LRC8D_MOUSE
ID LRC8D_MOUSE Reviewed; 859 AA.
AC Q8BGR2; Q3UVA9; Q8CI13;
DT 31-AUG-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Volume-regulated anion channel subunit LRRC8D {ECO:0000305};
DE AltName: Full=Leucine-rich repeat-containing protein 5 {ECO:0000312|MGI:MGI:1922368};
DE AltName: Full=Leucine-rich repeat-containing protein 8D {ECO:0000303|PubMed:24782309};
GN Name=Lrrc8d {ECO:0000303|PubMed:24782309, ECO:0000312|MGI:MGI:1922368};
GN Synonyms=Lrrc5 {ECO:0000312|MGI:MGI:1922368};
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 MRNA].
RC STRAIN=C57BL/6J; TISSUE=Bone, Corpora quadrigemina, Liver, and Retina;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Kidney;
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 [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Kidney, Lung, and Pancreas;
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 [4]
RP SUBUNIT, AND INTERACTION WITH LRRC8B; LRRC8C AND LRRC8A.
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 [5]
RP FUNCTION, SUBCELLULAR LOCATION, 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).
CC -!- FUNCTION: Non-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:29773801). The VRAC channel conducts iodide
CC better than chloride and can also conduct organic osmolytes like
CC taurine (By similarity). Plays a redundant role in the efflux of amino
CC acids, such as aspartate, in response to osmotic stress family member
CC (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on
CC the precise subunit composition (By similarity). Also acts as a
CC 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:29773801). VRAC channels containing LRRC8D inhibit transport of
CC immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune
CC messenger produced in response to DNA virus in the cytosol (By
CC similarity). {ECO:0000250|UniProtKB:Q7L1W4,
CC ECO:0000269|PubMed:29773801}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823,
CC ChEBI:CHEBI:17996; Evidence={ECO:0000250|UniProtKB:Q7L1W4};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=iodide(out) = iodide(in); Xref=Rhea:RHEA:66324,
CC ChEBI:CHEBI:16382; Evidence={ECO:0000250|UniProtKB:Q7L1W4};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=taurine(out) = taurine(in); Xref=Rhea:RHEA:66328,
CC ChEBI:CHEBI:507393; Evidence={ECO:0000250|UniProtKB:Q7L1W4};
CC -!- SUBUNIT: Heterohexamer (Probable). Oligomerizes with other LRRC8
CC proteins (LRRC8A, LRRC8B, LRRC8C and/or LRRC8E) to form a
CC heterohexamer. In vivo, the subunit composition may depend primarily on
CC expression levels, and heterooligomeric channels containing various
CC proportions of the different LRRC8 proteins may coexist
CC (PubMed:24782309). {ECO:0000269|PubMed:24782309, ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:29773801};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q7L1W4}. Endoplasmic
CC reticulum membrane {ECO:0000250|UniProtKB:Q7L1W4}; Multi-pass membrane
CC protein {ECO:0000250|UniProtKB:Q7L1W4}. Note=In the absence of LRRC8A,
CC resides primarily in a cytoplasmic compartment, probably the
CC endoplasmic reticulum (PubMed:29773801). Requires LRRC8A for expression
CC at the cell membrane (By similarity). {ECO:0000250|UniProtKB:Q7L1W4,
CC ECO:0000269|PubMed:29773801}.
CC -!- TISSUE SPECIFICITY: Expressed in pancreatic beta cells
CC (PubMed:29773801). Also expressed in glucagon-secreting pancreatic
CC alpha cells (PubMed:29773801). {ECO:0000269|PubMed:29773801}.
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:0000250|UniProtKB:Q7L1W4}.
CC -!- SIMILARITY: Belongs to the LRRC8 family. {ECO:0000305}.
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DR EMBL; AK046249; BAC32656.1; -; mRNA.
DR EMBL; AK050400; BAC34237.1; -; mRNA.
DR EMBL; AK080722; BAC37994.1; -; mRNA.
DR EMBL; AK137459; BAE23361.1; -; mRNA.
DR EMBL; BC037717; AAH37717.1; -; mRNA.
DR CCDS; CCDS19494.1; -.
DR RefSeq; NP_001116240.1; NM_001122768.1.
DR RefSeq; NP_848816.3; NM_178701.3.
DR RefSeq; XP_006534956.1; XM_006534893.2.
DR RefSeq; XP_006534957.1; XM_006534894.3.
DR RefSeq; XP_006534958.1; XM_006534895.3.
DR RefSeq; XP_006534959.1; XM_006534896.3.
DR RefSeq; XP_011247738.1; XM_011249436.1.
DR AlphaFoldDB; Q8BGR2; -.
DR SMR; Q8BGR2; -.
DR STRING; 10090.ENSMUSP00000113603; -.
DR iPTMnet; Q8BGR2; -.
DR PhosphoSitePlus; Q8BGR2; -.
DR EPD; Q8BGR2; -.
DR MaxQB; Q8BGR2; -.
DR PaxDb; Q8BGR2; -.
DR PRIDE; Q8BGR2; -.
DR ProteomicsDB; 252516; -.
DR Antibodypedia; 2631; 51 antibodies from 18 providers.
DR DNASU; 231549; -.
DR Ensembl; ENSMUST00000060531; ENSMUSP00000057293; ENSMUSG00000046079.
DR Ensembl; ENSMUST00000120847; ENSMUSP00000113603; ENSMUSG00000046079.
DR GeneID; 231549; -.
DR KEGG; mmu:231549; -.
DR UCSC; uc008ylg.2; mouse.
DR CTD; 55144; -.
DR MGI; MGI:1922368; Lrrc8d.
DR VEuPathDB; HostDB:ENSMUSG00000046079; -.
DR eggNOG; KOG0619; Eukaryota.
