., Ohta H., Ozono K., Hara J.;
RT "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in
RT humans.";
RL J. Clin. Invest. 112:1707-1713(2003).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=15094057; DOI=10.1016/s0014-5793(04)00332-1;
RA Kubota K., Kim J.Y., Sawada A., Tokimasa S., Fujisaki H.,
RA Matsuda-Hashii Y., Ozono K., Hara J.;
RT "LRRC8 involved in B cell development belongs to a novel family of leucine-
RT rich repeat proteins.";
RL FEBS Lett. 564:147-152(2004).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-200 AND SER-202, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Kidney, Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [8]
RP TISSUE SPECIFICITY.
RX PubMed=24725410; DOI=10.1016/j.cell.2014.03.024;
RA Qiu Z., Dubin A.E., Mathur J., Tu B., Reddy K., Miraglia L.J.,
RA Reinhardt J., Orth A.P., Patapoutian A.;
RT "SWELL1, a plasma membrane protein, is an essential component of volume-
RT regulated anion channel.";
RL Cell 157:447-458(2014).
RN [9]
RP SUBUNIT, INTERACTION WITH LRRC8B; LRRC8C AND LRRC8D, AND SUBCELLULAR
RP LOCATION.
RX PubMed=24782309; DOI=10.1074/jbc.m114.571257;
RA Lee C.C., Freinkman E., Sabatini D.M., Ploegh H.L.;
RT "The protein synthesis inhibitor blasticidin S enters mammalian cells via
RT leucine-rich repeat-containing protein 8D.";
RL J. Biol. Chem. 289:17124-17131(2014).
RN [10]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=24752297; DOI=10.1084/jem.20131379;
RA Kumar L., Chou J., Yee C.S., Borzutzky A., Vollmann E.H., von Andrian U.H.,
RA Park S.Y., Hollander G., Manis J.P., Poliani P.L., Geha R.S.;
RT "Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte
RT development and function.";
RL J. Exp. Med. 211:929-942(2014).
RN [11]
RP DISEASE, AND VARIANT EBO 443-PHE--ALA-810 DEL.
RX PubMed=28192143; DOI=10.1016/j.jaci.2016.12.974;
RA Platt C.D., Chou J., Houlihan P., Badran Y.R., Kumar L., Bainter W.,
RA Poliani P.L., Perez C.J., Dent S.Y.R., Clapham D.E., Benavides F.,
RA Geha R.S.;
RT "Leucine-rich repeat containing 8A (LRRC8A)-dependent volume-regulated
RT anion channel activity is dispensable for T-cell development and
RT function.";
RL J. Allergy Clin. Immunol. 140:1651-1659(2017).
RN [12]
RP DISRUPTION PHENOTYPE.
RX PubMed=29880644; DOI=10.1074/jbc.ra118.003853;
RA Lueck J.C., Puchkov D., Ullrich F., Jentsch T.J.;
RT "LRRC8/VRAC anion channels are required for late stages of spermatid
RT development in mice.";
RL J. Biol. Chem. 293:11796-11808(2018).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29371604; DOI=10.1038/s41467-017-02664-0;
RA Kang C., Xie L., Gunasekar S.K., Mishra A., Zhang Y., Pai S., Gao Y.,
RA Kumar A., Norris A.W., Stephens S.B., Sah R.;
RT "SWELL1 is a glucose sensor regulating beta-cell excitability and systemic
RT glycaemia.";
RL Nat. Commun. 9:367-367(2018).
RN [14]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=29773801; DOI=10.1038/s41467-018-04353-y;
RA Stuhlmann T., Planells-Cases R., Jentsch T.J.;
RT "LRRC8/VRAC anion channels enhance beta-cell glucose sensing and insulin
RT secretion.";
RL Nat. Commun. 9:1974-1974(2018).
