S4A4_HUMAN
ID S4A4_HUMAN Reviewed; 1079 AA.
AC Q9Y6R1; C4B714; O15153; Q8NEJ2; Q9H262; Q9NRZ1; Q9UIC0; Q9UIC1; Q9UP50;
DT 20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Electrogenic sodium bicarbonate cotransporter 1;
DE Short=Sodium bicarbonate cotransporter;
DE AltName: Full=Na(+)/HCO3(-) cotransporter;
DE AltName: Full=Solute carrier family 4 member 4;
DE AltName: Full=kNBC1;
GN Name=SLC4A4; Synonyms=NBC, NBC1, NBCE1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=9235899; DOI=10.1074/jbc.272.31.19111;
RA Burnham C.E., Amlal H., Wang Z., Shull G.E., Soleimani M.;
RT "Cloning and functional expression of a human kidney Na+:HCO3-
RT cotransporter.";
RL J. Biol. Chem. 272:19111-19114(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Pancreas;
RX PubMed=9651366; DOI=10.1074/jbc.273.28.17689;
RA Abuladze N., Lee I., Newman D., Hwang J., Boorer K., Pushkin A., Kurtz I.;
RT "Molecular cloning, chromosomal localization, tissue distribution, and
RT functional expression of the human pancreatic sodium bicarbonate
RT cotransporter.";
RL J. Biol. Chem. 273:17689-17695(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Heart, Kidney, and Prostate;
RX PubMed=10069984; DOI=10.1152/ajpcell.1999.276.3.c576;
RA Choi I., Romero M.F., Khandoudi N., Bril A., Boron W.F.;
RT "Cloning and characterization of a human electrogenic Na+-HCO-3
RT cotransporter isoform (hhNBC).";
RL Am. J. Physiol. 276:C576-C584(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION IN CORNEAL ENDOTHELIAL
RP CELLS, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RC TISSUE=Corneal endothelium;
RX PubMed=12907161; DOI=10.1016/s0014-4835(03)00150-7;
RA Sun X.C., Bonanno J.A.;
RT "Identification and cloning of the Na/HCO3- cotransporter (NBC) in human
RT corneal endothelium.";
RL Exp. Eye Res. 77:287-295(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RC TISSUE=Skeletal muscle;
RA Pushkin A., Abuladze N., Kurtz I.;
RT "Homo sapiens sodium bicarbonate cotransporter NBC1 splice variant.";
RL Submitted (JUN-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
RA Yamada H., Nagayoshi A., Kuroda Y., Mizutani A., Ando H., Seki G.,
RA Mikoshiba K.;
RT "cDNA cloning and characterization of human sodium bicarbonate
RT cotransporter, bNBC, a brain type splicing variant of SLC4A4 gene.";
RL Submitted (NOV-2008) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC 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 [9]
RP REGULATION, MUTAGENESIS OF SER-1026, AND PHOSPHORYLATION AT SER-1026.
RX PubMed=11744745; DOI=10.1113/jphysiol.2001.012956;
RA Gross E., Hawkins K., Pushkin A., Sassani P., Dukkipati R., Abuladze N.,
RA Hopfer U., Kurtz I.;
RT "Phosphorylation of Ser(982) in the sodium bicarbonate cotransporter kNBC1
RT shifts the HCO(3)(-):Na(+) stoichiometry from 3:1 to 2:1 in murine proximal
RT tubule cells.";
RL J. Physiol. (Lond.) 537:659-665(2001).
RN [10]
RP ERRATUM OF PUBMED:11744745.
RA Gross E., Hawkins K., Pushkin A., Sassani P., Dukkipati R., Abuladze N.,
RA Hopfer U., Kurtz I.;
RL J. Physiol. (Lond.) 538:1003-1003(2002).
RN [11]
RP TISSUE SPECIFICITY.
RX PubMed=11743927; DOI=10.1016/s0003-9969(01)00098-x;
RA Park K., Hurley P.T., Roussa E., Cooper G.J., Smith C.P., Thevenod F.,
RA Steward M.C., Case R.M.;
RT "Expression of a sodium bicarbonate cotransporter in human parotid salivary
RT glands.";
RL Arch. Oral Biol. 47:1-9(2002).
RN [12]
RP REGULATION, MUTAGENESIS OF ASP-1030; ASP-1032 AND ASP-1033, AND INTERACTION
RP WITH CA2.
RX PubMed=12411514; DOI=10.1113/jphysiol.2002.029777;
RA Gross E., Pushkin A., Abuladze N., Fedotoff O., Kurtz I.;
RT "Regulation of the sodium bicarbonate cotransporter kNBC1 function: role of
RT Asp(986), Asp(988) and kNBC1-carbonic anhydrase II binding.";
RL J. Physiol. (Lond.) 544:679-685(2002).
RN [13]
RP GLYCOSYLATION.
RX PubMed=12604466; DOI=10.1152/ajprenal.00131.2002;
RA Choi I., Hu L., Rojas J.D., Schmitt B.M., Boron W.F.;
RT "Role of glycosylation in the renal electrogenic Na+-HCO3-cotransporter
RT (NBCe1).";
RL Am. J. Physiol. 284:F1199-F1206(2003).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=14559244; DOI=10.1016/j.bbrc.2003.09.147;
RA Yamada H., Yamazaki S., Moriyama N., Hara C., Horita S., Enomoto Y.,
RA Kudo A., Kawakami H., Tanaka Y., Fujita T., Seki G.;
RT "Localization of NBC-1 variants in human kidney and renal cell carcinoma.";
RL Biochem. Biophys. Res. Commun. 310:1213-1218(2003).
RN [15]
RP SUBCELLULAR LOCATION, AND TOPOLOGY.
RX PubMed=12534288; DOI=10.1021/bi026826q;
RA Tatishchev S., Abuladze N., Pushkin A., Newman D., Liu W., Weeks D.,
RA Sachs G., Kurtz I.;
RT "Identification of membrane topography of the electrogenic sodium
RT bicarbonate cotransporter pNBC1 by in vitro transcription/translation.";
RL Biochemistry 42:755-765(2003).