DR GeneTree; ENSGT00940000154043; -.
DR HOGENOM; CLU_019019_0_0_1; -.
DR InParanoid; Q8BGR2; -.
DR OMA; VKFIFIL; -.
DR OrthoDB; 187778at2759; -.
DR PhylomeDB; Q8BGR2; -.
DR TreeFam; TF331443; -.
DR Reactome; R-MMU-5223345; Miscellaneous transport and binding events.
DR BioGRID-ORCS; 231549; 2 hits in 72 CRISPR screens.
DR ChiTaRS; Lrrc8d; mouse.
DR PRO; PR:Q8BGR2; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q8BGR2; protein.
DR Bgee; ENSMUSG00000046079; Expressed in otolith organ and 243 other tissues.
DR ExpressionAtlas; Q8BGR2; baseline and differential.
DR Genevisible; Q8BGR2; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0034702; C:ion channel complex; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005225; F:volume-sensitive anion channel activity; IMP:UniProtKB.
DR GO; GO:0098656; P:anion transmembrane transport; ISS:UniProtKB.
DR GO; GO:0015810; P:aspartate transmembrane transport; ISS:UniProtKB.
DR GO; GO:0001678; P:cellular glucose homeostasis; IMP:UniProtKB.
DR GO; GO:0071470; P:cellular response to osmotic stress; ISS:UniProtKB.
DR GO; GO:0034214; P:protein hexamerization; ISS:UniProtKB.
DR GO; GO:0015734; P:taurine transport; ISS:UniProtKB.
DR Gene3D; 3.80.10.10; -; 1.
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; 2.
DR Pfam; PF12534; Pannexin_like; 1.
DR SMART; SM00369; LRR_TYP; 7.
DR PROSITE; PS51450; LRR; 9.
PE 1: Evidence at protein level;
KW Cell membrane; Disulfide bond; Endoplasmic reticulum; Ion channel;
KW Ion transport; Leucine-rich repeat; Membrane; Phosphoprotein;
KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..859
FT /note="Volume-regulated anion channel subunit LRRC8D"
FT /id="PRO_0000084494"
FT TOPO_DOM 1..22
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT TRANSMEM 23..48
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT TOPO_DOM 49..164
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT TRANSMEM 165..183
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT TOPO_DOM 184..309
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT TRANSMEM 310..331
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT TOPO_DOM 332..361
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT TRANSMEM 362..387
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT TOPO_DOM 388..859
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT REPEAT 515..535
FT /note="LRR 1"
FT REPEAT 539..560
FT /note="LRR 2"
FT REPEAT 562..583
FT /note="LRR 3"
FT REPEAT 590..610
FT /note="LRR 4"
FT REPEAT 613..633
FT /note="LRR 5"
FT REPEAT 637..658
FT /note="LRR 6"
FT REPEAT 660..681
FT /note="LRR 7"
FT REPEAT 685..706
FT /note="LRR 8"
FT REPEAT 708..729
FT /note="LRR 9"
FT REPEAT 731..752
FT /note="LRR 10"
FT REPEAT 754..775
FT /note="LRR 11"
FT REPEAT 777..798
FT /note="LRR 12"
FT REPEAT 800..821
FT /note="LRR 13"
FT REGION 110..138
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 222..252
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 123..138
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 228..252
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 242
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT MOD_RES 243
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT MOD_RES 247
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7L1W4"
FT DISULFID 54..355
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT CONFLICT 75
FT /note="I -> V (in Ref. 2; AAH37717)"
FT /evidence="ECO:0000305"
FT CONFLICT 128
FT /note="A -> V (in Ref. 2; AAH37717)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 859 AA; 98113 MW; 7A8DD3CF52AB982D CRC64;
MFTLAEVASL NDIQPTYRIL KPWWDVFMDY LAVVMLMVAI FAGTMQLTKD QVVCLPVLPS
PANSKAHTPP GNADITTEVP RMETATHQDQ NGQTTTNDVA FGTSAVTPDI PLQATHPHAE
STLPNQEAKK EKRDPTGRKT NLDFQQYVFI NQMCYHLALP WYSKYFPYLA LIHTIILMVS
SNFWFKYPKT CSKVEHFVSI LGKCFESPWT TKALSETACE DSEENKQRIT GAQTLPKHVS
TSSDEGSPSA STPMINKTGF KFSAEKPVIE VPSMTILDKK DGEQAKALFE KVRKFRAHVE
DSDLIYKLYV VQTLIKTAKF IFILCYTANF VNAISFEHVC KPKVEHLTGY EVFECTHNMA
YMLKKLLISY ISIICVYGFI CLYTLFWLFR IPLKEYSFEK VREESSFSDI PDVKNDFAFL
LHMVDQYDQL YSKRFGVFLS EVSENKLREI SLNHEWTFEK LRQHVSRNAQ DKQELHLFML
SGVPDAVFDL TDLDVLKLEL IPEAKIPAKI SQMTNLQELH LCHCPAKVEQ TAFSFLRDHL
RCLHVKFTDV AEIPAWVYLL KNLRELYLIG NLNSENNKMI GLESLRELRH LKILHVKSNL
TKVPSNITDV APHLTKLVIH NDGTKLLVLN SLKKMMNVAE LELQNCELER IPHAIFSLSN
LQELDLKSNN IRTIEEIISF QHLKRLTCLK LWHNKIVAIP PSITHVKNLE SLYFSNNKLE
SLPTAVFSLQ KLRCLDVSYN NISTIPIEIG LLQNLQHLHI TGNKVDILPK QLFKCVKLRT
LNLGQNCIAS LPEKISQLTQ LTQLELKGNC LDRLPAQLGQ CRMLKKSGLV VEDQLFDTLP
LEVKEALNQD VNVPFANGI