RN [15]
RP FUNCTION, SUBCELLULAR LOCATION, DISEASE, DISRUPTION PHENOTYPE, TISSUE
RP SPECIFICITY, AND VARIANT EBO 443-PHE--ALA-810 DEL.
RX PubMed=30135305; DOI=10.1172/jci.insight.99767;
RA Bao J., Perez C.J., Kim J., Zhang H., Murphy C.J., Hamidi T., Jaubert J.,
RA Platt C.D., Chou J., Deng M., Zhou M.H., Huang Y., Gaitan-Penas H.,
RA Guenet J.L., Lin K., Lu Y., Chen T., Bedford M.T., Dent S.Y.,
RA Richburg J.H., Estevez R., Pan H.L., Geha R.S., Shi Q., Benavides F.;
RT "Deficient LRRC8A-dependent volume-regulated anion channel activity is
RT associated with male infertility in mice.";
RL JCI Insight 3:0-0(2018).
RN [16]
RP FUNCTION.
RX PubMed=31387946; DOI=10.1074/jbc.ra119.008840;
RA Chen L., Becker T.M., Koch U., Stauber T.;
RT "The LRRC8/VRAC anion channel facilitates myogenic differentiation of
RT murine myoblasts by promoting membrane hyperpolarization.";
RL J. Biol. Chem. 294:14279-14288(2019).
RN [17]
RP FUNCTION, DISRUPTION PHENOTYPE, AND INTERACTION WITH GRB2.
RX PubMed=32930093; DOI=10.7554/elife.58941;
RA Kumar A., Xie L., Ta C.M., Hinton A.O., Gunasekar S.K., Minerath R.A.,
RA Shen K., Maurer J.M., Grueter C.E., Abel E.D., Meyer G., Sah R.;
RT "SWELL1 regulates skeletal muscle cell size, intracellular signaling,
RT adiposity and glucose metabolism.";
RL Elife 9:0-0(2020).
RN [18]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=32277911; DOI=10.1016/j.immuni.2020.03.016;
RA Zhou C., Chen X., Planells-Cases R., Chu J., Wang L., Cao L., Li Z.,
RA Lopez-Cayuqueo K.I., Xie Y., Ye S., Wang X., Ullrich F., Ma S., Fang Y.,
RA Zhang X., Qian Z., Liang X., Cai S.Q., Jiang Z., Zhou D., Leng Q.,
RA Xiao T.S., Lan K., Yang J., Li H., Peng C., Qiu Z., Jentsch T.J., Xiao H.;
RT "Transfer of cgamp into bystander cells via LRRC8 volume-regulated anion
RT channels augments STING-mediated interferon responses and anti-viral
RT immunity.";
RL Immunity 52:767-781(2020).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 398-810, STRUCTURE BY ELECTRON
RP MICROSCOPY (3.66 ANGSTROMS), STRUCTURE BY ELECTRON MICROSCOPY (7.94
RP ANGSTROMS) IN COMPLEX WITH LRRC8C, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION,
RP TOPOLOGY, DISULFIDE BONDS, AND MUTAGENESIS OF ARG-103.
RX PubMed=29769723; DOI=10.1038/s41586-018-0134-y;
RA Deneka D., Sawicka M., Lam A.K.M., Paulino C., Dutzler R.;
RT "Structure of a volume-regulated anion channel of the LRRC8 family.";
RL Nature 558:254-259(2018).
RN [20] {ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ, ECO:0007744|PDB:6O00}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.21 ANGSTROMS) IN COMPLEX WITH DCPIB,
RP ACTIVITY REGULATION, DISULFIDE BONDS, SUBUNIT, AND DOMAIN.
RX PubMed=30775971; DOI=10.7554/elife.42636;
RA Kern D.M., Oh S., Hite R.K., Brohawn S.G.;
RT "Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel
RT LRRC8A in lipid nanodiscs.";
RL Elife 8:0-0(2019).