RN [16]
RP REGULATION, INTERACTION WITH CA2 AND CA4, AND MUTAGENESIS OF GLY-767.
RX PubMed=14567693; DOI=10.1021/bi0353124;
RA Alvarez B.V., Loiselle F.B., Supuran C.T., Schwartz G.J., Casey J.R.;
RT "Direct extracellular interaction between carbonic anhydrase IV and the
RT human NBC1 sodium/bicarbonate co-transporter.";
RL Biochemistry 42:12321-12329(2003).
RN [17]
RP REGULATION, MUTAGENESIS OF THR-49 AND SER-1026, AND PHOSPHORYLATION AT
RP THR-49.
RX PubMed=12730338; DOI=10.1113/jphysiol.2003.042226;
RA Gross E., Fedotoff O., Pushkin A., Abuladze N., Newman D., Kurtz I.;
RT "Phosphorylation-induced modulation of pNBC1 function: distinct roles for
RT the amino- and carboxy-termini.";
RL J. Physiol. (Lond.) 549:673-682(2003).
RN [18]
RP TISSUE SPECIFICITY.
RX PubMed=15329059; DOI=10.1111/j.1365-201x.2004.01297.x;
RA Kristensen J.M., Kristensen M., Juel C.;
RT "Expression of Na+/HCO3- co-transporter proteins (NBCs) in rat and human
RT skeletal muscle.";
RL Acta Physiol. Scand. 182:69-76(2004).
RN [19]
RP MUTAGENESIS OF PHE-1057, AND SUBCELLULAR LOCATION.
RX PubMed=15273250; DOI=10.1074/jbc.m405780200;
RA Li H.C., Worrell R.T., Matthews J.B., Husseinzadeh H., Neumeier L.,
RA Petrovic S., Conforti L., Soleimani M.;
RT "Identification of a carboxyl-terminal motif essential for the targeting of
RT Na+-HCO-3 cotransporter NBC1 to the basolateral membrane.";
RL J. Biol. Chem. 279:43190-43197(2004).
RN [20]
RP INTERACTION WITH CA2, AND MUTAGENESIS OF 1002-LEU--ASN-1004 AND
RP 1030-ASP--ASP-1033.
RX PubMed=15218065; DOI=10.1113/jphysiol.2004.065110;
RA Pushkin A., Abuladze N., Gross E., Newman D., Tatishchev S., Lee I.,
RA Fedotoff O., Bondar G., Azimov R., Ngyuen M., Kurtz I.;
RT "Molecular mechanism of kNBC1-carbonic anhydrase II interaction in proximal
RT tubule cells.";
RL J. Physiol. (Lond.) 559:55-65(2004).
RN [21]
RP INTERACTION WITH CA4.
RX PubMed=15563508; DOI=10.1093/hmg/ddi023;
RA Yang Z., Alvarez B.V., Chakarova C., Jiang L., Karan G., Frederick J.M.,
RA Zhao Y., Sauve Y., Li X., Zrenner E., Wissinger B., Den Hollander A.I.,
RA Katz B., Baehr W., Cremers F.P., Casey J.R., Bhattacharya S.S., Zhang K.;
RT "Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal
RT photoreceptor degeneration.";
RL Hum. Mol. Genet. 14:255-265(2005).
RN [22]
RP MUTAGENESIS OF TYR-477; ASP-493; ALA-494; GLU-503; SER-504; GLU-536;
RP GLU-552; ARG-554; ARG-582; GLU-586; ASP-599; ALA-600; LYS-602; LYS-603;
RP ASP-691; PHE-700; LYS-711; LYS-712; LYS-714; THR-715; THR-721; ARG-724;
RP LYS-725; SER-728; ASP-729; ASP-743; ASP-749; LYS-752; ARG-766; GLU-775;
RP ASP-798; 808-ARG--LYS-809; 814-LYS--LYS-815; HIS-820; ASP-822; HIS-851;
RP ASP-853; 858-GLU--GLU-860; 875-GLU--ARG-877; LYS-898; 925-ARG--LYS-927;
RP ARG-948; ARG-949; HIS-951; LYS-968 AND ARG-987.
RX PubMed=15817634; DOI=10.1113/jphysiol.2005.084988;
RA Abuladze N., Azimov R., Newman D., Sassani P., Liu W., Tatishchev S.,
RA Pushkin A., Kurtz I.;
RT "Critical amino acid residues involved in the electrogenic sodium-
RT bicarbonate cotransporter kNBC1-mediated transport.";
RL J. Physiol. (Lond.) 565:717-730(2005).
RN [23]
RP FUNCTION, FUNCTION (ISOFORM 2), AND INTERACTION WITH AHCYL1 (ISOFORM 1).
RX PubMed=16769890; DOI=10.1073/pnas.0602250103;
RA Shirakabe K., Priori G., Yamada H., Ando H., Horita S., Fujita T.,
RA Fujimoto I., Mizutani A., Seki G., Mikoshiba K.;
RT "IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein,
RT specifically binds to and activates pancreas-type Na+/HCO3-cotransporter 1
RT (pNBC1).";
RL Proc. Natl. Acad. Sci. U.S.A. 103:9542-9547(2006).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-254; SER-257 AND SER-1034,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [25]
RP DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-641 AND ASN-661.
RX PubMed=25568315; DOI=10.1074/jbc.m114.619320;
RA Zhu Q., Kao L., Azimov R., Abuladze N., Newman D., Kurtz I.;
RT "Interplay between disulfide bonding and N-glycosylation defines SLC4 Na+-
RT coupled transporter extracellular topography.";
RL J. Biol. Chem. 290:5391-5404(2015).
RN [26] {ECO:0007744|PDB:6CAA}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.90 ANGSTROMS) OF 77-1079, FUNCTION,
RP SUBUNIT, SUBCELLULAR LOCATION, TOPOLOGY, AND MUTAGENESIS OF SER-527;
RP 527-SER--THR-529; ASP-798; THR-802; VAL-842; ALA-844; THR-845 AND ILE-847.
