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Reviewed, UniProtKB/Swiss-Prot Q9Y6M7 (S4A7_HUMAN)

Last modified July 22, 2008. Version 50. Feed History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Sodium bicarbonate cotransporter 3
Alternative name(s):
    Sodium bicarbonate cotransporter 2
    Sodium bicarbonate cotransporter 2b
      Short name=Bicarbonate transporter
    Solute carrier family 4 member 7
Gene names
Name: SLC4A7
Synonyms: BT, NBC2, NBC2B, NBC3, SBC2, SLC4A6
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1214 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Electroneutral sodium- and bicarbonate-dependent cotransporter with a Na(+):HCO3(-) 1:1 stoichiometry. Regulates intracellular pH and may play a role in bicarbonate salvage in secretory epithelia. May also have an associated sodium channel activity.

Enzyme regulation

Transporter activity is regulated by CA2/carbonic anhydrase 2, cAMP and PKA. Insensitive to stilbene derivatives. Ref.2 states it is inhibited by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA).

Subunit structure

Interacts with CFTR through SLC9A3R1/EBP50. Interacts with USH1C. Forms a complex with ATP6V1B1 and SLC9A3R1/EBP50. Interacts in a pH dependent-manner with CA2/carbonic anhydrase 2.

Subcellular location

Basolateral cell membrane; Multi-pass membrane protein. Apical cell membrane; Multi-pass membrane proteinBy similarity. Cell projectionstereociliumBy similarity. Note= Also described at the apical cell membrane. Localizes to the stereocilia of cochlear outer hair cells and to the lateral membrane of cochlear inner hair cells By similarity.

Tissue specificity

Highly expressed in testis and spleen. Also expressed in retina, colon, small intestine, ovary, thymus, prostate, muscle, heart and kidney. Isoform 1 is expressed in skeletal muscle and heart muscle.

Domain

The PDZ-binding motif mediates interaction with the CFTR, SLC9A3R1/EBP50 complex and probably with USH1C.

Post-translational modification

N-glycosylated By similarity.

Sequence similarities

Belongs to the anion exchanger (TC 2.A.31) family. [View classification]

Biophysicochemical properties

Kinetic parameters:

KM=24 mM for external sodium

Ontologies

Keywords

   Biological processIon transport
Sodium transport
Symport
Transport
   Cellular componentCell membrane
Cell projection
Membrane
   Coding sequence diversityAlternative splicing
   DomainTransmembrane
   LigandSodium
   PTMGlycoprotein
Phosphoprotein

Gene Ontology (GO)

   Biological processbicarbonate transport Ref.2

Non-traceable author statement. Source: UniProtKB

   Cellular componentintegral to membrane Ref.2

Non-traceable author statement. Source: UniProtKB

   Molecular functionprotein binding

Inferred from physical interaction. Source: IntAct

sodium:bicarbonate symporter activity Ref.2

Non-traceable author statement. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

YWHABP319461EBI-1044546,EBI-359815

Alternative products

This entry describes 5 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9Y6M7-1)

Also known as: mNBC3; NBCn1-A;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q9Y6M7-2)

The sequence of this isoform differs from the canonical sequence as follows:
     251-374: Missing.
Isoform 3 (identifier: Q9Y6M7-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-90: Missing.
     91-118: SQRVQFILGTEDDDEEHIPHDLFTEMDE → MAVTQFIHFREEIMGNMFFIIIFSTKDK
     251-374: Missing.
     1189-1214: PDKPVSVKISFEDEPRKKYVDAETSL → GDPSIGNISDEMAKTAQWKALSMNTENAKVTRSNMSPDKPVSVK
Isoform 4 (identifier: Q9Y6M7-4)

The sequence of this isoform differs from the canonical sequence as follows:
     1-90: Missing.
     91-118: SQRVQFILGTEDDDEEHIPHDLFTEMDE → MAVTQFIHFREEIMGNMFFIIIFSTKDK
     251-374: Missing.
Isoform 5 (identifier: Q9Y6M7-5)

The sequence of this isoform differs from the canonical sequence as follows:
     1-450: Missing.
     451-465: PAVLLTGLTEVPVPT → MEVVEAEKIVLLTSA
     1188-1188: S → SVDPSIVNISDEMAKTAQWKALSMNSENAKVTRSNMS
Notes: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 12141214Sodium bicarbonate cotransporter 3
PRO_0000079233