CC -!- FUNCTION: Essential component of the volume-regulated anion channel
CC (VRAC, also named VSOAC channel), an anion channel required to maintain
CC a constant cell volume in response to extracellular or intracellular
CC osmotic changes (PubMed:30135305, PubMed:29769723). The VRAC channel
CC conducts iodide better than chloride and can also conduct organic
CC osmolytes like taurine (By similarity). Mediates efflux of amino acids,
CC such as aspartate and glutamate, in response to osmotic stress (By
CC similarity). In complex with LRRC8C or LRRC8E, acts as a transporter of
CC immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune
CC messenger produced in response to DNA virus in the cytosol: mediates
CC both import and export of 2'-3'-cGAMP, thereby promoting transfer of
CC 2'-3'-cGAMP to bystander cells (PubMed:32277911). In contrast,
CC complexes containing LRRC8D inhibit transport of 2'-3'-cGAMP (By
CC similarity). Required for in vivo channel activity, together with at
CC least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E);
CC channel characteristics depend on the precise subunit composition (By
CC similarity). Can form functional channels by itself (in vitro) (By
CC similarity). Involved in B-cell development: required for the pro-B
CC cell to pre-B cell transition (PubMed:14660746, PubMed:24752297). Also
CC required for T-cell development (PubMed:24752297). Required for
CC myoblast differentiation: VRAC activity promotes membrane
CC hyperpolarization and regulates insulin-stimulated glucose metabolism
CC and oxygen consumption (PubMed:31387946, PubMed:32930093). Also acts as
CC a regulator of glucose-sensing in pancreatic beta cells: VRAC currents,
CC generated in response to hypotonicity- or glucose-induced beta cell
CC swelling, depolarize cells, thereby causing electrical excitation,
CC leading to increase glucose sensitivity and insulin secretion
CC (PubMed:29371604, PubMed:29773801). Also plays a role in lysosome
CC homeostasis by forming functional lysosomal VRAC channels in response
CC to low cytoplasmic ionic strength condition: lysosomal VRAC channels
CC are necessary for the formation of large lysosome-derived vacuoles,
CC which store and then expel excess water to maintain cytosolic water
CC homeostasis (By similarity). {ECO:0000250|UniProtKB:Q8IWT6,
CC ECO:0000269|PubMed:14660746, ECO:0000269|PubMed:24752297,
CC ECO:0000269|PubMed:29371604, ECO:0000269|PubMed:29769723,
CC ECO:0000269|PubMed:29773801, ECO:0000269|PubMed:30135305,
CC ECO:0000269|PubMed:31387946, ECO:0000269|PubMed:32277911,
CC ECO:0000269|PubMed:32930093}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823,
CC ChEBI:CHEBI:17996; Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=iodide(out) = iodide(in); Xref=Rhea:RHEA:66324,
CC ChEBI:CHEBI:16382; Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=taurine(out) = taurine(in); Xref=Rhea:RHEA:66328,
CC ChEBI:CHEBI:507393; Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-aspartate(out) = L-aspartate(in); Xref=Rhea:RHEA:66332,
CC ChEBI:CHEBI:29991; Evidence={ECO:0000250|UniProtKB:Q4V8I7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-glutamate(out) = L-glutamate(in); Xref=Rhea:RHEA:66336,
CC ChEBI:CHEBI:29985; Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=myo-inositol(out) = myo-inositol(in); Xref=Rhea:RHEA:32867,
CC ChEBI:CHEBI:17268; Evidence={ECO:0000250|UniProtKB:Q4V8I7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2',3'-cGAMP(out) = 2',3'-cGAMP(in); Xref=Rhea:RHEA:66320,
CC ChEBI:CHEBI:143093; Evidence={ECO:0000269|PubMed:32277911};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66321;
CC Evidence={ECO:0000269|PubMed:32277911};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:66322;
CC Evidence={ECO:0000269|PubMed:32277911};
CC -!- ACTIVITY REGULATION: Inhibited by (4-[(2-butyl-6,7-dichloro-2-
CC cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid), which
CC plugs the channel like a cork in a bottle by binding in the
CC extracellular selectivity filter and sterically occluding ion
CC conduction. {ECO:0000269|PubMed:30775971}.