RX PubMed=29500354; DOI=10.1038/s41467-018-03271-3;
RA Huynh K.W., Jiang J., Abuladze N., Tsirulnikov K., Kao L., Shao X.,
RA Newman D., Azimov R., Pushkin A., Zhou Z.H., Kurtz I.;
RT "CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter
RT NBCe1.";
RL Nat. Commun. 9:900-900(2018).
RN [27]
RP VARIANTS PRTA-OA SER-342 AND HIS-554.
RX PubMed=10545938; DOI=10.1038/15440;
RA Igarashi T., Inatomi J., Sekine T., Cha S.H., Kanai Y., Kunimi M.,
RA Tsukamoto K., Satoh H., Shimadzu M., Tozawa F., Mori T., Shiobara M.,
RA Seki G., Endou H.;
RT "Mutations in SLC4A4 cause permanent isolated proximal renal tubular
RT acidosis with ocular abnormalities.";
RL Nat. Genet. 23:264-266(1999).
RN [28]
RP VARIANT PRTA-OA LEU-471.
RX PubMed=15471865; DOI=10.1074/jbc.m406591200;
RA Dinour D., Chang M.-H., Satoh J., Smith B.L., Angle N., Knecht A.,
RA Serban I., Holtzman E.J., Romero M.F.;
RT "A novel missense mutation in the sodium bicarbonate cotransporter
RT (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion
RT transport defects.";
RL J. Biol. Chem. 279:52238-52246(2004).
RN [29]
RP VARIANTS PRTA-OA SER-342; LEU-471 AND HIS-554, AND MUTAGENESIS OF GLU-135.
RX PubMed=15713912; DOI=10.1152/ajprenal.00032.2005;
RA Li H.C., Szigligeti P., Worrell R.T., Matthews J.B., Conforti L.,
RA Soleimani M.;
RT "Missense mutations in Na+:HCO3- cotransporter NBC1 show abnormal
RT trafficking in polarized kidney cells: a basis of proximal renal tubular
RT acidosis.";
RL Am. J. Physiol. 289:F61-F71(2005).
RN [30]
RP VARIANTS PRTA-OA SER-342; SER-529; HIS-554; VAL-843 AND CYS-925.
RX PubMed=15930088; DOI=10.1681/asn.2004080667;
RA Horita S., Yamada H., Inatomi J., Moriyama N., Sekine T., Igarashi T.,
RA Endo Y., Dasouki M., Ekim M., Al-Gazali L., Shimadzu M., Seki G.,
RA Fujita T.;
RT "Functional analysis of NBC1 mutants associated with proximal renal tubular
RT acidosis and ocular abnormalities.";
RL J. Am. Soc. Nephrol. 16:2270-2278(2005).
RN [31]
RP VARIANT PRTA-OA PRO-566, CHARACTERIZATION OF VARIANT PRTA-OA PRO-566,
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16636648;
RA Demirci F.Y., Chang M.H., Mah T.S., Romero M.F., Gorin M.B.;
RT "Proximal renal tubular acidosis and ocular pathology: a novel missense
RT mutation in the gene (SLC4A4) for sodium bicarbonate cotransporter protein
RT (NBCe1).";
RL Mol. Vis. 12:324-330(2006).
RN [32]
RP VARIANT PRTA-OA ARG-530, CHARACTERIZATION OF VARIANTS PRTA-OA SER-342
RP SER-529; ARG-530 AND PRO-566, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17661077; DOI=10.1007/s00424-007-0319-y;
RA Suzuki M., Vaisbich M.H., Yamada H., Horita S., Li Y., Sekine T.,
RA Moriyama N., Igarashi T., Endo Y., Cardoso T.P., de Sa L.C., Koch V.H.,
RA Seki G., Fujita T.;
RT "Functional analysis of a novel missense NBC1 mutation and of other
RT mutations causing proximal renal tubular acidosis.";
RL Pflugers Arch. 455:583-593(2008).
CC -!- FUNCTION: Electrogenic sodium/bicarbonate cotransporter with a
CC Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3. May regulate
CC bicarbonate influx/efflux at the basolateral membrane of cells and
CC regulate intracellular pH. {ECO:0000269|PubMed:10069984,
CC ECO:0000269|PubMed:12907161, ECO:0000269|PubMed:16636648,
CC ECO:0000269|PubMed:16769890, ECO:0000269|PubMed:17661077,
CC ECO:0000269|PubMed:29500354, ECO:0000269|PubMed:9235899,
CC ECO:0000269|PubMed:9651366}.
CC -!- FUNCTION: [Isoform 2]: May have a higher activity than isoform 1.
CC {ECO:0000269|PubMed:16769890}.
CC -!- ACTIVITY REGULATION: Inhibited by stilbene derivatives and regulated by
CC cyclic AMP.
CC -!- SUBUNIT: Homodimer (PubMed:29500354). Interacts with CA2/carbonic
CC anhydrase 2 and CA4/carbonic anhydrase 4 which may regulate transporter
CC activity (PubMed:12411514, PubMed:14567693, PubMed:15218065,
CC PubMed:15563508). Isoform 1 but not isoform 2 interacts with AHCYL1
CC (via PEST domain when phosphorylated); the interaction increases SLC4A4
CC isoform 1 activity (PubMed:16769890). Interacts with AHCYL2 (By
CC similarity). {ECO:0000250|UniProtKB:O88343,
CC ECO:0000250|UniProtKB:Q9GL77, ECO:0000269|PubMed:12411514,
CC ECO:0000269|PubMed:14567693, ECO:0000269|PubMed:15218065,
CC ECO:0000269|PubMed:15563508, ECO:0000269|PubMed:16769890,
CC ECO:0000269|PubMed:29500354}.
