ID S4A5_HUMAN Reviewed; 1137 AA. AC Q9BY07; Q32MA7; Q59EQ9; Q8WXD3; Q8WXD7; Q96DS7; Q96DS8; Q9HBU5; DT 08-APR-2008, integrated into UniProtKB/Swiss-Prot. DT 08-APR-2008, sequence version 2. DT 30-NOV-2010, entry version 66. DE RecName: Full=Electrogenic sodium bicarbonate cotransporter 4; DE AltName: Full=NBCe2; DE AltName: Full=Solute carrier family 4 member 5; GN Name=SLC4A5; Synonyms=NBC4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY. RC TISSUE=Heart; RX MEDLINE=20435300; PubMed=10978526; DOI=10.1016/S0167-4781(00)00149-4; RA Pushkin A., Abuladze N., Newman D., Lee I., Xu G., Kurtz I.; RT "Cloning, characterization and chromosomal assignment of NBC4, a new RT member of the sodium bicarbonate cotransporter family."; RL Biochim. Biophys. Acta 1493:215-218(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY. RC TISSUE=Heart, and Testis; RX MEDLINE=20537950; PubMed=11087115; DOI=10.1080/15216540050176539; RA Pushkin A., Abuladze N., Newman D., Lee I., Xu G., Kurtz I.; RT "Two C-terminal variants of NBC4, a new member of the sodium RT bicarbonate cotransporter family: cloning, characterization, and RT localization."; RL IUBMB Life 50:13-19(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RC TISSUE=Testis; RX MEDLINE=22057591; PubMed=12063394; RA Pushkin A., Abuladze N., Newman D., Tatishchev S., Kurtz I.; RT "Genomic organization of the DCTN1-SLC4A5 locus encoding both NBC4 and RT p150(Glued)."; RL Cytogenet. Cell Genet. 95:163-168(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION, TISSUE SPECIFICITY, RP AND INHIBITION. RC TISSUE=Testis; RX MEDLINE=21648115; PubMed=11788353; RA Sassani P., Pushkin A., Gross E., Gomer A., Abuladze N., Dukkipati R., RA Carpenito G., Kurtz I.; RT "Functional characterization of NBC4: a new electrogenic sodium- RT bicarbonate cotransporter."; RL Am. J. Physiol. 282:C408-C416(2002). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION, AND INHIBITION. RX PubMed=11997242; DOI=10.1152/ajpcell.00589.2001; RA Virkki L.V., Wilson D.A., Vaughan-Jones R.D., Boron W.F.; RT "Functional characterization of human NBC4 as an electrogenic Na+-HCO RT cotransporter (NBCe2)."; RL Am. J. Physiol. 282:C1278-C1289(2002). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6), NUCLEOTIDE SEQUENCE [MRNA] RP (ISOFORM 8), FUNCTION, AND INHIBITION. RC TISSUE=Liver; RX MEDLINE=22360550; PubMed=12388414; RA Xu J., Wang Z., Barone S., Petrovic M., Amlal H., Conforti L., RA Petrovic S., Soleimani M.; RT "Expression of the Na+-HCO-3 cotransporter NBC4 in rat kidney and RT characterization of a novel NBC4 variant."; RL Am. J. Physiol. 284:F41-F50(2003). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7). 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 88-993 (ISOFORM 5), AND RP VARIANT TYR-253. RC TISSUE=Brain; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=17715183; DOI=10.1152/ajpregu.00356.2007; RA Damkier H.H., Nielsen S., Praetorius J.; RT "Molecular expression of SLC4-derived Na+-dependent anion transporters RT in selected human tissues."; RL Am. J. Physiol. 