CC -!- SUBUNIT: Hexamer; forms a trimer of dimers (PubMed:29769723,
CC PubMed:30775971). Heterohexamer; oligomerizes with other LRRC8 proteins
CC (LRRC8B, LRRC8C, LRRC8D and/or LRRC8E) to form a heterohexamer
CC (PubMed:24782309, PubMed:29769723). Can form homohexamers in vitro, but
CC these have lower conductance than heterohexamers (PubMed:29769723).
CC Detected in a channel complex that contains LRRC8A, LRRC8C and LRRC8E
CC (By similarity). In vivo, the subunit composition may depend primarily
CC on expression levels, and heterooligomeric channels containing various
CC proportions of the different LRRC8 proteins may coexist (Probable).
CC Interact with GRB2 (PubMed:32930093). {ECO:0000250|UniProtKB:Q8IWT6,
CC ECO:0000269|PubMed:24782309, ECO:0000269|PubMed:29769723,
CC ECO:0000269|PubMed:30775971, ECO:0000269|PubMed:32930093, ECO:0000305}.
CC -!- INTERACTION:
CC Q80WG5; Q80WG5: Lrrc8a; NbExp=4; IntAct=EBI-20718010, EBI-20718010;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:24782309,
CC ECO:0000269|PubMed:29769723, ECO:0000269|PubMed:30135305}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:29769723,
CC ECO:0000269|PubMed:30775971}. Lysosome membrane
CC {ECO:0000250|UniProtKB:Q8IWT6}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:29769723, ECO:0000269|PubMed:30775971}. Note=Mainly
CC localizes to the cell membrane, with some intracellular localization to
CC lysosomes. {ECO:0000250|UniProtKB:Q8IWT6}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed (PubMed:24725410,
CC PubMed:30135305). High levels detected in the bone marrow; lower levels
CC found in peripheral blood cells (PubMed:14660746, PubMed:15094057,
CC PubMed:24752297). Highly expressed in pancreatic beta cells
CC (PubMed:29773801). {ECO:0000269|PubMed:14660746,
CC ECO:0000269|PubMed:15094057, ECO:0000269|PubMed:24725410,
CC ECO:0000269|PubMed:24752297, ECO:0000269|PubMed:29773801,
CC ECO:0000269|PubMed:30135305}.
CC -!- DOMAIN: The volume-regulated anion channel (VRAC) channel forms a
CC trimer of dimers, with symmetry mismatch between the pore-forming
CC domain and the cytosolic LRR repeats, a topology similar to gap
CC junction proteins. {ECO:0000269|PubMed:30775971}.
CC -!- DOMAIN: The di-leucine motif is required for lysosomal localization.
CC {ECO:0000250|UniProtKB:Q8IWT6}.
CC -!- DOMAIN: The cytoplasmic N-terminus preceding the first transmembrane
CC (residues 1-22) regulates volume-regulated anion channel (VRAC)
CC conductance, ion permeability and inactivation gating.
CC {ECO:0000250|UniProtKB:Q8IWT6}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q8IWT6}.
CC -!- DISEASE: Note=Defects in Lrrc8a are the cause of ebouriffe (ebo), a
CC spontaneous mutation that causes male sterility (PubMed:8828840,
CC PubMed:28192143, PubMed:30135305). Spermatozoa present in the
CC epididymis display severe malformations, mostly of the tail
CC (PubMed:8828840, PubMed:28192143). A drastic decrease of the spermatid
CC population is observed, whereas spermatogonia and spermatocytes seem
CC moderately affected (PubMed:8828840, PubMed:28192143). Defects are
CC caused by decreased volume-regulated anion channel (VRAC) activity in
CC germ cells (PubMed:30135305). Oogenesis is not affected but embryos
CC derived from ebo/ebo females show early developmental failure
CC (PubMed:30135305). {ECO:0000269|PubMed:28192143,
CC ECO:0000269|PubMed:30135305, ECO:0000269|PubMed:8828840}.