CC -!- INTERACTION:
CC Q9Y6R1-1; Q9Y6R1-1: SLC4A4; NbExp=2; IntAct=EBI-6859278, EBI-6859278;
CC Q9Y6R1-1; P48283: CA4; Xeno; NbExp=2; IntAct=EBI-6859278, EBI-6859264;
CC -!- SUBCELLULAR LOCATION: Basolateral cell membrane
CC {ECO:0000269|PubMed:12907161, ECO:0000269|PubMed:15273250,
CC ECO:0000269|PubMed:16636648, ECO:0000269|PubMed:17661077,
CC ECO:0000305|PubMed:12534288, ECO:0000305|PubMed:29500354}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:12534288,
CC ECO:0000305|PubMed:29500354}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=hcNBC, hhNBC, hNBC1, pNBC, pNCB1, pNBC-1, NBC1b;
CC IsoId=Q9Y6R1-1; Sequence=Displayed;
CC Name=2; Synonyms=hkNBC, hkNBCe1, kNBC, kNBC1, kNBC-1, NBC1a;
CC IsoId=Q9Y6R1-2; Sequence=VSP_016704, VSP_016705;
CC Name=3;
CC IsoId=Q9Y6R1-3; Sequence=VSP_016704, VSP_016705, VSP_016706,
CC VSP_016707;
CC Name=4;
CC IsoId=Q9Y6R1-4; Sequence=VSP_016708;
CC Name=5;
CC IsoId=Q9Y6R1-5; Sequence=VSP_041003;
CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed in pancreas and to a lower
CC extent in heart, skeletal muscle, liver, parotid salivary glands,
CC prostate, colon, stomach, thyroid, brain and spinal chord. Corneal
CC endothelium cells express only isoform 1 (at protein level). Isoform 2
CC is specifically expressed in kidney at the level of proximal tubules.
CC {ECO:0000269|PubMed:10069984, ECO:0000269|PubMed:11743927,
CC ECO:0000269|PubMed:12907161, ECO:0000269|PubMed:14559244,
CC ECO:0000269|PubMed:15329059, ECO:0000269|PubMed:9235899,
CC ECO:0000269|PubMed:9651366}.
CC -!- PTM: Phosphorylation of Ser-1026 by PKA increases the binding of CA2
CC and changes the Na(+):HCO3(-) stoichiometry of the transporter from 3:1
CC to 2:1. Phosphorylated in presence of STK39 and dephosphorylated in
CC presence of PP1 phosphatase; phosphorylation seems to inhibit SLC4A4
CC activity. {ECO:0000250|UniProtKB:O88343, ECO:0000269|PubMed:11744745,
CC ECO:0000269|PubMed:12730338}.
CC -!- PTM: N-glycosylation is not necessary for the transporter basic
CC functions. {ECO:0000269|PubMed:12604466}.
CC -!- DISEASE: Renal tubular acidosis, proximal, with ocular abnormalities
CC and intellectual disability (pRTA-OA) [MIM:604278]: An extremely rare
CC autosomal recessive syndrome characterized by short stature, profound
CC proximal renal tubular acidosis, intellectual disability, bilateral
CC glaucoma, cataracts and bandkeratopathy. pRTA is due to a failure of
CC the proximal tubular cells to reabsorb filtered bicarbonate from the
CC urine, leading to urinary bicarbonate wasting and subsequent acidemia.
CC {ECO:0000269|PubMed:10545938, ECO:0000269|PubMed:15471865,
CC ECO:0000269|PubMed:15713912, ECO:0000269|PubMed:15930088,
CC ECO:0000269|PubMed:16636648, ECO:0000269|PubMed:17661077}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Note=Loss of interaction with and stimulation by CA4 is the
CC cause of retinitis pigmentosa type 17 (RP17).
CC -!- SIMILARITY: Belongs to the anion exchanger (TC 2.A.31) family.
CC {ECO:0000305}.
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DR EMBL; AF007216; AAC51645.1; -; mRNA.
DR EMBL; AF011390; AAC39840.1; -; mRNA.
DR EMBL; AF053753; AAF21718.1; -; mRNA.
DR EMBL; AF053754; AAF21719.1; -; mRNA.
DR EMBL; AF069510; AAD42020.1; -; mRNA.
DR EMBL; AF310248; AAG47773.1; -; mRNA.
DR EMBL; AF157492; AAF80343.1; -; mRNA.
DR EMBL; AB470072; BAH58226.1; -; mRNA.
DR EMBL; AC019089; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC079230; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC096713; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC110783; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC112226; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC030977; AAH30977.1; -; mRNA.
DR CCDS; CCDS3549.1; -. [Q9Y6R1-2]
DR CCDS; CCDS43236.1; -. [Q9Y6R1-1]
DR CCDS; CCDS47071.1; -. [Q9Y6R1-5]
DR RefSeq; NP_001091954.1; NM_001098484.2. [Q9Y6R1-1]
DR RefSeq; NP_003750.1; NM_003759.3. [Q9Y6R1-2]
DR PDB; 6CAA; EM; 3.90 A; A/B=77-1079.
DR PDBsum; 6CAA; -.
DR AlphaFoldDB; Q9Y6R1; -.
DR SMR; Q9Y6R1; -.
DR BioGRID; 114219; 6.
DR DIP; DIP-59373N; -.
DR IntAct; Q9Y6R1; 9.
DR MINT; Q9Y6R1; -.
DR STRING; 9606.ENSP00000393557; -.
DR DrugBank; DB01390; Sodium bicarbonate.
DR TCDB; 2.A.31.2.12; the anion exchanger (ae) family.
DR GlyGen; Q9Y6R1; 3 sites, 1 O-linked glycan (1 site).
DR iPTMnet; Q9Y6R1; -.
DR PhosphoSitePlus; Q9Y6R1; -.
DR SwissPalm; Q9Y6R1; -.
DR BioMuta; SLC4A4; -.
DR DMDM; 74721543; -.
DR jPOST; Q9Y6R1; -.
DR MassIVE; Q9Y6R1; -.
DR MaxQB; Q9Y6R1; -.
DR PaxDb; Q9Y6R1; -.
DR PeptideAtlas; Q9Y6R1; -.
DR PRIDE; Q9Y6R1; -.