Regions

Topological domain1 – 608608Extracellular Potential
Transmembrane609 – 62921 Potential
Topological domain630 – 6378Cytoplasmic Potential
Transmembrane638 – 65821 Potential
Topological domain659 – 69537Extracellular Potential
Transmembrane696 – 71621 Potential
Topological domain717 – 7259Cytoplasmic Potential
Transmembrane726 – 74621 Potential
Topological domain747 – 81771Extracellular Potential
Transmembrane818 – 83821 Potential
Topological domain839 – 86123Cytoplasmic Potential
Transmembrane862 – 88221 Potential
Topological domain883 – 90826Extracellular Potential
Transmembrane909 – 92921 Potential
Topological domain930 – 95425Cytoplasmic Potential
Transmembrane955 – 97521 Potential
Topological domain976 – 101136Extracellular Potential
Transmembrane1012 – 103221 Potential
Topological domain1033 – 10342Cytoplasmic Potential
Transmembrane1035 – 105521 Potential
Topological domain1056 – 109237Extracellular Potential
Transmembrane1093 – 111321 Potential
Topological domain1114 – 1214101Cytoplasmic Potential
Region1134 – 11363CA2-binding
Motif1211 – 12144PDZ-binding

Amino acid modifications

Modified residue4071Phosphoserine By similarity
Modified residue11671Phosphothreonine
Modified residue11761Phosphoserine
Modified residue12131Phosphoserine
Glycosylation1711N-linked (GlcNAc...) Potential
Glycosylation2691N-linked (GlcNAc...) Potential
Glycosylation3981N-linked (GlcNAc...) Potential
Glycosylation4061N-linked (GlcNAc...) Potential
Glycosylation7861N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence1 – 450450Missing in isoform 5.
VSP_017159
Alternative sequence1 – 9090Missing in isoform 3 and isoform 4.
VSP_017160
Alternative sequence91 – 11828SQRVQ…TEMDE → MAVTQFIHFREEIMGNMFFI IIFSTKDK in isoform 3 and isoform 4.
VSP_017161
Alternative sequence251 – 374124Missing in isoform 2, isoform 3 and isoform 4.
VSP_017162
Alternative sequence451 – 46515PAVLL…VPVPT → MEVVEAEKIVLLTSA in isoform 5.
VSP_017163
Alternative sequence11881S → SVDPSIVNISDEMAKTAQWK ALSMNSENAKVTRSNMS in isoform 5.
VSP_017164
Alternative sequence1189 – 121426PDKPV…AETSL → GDPSIGNISDEMAKTAQWKA LSMNTENAKVTRSNMSPDKP VSVK in isoform 3.
VSP_017165

Experimental info

Mutagenesis1135 – 11362DD → NN: Loss of interaction with CA2. Loss of regulation by CA2
Mutagenesis1163 – 11653DDD → NNN: No effect on interaction with CA2. No effect on regulation by CA2
Mutagenesis12141L → G: Loss of interaction with ATP6V1B1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (mNBC3) (NBCn1-A) [UniParc].

Last modified November 1, 1999. Version 1.
Checksum: EF203500B5BF5267

FASTA1,214136,043
        10         20         30         40         50         60 
MERFRLEKKL PGPDEEAVVD LGKTSSTVNT KFEKEELESH RAVYIGVHVP FSKESRRRHR 

        70         80         90        100        110        120 
HRGHKHHHRR RKDKESDKED GRESPSYDTP SQRVQFILGT EDDDEEHIPH DLFTEMDELC 

       130        140        150        160        170        180 
YRDGEEYEWK ETARWLKFEE DVEDGGDRWS KPYVATLSLH SLFELRSCIL NGTVMLDMRA 

       190        200        210        220        230        240 
STLDEIADMV LDNMIASGQL DESIRENVRE ALLKRHHHQN EKRFTSRIPL VRSFADIGKK 

       250        260        270        280        290        300 
HSDPHLLERN GEGLSASRHS LRTGLSASNL SLRGESPLSL LLGHLLPSSR AGTPAGSRCT 

       310        320        330        340        350        360 
TPVPTPQNSP PSSPSISRLT SRSSQKSQRQ APELLVSPAS DDIPTVVIHP PEEDLEAALK 

       370        380        390        400        410        420 
GEEQKNEENV DLTPGILASP QSAPGNLDNS KSGEIKGNGS GGSRENSTVD FSKVDMNFMR 

       430        440        450        460        470        480 
KIPTGAEASN VLVGEVDFLE RPIIAFVRLA PAVLLTGLTE VPVPTRFLFL LLGPAGKAPQ 

       490        500        510        520        530        540 
YHEIGRSIAT LMTDEIFHDV AYKAKDRNDL LSGIDEFLDQ VTVLPPGEWD PSIRIEPPKS 

       550        560        570        580        590        600 
VPSQEKRKIP VFHNGSTPTL GETPKEAAHH AGPELQRTGR LFGGLILDIK RKAPFFLSDF 

       610        620        630        640        650        660 
KDALSLQCLA SILFLYCACM SPVITFGGLL GEATEGRISA IESLFGASLT GIAYSLFAGQ 

       670        680        690        700        710        720 
PLTILGSTGP VLVFEKILYK FCRDYQLSYL SLRTSIGLWT SFLCIVLVAT DASSLVCYIT 

       730        740        750        760        770        780 
RFTEEAFAAL ICIIFIYEAL EKLFDLGETY AFNMHNNLDK LTSYSCVCTE PPNPSNETLA 