CC -!- DISRUPTION PHENOTYPE: Increased prenatal and postnatal mortality,
CC growth retardation, and multiple tissue abnormalities
CC (PubMed:24752297). B-cell development is slightly impaired, without
CC affecting B-cell function (PubMed:24752297). Mice however show a cell-
CC autonomous early block in thymocyte development and impairs peripheral
CC T-cell expansion and function (PubMed:24752297). Conditional deletion
CC in germ cells leads to abnormal sperm and male infertility: the
CC cytoplasm of late spermatids appears swollen, preventing reduction of
CC the cytoplasm during further development into spermatozoa
CC (PubMed:29880644, PubMed:30135305). Spermatozoa display severely
CC disorganized mitochondrial sheaths in the midpiece region, as well as
CC angulated or coiled flagella, resulting in dramatically reduced sperm
CC motility (PubMed:29880644). Conditional deletion in Sertoli cells does
CC not affect male fertility (PubMed:29880644). Conditional deletion in
CC pancreatic beta cells have normal resting serum glucose levels but
CC impaired glucose tolerance (PubMed:29371604, PubMed:29773801).
CC Conditional deletion in myotubes leads to impaired myoblast
CC differentiation: mice have smaller myofibers, generate less force ex
CC vivo, and display reduced exercise endurance, associated with increased
CC adiposity under basal conditions, and glucose intolerance and insulin
CC resistance when raised on a high-fat diet (PubMed:32930093).
CC {ECO:0000269|PubMed:24752297, ECO:0000269|PubMed:29371604,
CC ECO:0000269|PubMed:29773801, ECO:0000269|PubMed:29880644,
CC ECO:0000269|PubMed:30135305, ECO:0000269|PubMed:32930093}.
CC -!- SIMILARITY: Belongs to the LRRC8 family. {ECO:0000305}.
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DR EMBL; AL845258; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466542; EDL08450.1; -; Genomic_DNA.
DR EMBL; BC048152; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS15875.1; -.
DR RefSeq; NP_808393.1; NM_177725.4.
DR PDB; 6FNW; X-ray; 1.80 A; A=398-810.
DR PDB; 6G8Z; EM; 3.66 A; A/B/C/D/E/F=1-810.
DR PDB; 6G9L; EM; 5.01 A; A/B/C/D/E/F=1-810.
DR PDB; 6G9O; EM; 4.25 A; A/B/C/D/E/F=1-810.
DR PDB; 6NZW; EM; 3.21 A; A/B/C/D/E/F=1-810.
DR PDB; 6NZZ; EM; 3.32 A; A/B/C/D/E/F=1-810.
DR PDB; 6O00; EM; 4.18 A; A/B/C/D/E/F=1-810.
DR PDB; 7M17; EM; 3.65 A; A/B/C/D/E/F=1-810.
DR PDB; 7M19; EM; 3.69 A; A/B/C/D/E/F=1-810.
DR PDB; 7P60; EM; 3.80 A; A/B/C/D/E/F=1-810.
DR PDB; 7P6K; EM; 3.80 A; A/B/C/D/E/F=1-810.
DR PDBsum; 6FNW; -.
DR PDBsum; 6G8Z; -.
DR PDBsum; 6G9L; -.
DR PDBsum; 6G9O; -.
DR PDBsum; 6NZW; -.
DR PDBsum; 6NZZ; -.
DR PDBsum; 6O00; -.
DR PDBsum; 7M17; -.
DR PDBsum; 7M19; -.
DR PDBsum; 7P60; -.