DR ProteomicsDB; 86772; -. [Q9Y6R1-1]
DR ProteomicsDB; 86773; -. [Q9Y6R1-2]
DR ProteomicsDB; 86774; -. [Q9Y6R1-3]
DR ProteomicsDB; 86775; -. [Q9Y6R1-4]
DR ProteomicsDB; 86776; -. [Q9Y6R1-5]
DR Antibodypedia; 24400; 202 antibodies from 28 providers.
DR DNASU; 8671; -.
DR Ensembl; ENST00000264485.11; ENSP00000264485.5; ENSG00000080493.18. [Q9Y6R1-1]
DR Ensembl; ENST00000340595.4; ENSP00000344272.3; ENSG00000080493.18. [Q9Y6R1-2]
DR Ensembl; ENST00000351898.10; ENSP00000307349.7; ENSG00000080493.18. [Q9Y6R1-4]
DR Ensembl; ENST00000425175.5; ENSP00000393557.1; ENSG00000080493.18. [Q9Y6R1-5]
DR Ensembl; ENST00000512686.5; ENSP00000422400.1; ENSG00000080493.18. [Q9Y6R1-3]
DR Ensembl; ENST00000649996.1; ENSP00000497468.1; ENSG00000080493.18. [Q9Y6R1-1]
DR GeneID; 8671; -.
DR KEGG; hsa:8671; -.
DR MANE-Select; ENST00000264485.11; ENSP00000264485.5; NM_001098484.3; NP_001091954.1.
DR UCSC; uc003hfy.4; human. [Q9Y6R1-1]
DR CTD; 8671; -.
DR DisGeNET; 8671; -.
DR GeneCards; SLC4A4; -.
DR HGNC; HGNC:11030; SLC4A4.
DR HPA; ENSG00000080493; Tissue enhanced (kidney, pancreas).
DR MalaCards; SLC4A4; -.
DR MIM; 603345; gene.
DR MIM; 604278; phenotype.
DR neXtProt; NX_Q9Y6R1; -.
DR OpenTargets; ENSG00000080493; -.
DR Orphanet; 93607; Autosomal recessive proximal renal tubular acidosis.
DR PharmGKB; PA35898; -.
DR VEuPathDB; HostDB:ENSG00000080493; -.
DR eggNOG; KOG1172; Eukaryota.
DR GeneTree; ENSGT00940000156290; -.
DR HOGENOM; CLU_002289_5_0_1; -.
DR InParanoid; Q9Y6R1; -.
DR OMA; LCMAPAN; -.
DR OrthoDB; 265068at2759; -.
DR PhylomeDB; Q9Y6R1; -.
DR TreeFam; TF313630; -.
DR PathwayCommons; Q9Y6R1; -.
DR Reactome; R-HSA-425381; Bicarbonate transporters.
DR Reactome; R-HSA-5619054; Defective SLC4A4 causes renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA).
DR SignaLink; Q9Y6R1; -.
DR SIGNOR; Q9Y6R1; -.
DR BioGRID-ORCS; 8671; 12 hits in 1062 CRISPR screens.
DR ChiTaRS; SLC4A4; human.
DR GeneWiki; SLC4A4; -.
DR GenomeRNAi; 8671; -.
DR Pharos; Q9Y6R1; Tbio.
DR PRO; PR:Q9Y6R1; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q9Y6R1; protein.
DR Bgee; ENSG00000080493; Expressed in jejunal mucosa and 180 other tissues.
DR ExpressionAtlas; Q9Y6R1; baseline and differential.
DR Genevisible; Q9Y6R1; HS.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; IDA:ARUK-UCL.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0016020; C:membrane; IDA:ARUK-UCL.
DR GO; GO:0005886; C:plasma membrane; IDA:ARUK-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005452; F:inorganic anion exchanger activity; IEA:InterPro.
DR GO; GO:0008510; F:sodium:bicarbonate symporter activity; IMP:UniProtKB.
DR GO; GO:0015293; F:symporter activity; IMP:ARUK-UCL.
DR GO; GO:0022857; F:transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0015701; P:bicarbonate transport; IDA:ARUK-UCL.
DR GO; GO:0050801; P:ion homeostasis; IBA:GO_Central.
DR GO; GO:0045821; P:positive regulation of glycolytic process; IGI:ARUK-UCL.
DR GO; GO:0051453; P:regulation of intracellular pH; IDA:ARUK-UCL.
DR GO; GO:0042391; P:regulation of membrane potential; IDA:ARUK-UCL.
DR GO; GO:0036376; P:sodium ion export across plasma membrane; IMP:ARUK-UCL.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IDA:ARUK-UCL.
DR GO; GO:0006814; P:sodium ion transport; IDA:UniProtKB.
DR GO; GO:0055085; P:transmembrane transport; IMP:ARUK-UCL.
DR GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL.
DR Gene3D; 3.40.930.10; -; 1.
DR InterPro; IPR013769; Band3_cytoplasmic_dom.
DR InterPro; IPR011531; HCO3_transpt-like_TM_dom.
DR InterPro; IPR003020; HCO3_transpt_euk.
DR InterPro; IPR003024; Na/HCO3_transpt.
DR InterPro; IPR016152; PTrfase/Anion_transptr.
DR PANTHER; PTHR11453; PTHR11453; 1.
DR Pfam; PF07565; Band_3_cyto; 1.
DR Pfam; PF00955; HCO3_cotransp; 1.
DR PRINTS; PR01231; HCO3TRNSPORT.
DR PRINTS; PR01232; NAHCO3TRSPRT.
DR SUPFAM; SSF55804; SSF55804; 1.