293:R2136-R2146(2007). CC -!- FUNCTION: Mediates sodium- and bicarbonate-dependent electrogenic CC sodium bicarbonate cotransport, with a Na(+):HCO3(-) stoichiometry CC of 2:1. May have a housekeeping function in regulating the pH of CC tissues in which it is expressed. May play a role in mediating CC Na(+):HCO3(-) cotransport in hepatocytes and intrahepatic CC cholangiocytes. Also may be important in protecting the renal CC paranchyma from alterations in urine pH. CC -!- ENZYME REGULATION: Activity is inhibited by 4,4'-di- CC isothiocyanatostilbene-2,2'-disulfonic acid (DIDS - an inhibitor CC of several anion channels and transporters). CC -!- SUBCELLULAR LOCATION: Apical cell membrane; Multi-pass membrane CC protein. Note=Expressed in the apical plasma membrane domain of a CC subset of collecting ducts in the renal medulla. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=8; CC Name=1; Synonyms=NBC4a; CC IsoId=Q9BY07-1; Sequence=Displayed; CC Name=2; Synonyms=NBC4b; CC IsoId=Q9BY07-2; Sequence=VSP_052778; CC Name=3; Synonyms=NBC4c; CC IsoId=Q9BY07-3; Sequence=VSP_052776; CC Name=4; Synonyms=NBC4d; CC IsoId=Q9BY07-4; Sequence=VSP_052775; CC Name=5; Synonyms=isoform d variant; CC IsoId=Q9BY07-5; Sequence=VSP_052771, VSP_052773, VSP_052777; CC Note=No experimental confirmation available. Incomplete CC sequence; CC Name=6; Synonyms=NBC4f; CC IsoId=Q9BY07-6; Sequence=VSP_052772, VSP_052774, VSP_052776, CC VSP_052778, VSP_052780, VSP_052781; CC Name=7; CC IsoId=Q9BY07-7; Sequence=VSP_052770, VSP_052772, VSP_052776; CC Note=No experimental confirmation available; CC Name=8; Synonyms=NBC4e; CC IsoId=Q9BY07-8; Sequence=VSP_052779; CC -!- TISSUE SPECIFICITY: Highest expression observed in liver, spleen CC and testis; moderate expression in the choroid plexus, CC hippocampus, cerebrum and cerebellum of brain, and in kidney CC cortex and kidney medulla. Also observed in heart, pancreas, CC muscle, lung, placenta, stomach and small intestine. Weakest CC expression seen in peripheral blood lymphocytes, colon, duodenum, CC jejunum, ileum and skeletal muscle. CC -!- SIMILARITY: Belongs to the anion exchanger (TC 2.A.31) family. CC -!- SEQUENCE CAUTION: CC Sequence=AAG18492.1; Type=Frameshift; Positions=1047; CC Sequence=AAL50802.1; Type=Frameshift; Positions=760, 925, 1047; CC Sequence=EAW99691.1; Type=Frameshift; Positions=1047; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF207661; AAG18492.1; ALT_FRAME; mRNA. DR EMBL; AF243499; AAK26741.1; -; mRNA. DR EMBL; AF293338; AAK97073.1; -; mRNA. DR EMBL; AF293337; AAK97072.1; -; mRNA. DR EMBL; AF452248; AAL48291.1; -; mRNA. DR EMBL; AF453528; AAL50802.1; ALT_FRAME; mRNA. DR EMBL; CH471053; EAW99690.1; -; Genomic_DNA. DR EMBL; CH471053; EAW99691.1; ALT_FRAME; Genomic_DNA. DR EMBL; CH471053; EAW99693.1; -; Genomic_DNA. DR EMBL; BC109221; AAI09222.1; -; mRNA. DR EMBL; AB209752; BAD92989.1; -; mRNA. DR IPI; IPI00061148; -. DR IPI; IPI00107529; -. DR IPI; IPI00218089; -. DR IPI; IPI00655610; -. DR IPI; IPI00889641; -. DR IPI; IPI00889661; -. DR IPI; IPI00889759; -. DR