DR PDBsum; 7P6K; -.
DR AlphaFoldDB; Q80WG5; -.
DR SMR; Q80WG5; -.
DR BioGRID; 232303; 1.
DR IntAct; Q80WG5; 2.
DR MINT; Q80WG5; -.
DR STRING; 10090.ENSMUSP00000092690; -.
DR GlyGen; Q80WG5; 2 sites.
DR iPTMnet; Q80WG5; -.
DR PhosphoSitePlus; Q80WG5; -.
DR EPD; Q80WG5; -.
DR jPOST; Q80WG5; -.
DR MaxQB; Q80WG5; -.
DR PaxDb; Q80WG5; -.
DR PeptideAtlas; Q80WG5; -.
DR PRIDE; Q80WG5; -.
DR ProteomicsDB; 252672; -.
DR Ensembl; ENSMUST00000095078; ENSMUSP00000092690; ENSMUSG00000007476.
DR Ensembl; ENSMUST00000113654; ENSMUSP00000109284; ENSMUSG00000007476.
DR Ensembl; ENSMUST00000139454; ENSMUSP00000139038; ENSMUSG00000099041.
DR GeneID; 241296; -.
DR KEGG; mmu:241296; -.
DR UCSC; uc008jbu.2; mouse.
DR CTD; 56262; -.
DR MGI; MGI:2652847; Lrrc8a.
DR VEuPathDB; HostDB:ENSMUSG00000007476; -.
DR VEuPathDB; HostDB:ENSMUSG00000099041; -.
DR eggNOG; KOG0619; Eukaryota.
DR GeneTree; ENSGT00940000154043; -.
DR HOGENOM; CLU_019019_0_0_1; -.
DR InParanoid; Q80WG5; -.
DR OMA; PMLQRSK; -.
DR OrthoDB; 158390at2759; -.
DR PhylomeDB; Q80WG5; -.
DR TreeFam; TF331443; -.
DR Reactome; R-MMU-5223345; Miscellaneous transport and binding events.
DR BioGRID-ORCS; 241296; 6 hits in 72 CRISPR screens.
DR ChiTaRS; Lrrc8a; mouse.
DR PRO; PR:Q80WG5; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q80WG5; protein.
DR Bgee; ENSMUSG00000007476; Expressed in ankle joint and 254 other tissues.
DR Genevisible; Q80WG5; MM.
DR GO; GO:0009986; C:cell surface; ISO:MGI.
DR GO; GO:1905103; C:integral component of lysosomal membrane; ISO:MGI.
DR GO; GO:0016021; C:integral component of membrane; ISO:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0034702; C:ion channel complex; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005253; F:anion channel activity; ISO:MGI.
DR GO; GO:0140360; F:cyclic-GMP-AMP transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005225; F:volume-sensitive anion channel activity; IDA:UniProtKB.
DR GO; GO:0098656; P:anion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006820; P:anion transport; ISS:UniProtKB.
DR GO; GO:0015810; P:aspartate transmembrane transport; ISO:MGI.
DR GO; GO:0006884; P:cell volume homeostasis; ISS:UniProtKB.
DR GO; GO:0001678; P:cellular glucose homeostasis; IMP:UniProtKB.
DR GO; GO:1902476; P:chloride transmembrane transport; ISO:MGI.
DR GO; GO:0140361; P:cyclic-GMP-AMP transmembrane import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0032024; P:positive regulation of insulin secretion; IMP:UniProtKB.
DR GO; GO:0045663; P:positive regulation of myoblast differentiation; IMP:UniProtKB.
DR GO; GO:0002329; P:pre-B cell differentiation; IMP:UniProtKB.
DR GO; GO:0034214; P:protein hexamerization; IDA:UniProtKB.
DR GO; GO:0006970; P:response to osmotic stress; ISS:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; IMP:UniProtKB.
DR GO; GO:0015734; P:taurine transport; ISO:MGI.