DR TIGRFAMs; TIGR00834; ae; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Disease variant;
KW Disulfide bond; Glycoprotein; Ion transport; Membrane; Phosphoprotein;
KW Reference proteome; Retinitis pigmentosa; Sodium; Sodium transport;
KW Symport; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1079
FT /note="Electrogenic sodium bicarbonate cotransporter 1"
FT /id="PRO_0000079227"
FT TOPO_DOM 1..466
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 467..491
FT /note="Helical; Name=1"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TOPO_DOM 492..501
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 502..520
FT /note="Helical; Name=2"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TOPO_DOM 521
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 522..542
FT /note="Discontinuously helical; Name=3"
FT /evidence="ECO:0000305|PubMed:29500354"
FT TOPO_DOM 543..550
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 551..571
FT /note="Helical; Name=4"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TOPO_DOM 572..585
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 586..609
FT /note="Helical; Name=5"
FT /evidence="ECO:0000305|PubMed:29500354"
FT TOPO_DOM 610..692
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 693..710
FT /note="Helical; Name=6"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TOPO_DOM 711..725
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 726..745
FT /note="Helical; Name=7"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TOPO_DOM 746..779
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 780..807
FT /note="Helical; Name=8"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TOPO_DOM 808..819
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 820..836
FT /note="Helical; Name=9"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TOPO_DOM 837
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 838..855
FT /note="Discontinuously helical; Name=10"
FT /evidence="ECO:0000305|PubMed:29500354"
FT TOPO_DOM 856..877
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 878..894
FT /note="Helical; Name=11"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TOPO_DOM 895..901
FT /note="Extracellular"
FT /evidence="ECO:0000305|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT TRANSMEM 902..918
FT /note="Helical; Name=12"
FT /evidence="ECO:0000305|PubMed:29500354"
FT TOPO_DOM 919..960
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT INTRAMEM 961..986
FT /note="Discontinuously helical"
FT /evidence="ECO:0000305|PubMed:29500354"
FT TOPO_DOM 987..1079
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:12534288,
FT ECO:0000305|PubMed:29500354"
FT REGION 1..62
FT /note="Required for interaction with AHCYL1"
FT /evidence="ECO:0000269|PubMed:16769890"
FT REGION 39..78
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 238..265
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 748..779
FT /note="Interaction with CA4"
FT REGION 1002..1004
FT /note="CA2-binding"
FT REGION 1012..1079
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1030..1033
FT /note="CA2-binding"
FT REGION 1057..1059
FT /note="Required for basolateral targeting"
FT COMPBIAS 39..53
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 54..73
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 238..260
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1012..1039
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1060..1079
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 30
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 49
FT /note="Phosphothreonine; by PKA"
FT /evidence="ECO:0000269|PubMed:12730338"
FT MOD_RES 61
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 65
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 68
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 223
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 232
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 233
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 245
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 249
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9JI66"
FT MOD_RES 254
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 256
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 257
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 262
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 1026
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:11744745"
FT MOD_RES 1029
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 1034
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 1044
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88343"
FT MOD_RES 1069
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JI66"
FT CARBOHYD 641
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:25568315"
FT CARBOHYD 661
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:25568315"
FT DISULFID 627..629
FT /evidence="ECO:0000269|PubMed:25568315"
FT DISULFID 674..686
FT /evidence="ECO:0000269|PubMed:25568315"
FT VAR_SEQ 1..44
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9235899"
FT /id="VSP_016704"
FT VAR_SEQ 45..85
FT /note="HKRKTGHKEKKEKERISENYSDKSDIENADESSSSILKPLI -> MSTENVE
FT GKPSNLGERGRARSSTFLRVVQPMFNHSIFTSAV (in isoform 2 and
FT isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9235899"
FT /id="VSP_016705"
FT VAR_SEQ 635..690
FT /note="ANISISNDTTLAPEYLPTMSSTDMYHNTTFDWAFLSKKECSKYGGNLVGNNC
FT NFVP -> GEGITLCVYARFVFGGRCRLHACKFSTCCHGPQELVLFFSLKNSATEFDVS
FT LPEVF (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_016706"
FT VAR_SEQ 691..1079
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_016707"
FT VAR_SEQ 813..896
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|Ref.5"
FT /id="VSP_016708"
FT VAR_SEQ 1034..1079
FT /note="SDCPYSEKVPSIKIPMDIMEQQPFLSDSKPSDRERSPTFLERHTSC -> EK
FT DHQHSLNATHHADKIPFLQSLGMPSPPRTPVKVVPQIRIELEPEDNDYFWRSKGTETTL
FT (in isoform 5)"
FT /evidence="ECO:0000303|Ref.6"
FT /id="VSP_041003"
FT VARIANT 342
FT /note="R -> S (in pRTA-OA; decreased localization to the
FT basolateral membrane; mistargeting to the apical membrane
FT probably explains the loss of the cotransporter activity;
FT dbSNP:rs121908856)"
FT /evidence="ECO:0000269|PubMed:10545938,
FT ECO:0000269|PubMed:15713912, ECO:0000269|PubMed:15930088,
FT ECO:0000303|PubMed:17661077"
FT /id="VAR_024751"
FT VARIANT 471
FT /note="S -> L (in pRTA-OA; mistargeting to the apical
FT membrane and altered function)"
FT /evidence="ECO:0000269|PubMed:15471865,
FT ECO:0000269|PubMed:15713912"
FT /id="VAR_024752"
FT VARIANT 529
FT /note="T -> S (in pRTA-OA; decreased cotransporter
FT activity)"
FT /evidence="ECO:0000269|PubMed:15930088,
FT ECO:0000303|PubMed:17661077"
FT /id="VAR_024753"
FT VARIANT 530
FT /note="G -> R (in pRTA-OA; decreased cotransporter
FT activity; no effect on localization to the basolateral
FT membrane)"
FT /evidence="ECO:0000303|PubMed:17661077"
FT /id="VAR_071661"
FT VARIANT 554
FT /note="R -> H (in pRTA-OA; mistargeting and altered
FT function; dbSNP:rs121908857)"
FT /evidence="ECO:0000269|PubMed:10545938,
FT ECO:0000269|PubMed:15713912, ECO:0000269|PubMed:15930088"
FT /id="VAR_024754"
FT VARIANT 566
FT /note="L -> P (in pRTA-OA; loss of localization to the
FT plasma membrane; the retention in the cytoplasm probably
FT explains the loss of the cotransporter activity)"
FT /evidence="ECO:0000269|PubMed:16636648,
FT ECO:0000303|PubMed:17661077"
FT /id="VAR_071662"
FT VARIANT 843
FT /note="A -> V (in pRTA-OA; altered function)"
FT /evidence="ECO:0000269|PubMed:15930088"
FT /id="VAR_024755"
FT VARIANT 925
FT /note="R -> C (in pRTA-OA; altered function;
FT dbSNP:rs1203164637)"
FT /evidence="ECO:0000269|PubMed:15930088"
FT /id="VAR_024756"
FT MUTAGEN 49
FT /note="T->A: Loss of conductance regulation by cAMP;
FT isoform 1."