IPI; IPI00889761; -. DR RefSeq; NP_067019.3; NM_021196.3. DR RefSeq; NP_597812.1; NM_133478.2. DR UniGene; Hs.724557; -. DR HSSP; P02730; 1BNX. DR ProteinModelPortal; Q9BY07; -. DR SMR; Q9BY07; 111-428, 505-546. DR STRING; Q9BY07; -. DR TCDB; 2.A.31.2.8; anion exchanger (AE) family. DR PhosphoSite; Q9BY07; -. DR PRIDE; Q9BY07; -. DR Ensembl; ENST00000357822; ENSP00000350475; ENSG00000188687. DR Ensembl; ENST00000377634; ENSP00000366861; ENSG00000188687. DR GeneID; 57835; -. DR KEGG; hsa:57835; -. DR UCSC; uc002skn.1; human. DR UCSC; uc002sko.1; human. DR UCSC; uc002skp.1; human. DR UCSC; uc010ffc.1; human. DR CTD; 57835; -. DR GeneCards; GC02M074443; -. DR HGNC; HGNC:18168; SLC4A5. DR MIM; 606757; gene. DR PharmGKB; PA38304; -. DR HOVERGEN; HBG004326; -. DR InParanoid; Q9BY07; -. DR Reactome; REACT_15518; Transmembrane transport of small molecules. DR NextBio; 64831; -. DR ArrayExpress; Q9BY07; -. DR Bgee; Q9BY07; -. DR CleanEx; HS_SLC4A5; -. DR Genevestigator; Q9BY07; -. DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016021; C:integral to membrane; NAS:UniProtKB. DR GO; GO:0005452; F:inorganic anion exchanger activity; IEA:InterPro. DR GO; GO:0008510; F:sodium:bicarbonate symporter activity; NAS:UniProtKB. DR InterPro; IPR011531; HCO3_transpt_C. DR InterPro; IPR013769; HCO3_transpt_cyt. DR InterPro; IPR003020; HCO3_transpt_euk. DR InterPro; IPR003024; Na/HCO3_transpt. DR InterPro; IPR016152; PTrfase/Anion_transptr. DR Gene3D; G3DSA:3.40.1100.10; HCO3_transpt_cyt; 1. DR PANTHER; PTHR11453; HCO3_transpt_euk; 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; PTrfase/Anion_transptr; 1. DR TIGRFAMs; TIGR00834; ae; 1. DR PROSITE; PS00219; ANION_EXCHANGER_1; FALSE_NEG. DR PROSITE; PS00220; ANION_EXCHANGER_2; FALSE_NEG. PE 2: Evidence at transcript level; KW Alternative splicing; Anion exchange; Cell membrane; KW Complete proteome; Ion transport; Membrane; Polymorphism; Sodium; KW Sodium transport; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1 1137 Electrogenic sodium bicarbonate FT cotransporter 4. FT /FTId=PRO_0000328920. FT TOPO_DOM 1 523 Cytoplasmic (Potential). FT TRANSMEM 524 544 Helical; (Potential). FT TOPO_DOM 545 566 Extracellular (Potential). FT TRANSMEM 567 587 Helical; (Potential). FT TOPO_DOM 588 608 Cytoplasmic (Potential). FT TRANSMEM 609 629 Helical; (Potential). FT TOPO_DOM 630 639 Extracellular (Potential). FT TRANSMEM 640 660 Helical; (Potential). FT TOPO_DOM 661 738 Cytoplasmic (Potential). FT TRANSMEM 739 759 Helical; (Potential). FT TOPO_DOM 760 776 Extracellular (Potential). FT TRANSMEM 777 797 Helical; (Potential). FT TOPO_DOM 798 827 Cytoplasmic (Potential). FT TRANSMEM 828 848 Helical; (Potential). FT TOPO_DOM 849 873 Extracellular (Potential). FT TRANSMEM 874 894 Helical; (Potential). FT TOPO_DOM 895 930 Cytoplasmic (Potential). FT TRANSMEM 931 951 Helical; (Potential). FT TOPO_DOM 952 952 Extracellular (Potential). FT TRANSMEM 953 973 Helical; (Potential). FT TOPO_DOM 974 1011 Cytoplasmic (Potential). FT TRANSMEM 1012 1032 Helical; (Potential). FT TRANSMEM 1033 