DR Gene3D; 3.80.10.10; -; 2.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR021040; LRRC8_Pannexin-like.
DR Pfam; PF13855; LRR_8; 3.
DR Pfam; PF12534; Pannexin_like; 1.
DR SMART; SM00369; LRR_TYP; 8.
DR PROSITE; PS51450; LRR; 11.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell membrane; Differentiation; Disulfide bond;
KW Glycoprotein; Ion channel; Ion transport; Leucine-rich repeat; Lysosome;
KW Membrane; Phosphoprotein; Reference proteome; Repeat; Spermatogenesis;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..810
FT /note="Volume-regulated anion channel subunit LRRC8A"
FT /id="PRO_0000084500"
FT TOPO_DOM 1..22
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:29769723"
FT TRANSMEM 23..47
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:30775971,
FT ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ,
FT ECO:0007744|PDB:6O00"
FT TOPO_DOM 48..123
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:29769723"
FT TRANSMEM 124..142
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:30775971,
FT ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ,
FT ECO:0007744|PDB:6O00"
FT TOPO_DOM 143..264
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:29769723"
FT TRANSMEM 265..286
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:30775971,
FT ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ,
FT ECO:0007744|PDB:6O00"
FT TOPO_DOM 287..316
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:29769723"
FT TRANSMEM 317..341
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:30775971,
FT ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ,
FT ECO:0007744|PDB:6O00"
FT TOPO_DOM 342..810
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:29769723"
FT REPEAT 399..422
FT /note="LRR 1"
FT /evidence="ECO:0000255"
FT REPEAT 423..445
FT /note="LRR 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 447..468
FT /note="LRR 3"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 469..492
FT /note="LRR 4"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 493..515
FT /note="LRR 5"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 518..542
FT /note="LRR 6"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 543..565
FT /note="LRR 7"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 567..589
FT /note="LRR 8"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 590..613
FT /note="LRR 9"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 614..637
FT /note="LRR 10"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 639..661
FT /note="LRR 11"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 662..684
FT /note="LRR 12"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 686..707
FT /note="LRR 13"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 708..730
FT /note="LRR 14"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 732..753
FT /note="LRR 15"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 754..776
FT /note="LRR 16"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT REPEAT 778..801
FT /note="LRR 17"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:29769723"
FT MOTIF 706..707
FT /note="Di-leucine motif"
FT /evidence="ECO:0000250|UniProtKB:Q8IWT6"
FT SITE 103
FT /note="Required for anion selectivity"
FT /evidence="ECO:0000250|UniProtKB:Q8IWT6"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q8IWT6"
FT MOD_RES 200
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 202
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 215
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8IWT6"
FT MOD_RES 217
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8IWT6"
FT CARBOHYD 66
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 83
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 54..310
FT /evidence="ECO:0000269|PubMed:29769723,
FT ECO:0000269|PubMed:30775971, ECO:0007744|PDB:6G8Z,
FT ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ,
FT ECO:0007744|PDB:6O00"
FT DISULFID 57..65
FT /evidence="ECO:0000269|PubMed:29769723,
FT ECO:0000269|PubMed:30775971, ECO:0007744|PDB:6G8Z,
FT ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ,
FT ECO:0007744|PDB:6O00"
FT DISULFID 113..295
FT /evidence="ECO:0000269|PubMed:29769723,
FT ECO:0000269|PubMed:30775971, ECO:0007744|PDB:6G8Z,
FT ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ,
FT ECO:0007744|PDB:6O00"
FT VARIANT 443..810
FT /note="Missing (in ebo; causes male sterility)"
FT /evidence="ECO:0000269|PubMed:28192143,
FT ECO:0000269|PubMed:30135305"
FT MUTAGEN 103
FT /note="R->A: No effect on anion channel activity. Impairs
FT channel selectivity, so that the channel is also permeable
FT to Na(+) ions."