FT /evidence="ECO:0000269|PubMed:12730338"
FT MUTAGEN 49
FT /note="T->D: Loss of conductance regulation by cAMP;
FT isoform 1."
FT /evidence="ECO:0000269|PubMed:12730338"
FT MUTAGEN 135
FT /note="E->R: Mistargeting and altered function."
FT /evidence="ECO:0000269|PubMed:15713912"
FT MUTAGEN 477
FT /note="Y->F: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 493
FT /note="D->N: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 494
FT /note="A->K: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 503
FT /note="E->Q: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 504
FT /note="S->L: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 527..529
FT /note="SST->GFS: Confers anion exchange activity; when
FT associated with E-798; S-842; T-844 and R-847."
FT /evidence="ECO:0000269|PubMed:29500354"
FT MUTAGEN 527
FT /note="S->C: Severely reduces transporter activity."
FT /evidence="ECO:0000269|PubMed:29500354"
FT MUTAGEN 536
FT /note="E->Q: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 552
FT /note="E->N: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 554
FT /note="R->D: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 582
FT /note="R->N: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 582
FT /note="R->Q: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 586
FT /note="E->Q: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 599
FT /note="D->N: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 600
FT /note="A->T: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 602
FT /note="K->Q: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 603
FT /note="K->Q: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 691
FT /note="D->R: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 700
FT /note="F->M: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 711
FT /note="K->E,N,Q: Strong reduction of the sodium-dependent
FT ion transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 711
FT /note="K->R: No effect on the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 712
FT /note="K->N: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 714
FT /note="K->Q: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 715
FT /note="T->N: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 721
FT /note="T->G: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 724
FT /note="R->E: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 725
FT /note="K->N: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 728
FT /note="S->G: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 729
FT /note="D->N,R: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 743
FT /note="D->K,N: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 749
FT /note="D->N: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 752
FT /note="K->Q: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 766
FT /note="R->Q: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 767
FT /note="G->T: Alters interaction with CA4."
FT /evidence="ECO:0000269|PubMed:14567693"
FT MUTAGEN 775
FT /note="E->N: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 798
FT /note="D->C: Abolishes transporter activity."
FT /evidence="ECO:0000269|PubMed:29500354"
FT MUTAGEN 798
FT /note="D->E: Severely reduces transporter activity. Confers
FT anion exchange activity; when associated with SST-527--529-
FT GFS; S-842; T-844 and R-847."
FT /evidence="ECO:0000269|PubMed:29500354"
FT MUTAGEN 798
FT /note="D->N,R: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 802
FT /note="T->C: Abolishes transporter activity."
FT /evidence="ECO:0000269|PubMed:29500354"
FT MUTAGEN 808..809
FT /note="RK->NN: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 814..815
FT /note="KK->NN: Moderate reduction of the sodium-dependent
FT ion transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 820
FT /note="H->D,N,S,R: Moderate reduction of the sodium-
FT dependent ion transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 822
FT /note="D->N: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 842
FT /note="V->S: Confers anion exchange activity; when
FT associated with SST-527--529-GFS; D-798; T-844 and R-847."
FT /evidence="ECO:0000269|PubMed:29500354"
FT MUTAGEN 844
FT /note="A->T: Confers anion exchange activity; when
FT associated with SST-527--529-GFS; D-798; S-842 and R-847."
FT /evidence="ECO:0000269|PubMed:29500354"
FT MUTAGEN 845
FT /note="T->C: Strongly reduces transporter activity."
FT /evidence="ECO:0000269|PubMed:29500354"
FT MUTAGEN 847
FT /note="I->R: Abolishes transporter activity. Confers anion
FT exchange activity; when associated with SST-527--529-GFS;
FT D-798; S-842 and T-844."
FT /evidence="ECO:0000269|PubMed:29500354"
FT MUTAGEN 851
FT /note="H->N: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 853
FT /note="D->N: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 858..860
FT /note="ETE->MSK: Moderate reduction of the sodium-dependent
FT ion transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 875..877
FT /note="EQR->QQQ: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 875
FT /note="E->Q: Strong reduction of the sodium-dependent ion
FT transport activity."
FT MUTAGEN 898
FT /note="K->E: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 925..927
FT /note="RLK->NLN: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 948
FT /note="R->E: Strong reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 949
FT /note="R->E: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 951
FT /note="H->D: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 951
FT /note="H->N,R: Prevents membrane targeting."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 968
FT /note="K->Q: Moderate reduction of the sodium-dependent ion
FT transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 987
FT /note="R->E,N: Moderate reduction of the sodium-dependent
FT ion transport activity."
FT /evidence="ECO:0000269|PubMed:15817634"
FT MUTAGEN 1002
FT /note="L->N: Partial loss of interaction with CA2."
FT /evidence="ECO:0000269|PubMed:15218065"
FT MUTAGEN 1003
FT /note="D->N: Abolishes interaction with CA2."
FT /evidence="ECO:0000269|PubMed:15218065"
FT MUTAGEN 1004
FT /note="D->N: Partial loss of interaction with CA2."
FT /evidence="ECO:0000269|PubMed:15218065"
FT MUTAGEN 1026
FT /note="S->A: Prevents phosphorylation by PKA. Loss of
FT regulation by cAMP of the transporter stoichiometry."
FT /evidence="ECO:0000269|PubMed:11744745,
FT ECO:0000269|PubMed:12730338"
FT MUTAGEN 1026
FT /note="S->D: Loss of regulation by cAMP of the transporter
FT stoichiometry. Shifts transporter stoichiometry from 3:1 to
FT 2:1."