1053 Helical; (Potential). FT TOPO_DOM 1054 1137 Extracellular (Potential). FT COMPBIAS 433 497 Gly-rich. FT VAR_SEQ 27 91 ECPPIHIGLPVPTYPQRKTDQKGHLSGLQKVHWGLRPDQPQ FT QELTGPGSGASSQDSSMDLISRTR -> G (in isoform FT 7). FT /FTId=VSP_052770. FT VAR_SEQ 88 91 SRTR -> EHKG (in isoform 5). FT /FTId=VSP_052771. FT VAR_SEQ 774 811 Missing (in isoform 6 and isoform 7). FT /FTId=VSP_052772. FT VAR_SEQ 866 993 KAAGYHLDLFWVGILMALCSFMGLPWYVAATVISIAHIDSL FT KMETETSAPGEQPQFLGVREQRVTGIIVFILTGISVFLAPI FT LKCIPLPVLYGVFLYMGVASLNGIQMGTGGSEFKIQKKLTP FT FWERC -> GTESNRHHRLHPDGNLCLPGSHPKVYPPAGAV FT RSLPLHGRGLPEWHPVLGTLQALPDASQAPAGPCLPAARAA FT APDPPLHPGADPLPGGALDPQIHGGCHHLPGHDPGPHHRSK FT ASGFHLFPARPGLD (in isoform 5). FT /FTId=VSP_052773. FT VAR_SEQ 866 924 Missing (in isoform 6). FT /FTId=VSP_052774. FT VAR_SEQ 950 1046 Missing (in isoform 4). FT /FTId=VSP_052775. FT VAR_SEQ 973 988 Missing (in isoform 3, isoform 6 and FT isoform 7). FT /FTId=VSP_052776. FT VAR_SEQ 994 1137 Missing (in isoform 5). FT /FTId=VSP_052777. FT VAR_SEQ 1046 1046 M -> MSLSTTD (in isoform 2 and isoform FT 6). FT /FTId=VSP_052778. FT VAR_SEQ 1068 1137 Missing (in isoform 8). FT /FTId=VSP_052779. FT VAR_SEQ 1071 1075 NILPE -> KIEFP (in isoform 6). FT /FTId=VSP_052780. FT VAR_SEQ 1076 1137 Missing (in isoform 6). FT /FTId=VSP_052781. FT VARIANT 251 251 S -> N (in dbSNP:rs17009792). FT /FTId=VAR_048350. FT VARIANT 253 253 H -> Y (in dbSNP:rs55651232). FT /FTId=VAR_061032. FT CONFLICT 612 612 H -> Y (in Ref. 6; AAL48291/AAL50802). FT CONFLICT 699 699 A -> T (in Ref. 6; AAL48291). FT CONFLICT 759 759 L -> R (in Ref. 6; AAL50802). FT CONFLICT 813 813 T -> P (in Ref. 2; AAK26741). FT CONFLICT 896 896 T -> M (in Ref. 6; AAL48291). FT CONFLICT 923 923 G -> R (in Ref. 6; AAL48291). SQ SEQUENCE 1137 AA; 126255 MW; ED4E4A4DC2CA17F1 CRC64; MKVKEEKAGV GKLDHTNHRR RFPDQKECPP IHIGLPVPTY PQRKTDQKGH LSGLQKVHWG LRPDQPQQEL TGPGSGASSQ DSSMDLISRT RSPAAEQLQD ILGEEDEAPN PTLFTEMDTL QHDGDQMEWK ESARWIKFEE KVEEGGERWS KPHVSTLSLH SLFELRTCLQ TGTVLLDLDS GSLPQIIDDV IEKQIEDGLL RPELRERVSY VLLRRHRHQT KKPIHRSLAD IGKSVSTTNR SPARSPGAGP SLHHSTEDLR MRQSANYGRL CHAQSRSMND ISLTPNTDQR KNKFMKKIPK DSEASNVLVG EVDFLDQPFI AFVRLIQSAM LGGVTEVPVP TRFLFILLGP SGRAKSYNEI GRAIATLMVD DLFSDVAYKA RNREDLIAGI DEFLDEVIVL PPGEWDPNIR IEPPKKVPSA DKRKSVFSLA ELGQMNGSVG GGGGAPGGGN GGGGGGGSGG GAGSGGAGGT SSGDDGEMPA MHEIGEELIW TGRFFGGLCL DIKRKLPWFP SDFYDGFHIQ SISAILFIYL GCITNAITFG GLLGDATDNY QGVMESFLGT AMAGSLFCLF SGQPLIILSS TGPILIFEKL LFDFSKGNGL DYMEFRLWIG LHSAVQCLIL VATDASFIIK YITRFTEEGF STLISFIFIY DAIKKMIGAF KYYPINMDFK PNFITTYKCE CVAPDTVNTT VFNASAPLAP DTNASLYNLL NLTALDWSLL SKKECLSYGG RLLGNSCKFI PDLALMSFIL FFGTYSMTLT LKKFKFSRYF PTKVRALVAD FSIVFSILMF CGIDACFGLE TPKLHVPSVI KPTRPDRGWF VAPFGKNPWW VYPASILPAL LVTILIFMDQ QITAVIVNRK ENKLKKAAGY HLDLFWVGIL MALCSFMGLP WYVAATVISI AHIDSLKMET ETSAPGEQPQ FLGVREQRVT GIIVFILTGI SVFLAPILKC IPLPVLYGVF LYMGVASLNG IQMGTGGSEF KIQKKLTPFW ERCKLFLMPA KHQPDHAFLR HVPLRRIHLF TLVQILCLAV LWILKSTVAA IIFPVMILGL IIVRRLLDFI FSQHDLAWID NILPEKEKKE TDKKRKRKKG AHEDCDEEPQ FPPPSVIKIP MESVQSDPQN GIHCIARKRS SSWSYSL //