FT /evidence="ECO:0000269|PubMed:29769723"
FT HELIX 17..20
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 23..25
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 27..48
FT /evidence="ECO:0007829|PDB:6NZW"
FT STRAND 53..56
FT /evidence="ECO:0007829|PDB:6NZZ"
FT STRAND 58..61
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 104..115
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 120..123
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 125..145
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 147..164
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 168..173
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 234..253
FT /evidence="ECO:0007829|PDB:6NZW"
FT TURN 254..256
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 259..285
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 286..288
FT /evidence="ECO:0007829|PDB:6NZW"
FT STRAND 291..296
FT /evidence="ECO:0007829|PDB:6NZW"
FT TURN 300..303
FT /evidence="ECO:0007829|PDB:6NZW"
FT STRAND 306..311
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 315..345
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 354..360
FT /evidence="ECO:0007829|PDB:6NZW"
FT STRAND 370..372
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 373..382
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 385..388
FT /evidence="ECO:0007829|PDB:6NZW"
FT TURN 389..394
FT /evidence="ECO:0007829|PDB:6NZW"
FT HELIX 398..410
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 413..419
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 428..434
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 440..444
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 450..455
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 457..461
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 463..467
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 473..478
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 481..483
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 485..494
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 497..501
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 505..507
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 510..514
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 520..525
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 535..538
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 539..542
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 548..553
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 560..564
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 565..567
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 571..575
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 586..589
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 594..600
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 608..612
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 618..620
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 630..637
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 643..645
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 656..660
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 665..668
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 679..683
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 689..691
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 702..706
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 712..714
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 725..729
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 735..737
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 748..752
FT /evidence="ECO:0007829|PDB:6FNW"
FT STRAND 758..760
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 771..775
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 781..783
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 788..792
FT /evidence="ECO:0007829|PDB:6FNW"
FT HELIX 796..807
FT /evidence="ECO:0007829|PDB:6FNW"
SQ SEQUENCE 810 AA; 94120 MW; E3B125BC9977DBB0 CRC64;
MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD KMICLPCKWV
TKDSCNDSFR GWAASSPEPT YPNSTVLPTP DTGPTGIKYD LDRHQYNYVD AVCYENRLHW
FAKYFPYLVL LHTLIFLACS NFWFKFPRTS SKLEHFVSIL LKCFDSPWTT RALSETVVEE
SDPKPAFSKM NGSMDKKSST VSEDVEATVP MLQRTKSRIE QGIVDRSETG VLDKKEGEQA
KALFEKVKKF RTHVEEGDIV YRLYMRQTII KVIKFALIIC YTVYYVHNIK FDVDCTVDIE
SLTGYRTYRC AHPLATLFKI LASFYISLVI FYGLICMYTL WWMLRRSLKK YSFESIREES
SYSDIPDVKN DFAFMLHLID QYDPLYSKRF AVFLSEVSEN KLRQLNLNNE WTLDKLRQRL
TKNAQDKLEL HLFMLSGIPD TVFDLVELEV LKLELIPDVT IPPSIAQLTG LKELWLYHTA
AKIEAPALAF LRENLRALHI KFTDIKEIPL WIYSLKTLEE LHLTGNLSAE NNRYIVIDGL
RELKRLKVLR LKSNLSKLPQ VVTDVGVHLQ KLSINNEGTK LIVLNSLKKM VNLTELELIR
CDLERIPHSI FSLHNLQEID LKDNNLKTIE EIISFQHLHR LTCLKLWYNH IAYIPIQIGN
LTNLERLYLN RNKIEKIPTQ LFYCRKLRYL DLSHNNLTFL PADIGLLQNL QNLAVTANRI
EALPPELFQC RKLRALHLGN NVLQSLPSRV GELTNLTQIE LRGNRLECLP VELGECPLLK
RSGLVVEEDL FSTLPPEVKE RLWRADKEQA