FT /evidence="ECO:0000269|PubMed:11744745,
FT ECO:0000269|PubMed:12730338"
FT MUTAGEN 1030..1033
FT /note="DNDD->NNNN: Abolishes interaction with CA2."
FT /evidence="ECO:0000269|PubMed:15218065"
FT MUTAGEN 1030
FT /note="D->N: Loss of regulation by cAMP of the transporter
FT stoichiometry. Abolishes interaction with CA2."
FT /evidence="ECO:0000269|PubMed:12411514"
FT MUTAGEN 1032
FT /note="D->N: Loss of regulation by cAMP of the transporter
FT stoichiometry. Partial loss of interaction with CA2."
FT /evidence="ECO:0000269|PubMed:12411514"
FT MUTAGEN 1033
FT /note="D->N: No effect on regulation by cAMP of the
FT transporter stoichiometry. Partial loss of interaction with
FT CA2."
FT /evidence="ECO:0000269|PubMed:12411514"
FT MUTAGEN 1057
FT /note="F->A: Targeting to apical membrane."
FT /evidence="ECO:0000269|PubMed:15273250"
FT CONFLICT 6
FT /note="V -> A (in Ref. 4; AAG47773)"
FT /evidence="ECO:0000305"
FT CONFLICT 49
FT /note="T -> A (in Ref. 6; BAH58226)"
FT /evidence="ECO:0000305"
FT CONFLICT 78
FT /note="S -> G (in Ref. 3; AAF21718)"
FT /evidence="ECO:0000305"
FT CONFLICT 256
FT /note="S -> F (in Ref. 3; AAD42020)"
FT /evidence="ECO:0000305"
FT CONFLICT 263
FT /note="D -> E (in Ref. 3; AAF21718)"
FT /evidence="ECO:0000305"
FT CONFLICT 298
FT /note="P -> H (in Ref. 6; BAH58226)"
FT /evidence="ECO:0000305"
FT CONFLICT 364
FT /note="H -> R (in Ref. 3; AAF21719)"
FT /evidence="ECO:0000305"
FT CONFLICT 605
FT /note="I -> V (in Ref. 3; AAF21718)"
FT /evidence="ECO:0000305"
FT CONFLICT 654
FT /note="S -> P (in Ref. 3; AAF21718)"
FT /evidence="ECO:0000305"
FT CONFLICT 749
FT /note="D -> G (in Ref. 3; AAF21719)"
FT /evidence="ECO:0000305"
FT CONFLICT 799
FT /note="Q -> R (in Ref. 4; AAG47773)"
FT /evidence="ECO:0000305"
FT CONFLICT 856
FT /note="K -> R (in Ref. 4; AAG47773)"
FT /evidence="ECO:0000305"
FT CONFLICT 912
FT /note="M -> R (in Ref. 3; AAF21718)"
FT /evidence="ECO:0000305"
FT CONFLICT 913
FT /note="G -> R (in Ref. 3; AAF21719)"
FT /evidence="ECO:0000305"
FT CONFLICT 940
FT /note="I -> V (in Ref. 3; AAF21718)"
FT /evidence="ECO:0000305"
FT CONFLICT 1007
FT /note="P -> S (in Ref. 3; AAF21719)"
FT /evidence="ECO:0000305"
FT CONFLICT 1069
FT /note="S -> P (in Ref. 3; AAF21719)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1079 AA; 121461 MW; 14B981A94DD64293 CRC64;
MEDEAVLDRG ASFLKHVCDE EEVEGHHTIY IGVHVPKSYR RRRRHKRKTG HKEKKEKERI
SENYSDKSDI ENADESSSSI LKPLISPAAE RIRFILGEED DSPAPPQLFT ELDELLAVDG
QEMEWKETAR WIKFEEKVEQ GGERWSKPHV ATLSLHSLFE LRTCMEKGSI MLDREASSLP
QLVEMIVDHQ IETGLLKPEL KDKVTYTLLR KHRHQTKKSN LRSLADIGKT VSSASRMFTN
PDNGSPAMTH RNLTSSSLND ISDKPEKDQL KNKFMKKLPR DAEASNVLVG EVDFLDTPFI
AFVRLQQAVM LGALTEVPVP TRFLFILLGP KGKAKSYHEI GRAIATLMSD EVFHDIAYKA
KDRHDLIAGI DEFLDEVIVL PPGEWDPAIR IEPPKSLPSS DKRKNMYSGG ENVQMNGDTP
HDGGHGGGGH GDCEELQRTG RFCGGLIKDI KRKAPFFASD FYDALNIQAL SAILFIYLAT
VTNAITFGGL LGDATDNMQG VLESFLGTAV SGAIFCLFAG QPLTILSSTG PVLVFERLLF
NFSKDNNFDY LEFRLWIGLW SAFLCLILVA TDASFLVQYF TRFTEEGFSS LISFIFIYDA
FKKMIKLADY YPINSNFKVG YNTLFSCTCV PPDPANISIS NDTTLAPEYL PTMSSTDMYH
NTTFDWAFLS KKECSKYGGN LVGNNCNFVP DITLMSFILF LGTYTSSMAL KKFKTSPYFP
TTARKLISDF AIILSILIFC VIDALVGVDT PKLIVPSEFK PTSPNRGWFV PPFGENPWWV
CLAAAIPALL VTILIFMDQQ ITAVIVNRKE HKLKKGAGYH LDLFWVAILM VICSLMALPW
YVAATVISIA HIDSLKMETE TSAPGEQPKF LGVREQRVTG TLVFILTGLS VFMAPILKFI
PMPVLYGVFL YMGVASLNGV QFMDRLKLLL MPLKHQPDFI YLRHVPLRRV HLFTFLQVLC
LALLWILKST VAAIIFPVMI LALVAVRKGM DYLFSQHDLS FLDDVIPEKD KKKKEDEKKK
KKKKGSLDSD NDDSDCPYSE KVPSIKIPMD IMEQQPFLSD SKPSDRERSP TFLERHTSC