       790        800        810        820        830        840 
QWKKDNITAH NISWRNLTVS ECKKLRGVFL GSACGHHGPY IPDVLFWCVI LFFTTFFLSS 

       850        860        870        880        890        900 
FLKQFKTKRY FPTKVRSTIS DFAVFLTIVI MVTIDYLVGV PSPKLHVPEK FEPTHPERGW 

       910        920        930        940        950        960 
IISPLGDNPW WTLLIAAIPA LLCTILIFMD QQITAVIINR KEHKLKKGAG YHLDLLMVGV 

       970        980        990       1000       1010       1020 
MLGVCSVMGL PWFVAATVLS ISHVNSLKVE SECSAPGEQP KFLGIREQRV TGLMIFILMG 

      1030       1040       1050       1060       1070       1080 
LSVFMTSVLK FIPMPVLYGV FLYMGVSSLK GIQLFDRIKL FGMPAKHQPD LIYLRYVPLW 

      1090       1100       1110       1120       1130       1140 
KVHIFTVIQL TCLVLLWVIK VSAAAVVFPM MVLALVFVRK LMDLCFTKRE LSWLDDLMPE 

      1150       1160       1170       1180       1190       1200 
SKKKKEDDKK KKEKEEAERM LQDDDDTVHL PFEGGSLLQI PVKALKYSPD KPVSVKISFE 

      1210 
DEPRKKYVDA ETSL 

« Hide

Isoform 2 [UniParc].

Checksum: 541839CC9B565896
Show »

1,090123,081
Isoform 3 [UniParc].

Checksum: A37799D93A1E30BC
Show »

1,018114,205
Isoform 4 [UniParc].

Checksum: 50FAA40A31468223
Show »

1,000112,448
Isoform 5 [UniParc].

Checksum: CCFB5D3479BF5870
Show »

80089,731

References

« Hide 'large scale' references
[1]"Molecular cloning of a new sodium bicarbonate cotransporter cDNA from human retina."
Ishibashi K., Sasaki S., Marumo F.
Biochem. Biophys. Res. Commun. 246:535-538(1998) [PubMed: 9610397] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), TISSUE SPECIFICITY.
Tissue: Retina.
[2]"Cloning, tissue distribution, genomic organization, and functional characterization of NBC3, a new member of the sodium bicarbonate cotransporter family."
Pushkin A., Abuladze N., Lee I., Newman D., Hwang J., Kurtz I.
J. Biol. Chem. 274:16569-16575(1999) [PubMed: 10347222] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, REGULATION.
Tissue: Kidney and Skeletal muscle.
[3]"Cloning of a HCO3 transporter, NT2-NBC, from human brain, similar to both the Anion exchangers (AEs) and the Na/Bicarbonate Cotransporters (NBCs)."
Romero M.F.
Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
Tissue: Neuroepithelium.
[4]The German cDNA consortium
Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
Tissue: Cervix.
[5]"The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3-cotransport isoform 3."
Park M., Ko S.B.H., Choi J.Y., Muallem G., Thomas P.J., Pushkin A., Lee M.-S., Kim J.Y., Lee M.G., Muallem S., Kurtz I.
J. Biol. Chem. 277:50503-50509(2002) [PubMed: 12403779] [Abstract]
Cited for: FUNCTION, INTERACTION WITH CFTR AND SLC9A3R1, DOMAIN.
[6]"The COOH termini of NBC3 and the 56-kDa H+-ATPase subunit are PDZ motifs involved in their interaction."
Pushkin A., Abuladze N., Newman D., Muronets V., Sassani P., Tatishchev S., Kurtz I.
Am. J. Physiol. 284:C667-C673(2003) [PubMed: 12444018] [Abstract]
Cited for: INTERACTION WITH ATP6V1B1 AND SLC9A3R1, MUTAGENESIS OF LEU-1214.
[7]"Regulation of the human NBC3 Na+/HCO3- cotransporter by carbonic anhydrase II and PKA."
Loiselle F.B., Morgan P.E., Alvarez B.V., Casey J.R.
Am. J. Physiol. 286:C1423-C1433(2004) [PubMed: 14736710] [Abstract]
Cited for: INTERACTION WITH CA2, REGULATION, MUTAGENESIS OF 1135-ASP-ASP-1136 AND 1163-ASP--ASP-1165.
[8]"Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry."
Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C.
Anal. Chem. 76:2763-2772(2004) [PubMed: 15144186] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1213, MASS SPECTROMETRY.
Tissue: T-cell.
[9]"Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2."
Reiners J., van Wijk E., Maerker T., Zimmermann U., Juergens K., te Brinke H., Overlack N., Roepman R., Knipper M., Kremer H., Wolfrum U.
Hum. Mol. Genet. 14:3933-3943(2005) [PubMed: 16301216] [Abstract]
Cited for: INTERACTION WITH USH1C.
[10]"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis."
Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III
J. Proteome Res. 7:1346-1351(2008) [PubMed: 18220336] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1167 AND SER-1176, MASS SPECTROMETRY.
+Additional computationally mapped references.