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Protein

Electrogenic sodium bicarbonate cotransporter 1

Gene

Slc4a4

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Electrogenic sodium/bicarbonate cotransporter with a Na+:HCO3- stoichiometry varying from 1:2 to 1:3. May regulate bicarbonate influx/efflux at the basolateral membrane of cells and regulate intracellular pH.By similarity3 Publications
Isoform 2: May have a higher activity than isoform 1.By similarity

Enzyme regulationi

Inhibited by stilbene derivatives and regulated by cyclic AMP.

GO - Molecular functioni

GO - Biological processi

  • regulation of intracellular pH Source: GO_Central
  • regulation of pH Source: RGD
  • sodium ion transport Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Ion transport, Sodium transport, Symport, Transport

Keywords - Ligandi

Sodium

Enzyme and pathway databases

ReactomeiR-RNO-425381. Bicarbonate transporters.

Protein family/group databases

TCDBi2.A.31.2.2. the anion exchanger (ae) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Electrogenic sodium bicarbonate cotransporter 1
Short name:
Sodium bicarbonate cotransporter
Alternative name(s):
NBC-like protein
Na(+)/HCO3(-) cotransporter
Solute carrier family 4 member 4
Gene namesi
Name:Slc4a4
Synonyms:Nbc, Nbc1, Nbce1, Rnbc1
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 14

Organism-specific databases

RGDi68936. Slc4a4.

Subcellular locationi

  • Basolateral cell membrane 1 Publication; Multi-pass membrane protein 1 Publication

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 468CytoplasmicSequence analysisAdd BLAST468
Transmembranei469 – 488HelicalSequence analysisAdd BLAST20
Topological domaini489 – 504ExtracellularSequence analysisAdd BLAST16
Transmembranei505 – 526HelicalSequence analysisAdd BLAST22
Topological domaini527 – 554CytoplasmicSequence analysisAdd BLAST28
Transmembranei555 – 580HelicalSequence analysisAdd BLAST26
Topological domaini581 – 691ExtracellularSequence analysisAdd BLAST111
Transmembranei692 – 710HelicalSequence analysisAdd BLAST19
Topological domaini711 – 725CytoplasmicSequence analysisAdd BLAST15
Transmembranei726 – 748HelicalSequence analysisAdd BLAST23
Topological domaini749 – 777ExtracellularSequence analysisAdd BLAST29
Transmembranei778 – 797HelicalSequence analysisAdd BLAST20
Topological domaini798 – 822CytoplasmicSequence analysisAdd BLAST25
Transmembranei823 – 847HelicalSequence analysisAdd BLAST25
Topological domaini848 – 881ExtracellularSequence analysisAdd BLAST34
Transmembranei882 – 901HelicalSequence analysisAdd BLAST20
Topological domaini902 – 949CytoplasmicSequence analysisAdd BLAST48
Transmembranei950 – 967HelicalSequence analysisAdd BLAST18
Topological domaini968 – 970ExtracellularSequence analysis3
Transmembranei971 – 986HelicalSequence analysisAdd BLAST16
Topological domaini987 – 1079CytoplasmicSequence analysisAdd BLAST93

GO - Cellular componenti

  • basolateral plasma membrane Source: UniProtKB
  • integral component of plasma membrane Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi243N → Q: No effect on N-glycosylation. 1 Publication1
Mutagenesisi252N → Q: No effect on N-glycosylation. 1 Publication1
Mutagenesisi541N → Q: No effect on N-glycosylation. 1 Publication1
Mutagenesisi636N → Q: No effect on N-glycosylation. Complete loss of N-glycosylation without effect on transporter basic function; when associated with Q-641 and Q-661. 1 Publication1
Mutagenesisi641N → Q: Reduces the extent of N-glycosylation. Complete loss of N-glycosylation without effect on transporter basic function; when associated with Q-636 and Q-661. 1 Publication1
Mutagenesisi661N → Q: Reduces the extent of N-glycosylation. Complete loss of N-glycosylation without effect on transporter basic function; when associated with Q-636 and Q-641. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000792311 – 1079Electrogenic sodium bicarbonate cotransporter 1Add BLAST1079

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei30PhosphotyrosineBy similarity1
Modified residuei61PhosphoserineBy similarity1
Modified residuei65PhosphoserineCombined sources1
Modified residuei68PhosphoserineCombined sources1
Modified residuei223PhosphoserineBy similarity1
Modified residuei232PhosphoserineBy similarity1
Modified residuei233PhosphoserineBy similarity1
Modified residuei245PhosphoserineCombined sources1
Modified residuei249PhosphothreonineCombined sources1
Modified residuei254PhosphothreonineCombined sources1
Modified residuei256PhosphoserineBy similarity1
Modified residuei257PhosphoserineCombined sources1
Modified residuei262PhosphoserineCombined sources1
Disulfide bondi627 ↔ 629By similarity
Glycosylationi641N-linked (GlcNAc...)1 Publication1
Glycosylationi661N-linked (GlcNAc...)1 Publication1
Disulfide bondi674 ↔ 686By similarity
Modified residuei1026Phosphoserine; by PKABy similarity1
Modified residuei1029PhosphoserineCombined sources1
Modified residuei1034PhosphoserineCombined sources1
Modified residuei1044PhosphoserineBy similarity1
Modified residuei1069PhosphoserineCombined sources1
Isoform 2 (identifier: Q9JI66-2)
Modified residuei2PhosphoserineCombined sources1
Isoform 3 (identifier: Q9JI66-3)
Modified residuei1026PhosphoserineCombined sources1
Modified residuei1029PhosphoserineCombined sources1
Modified residuei1060PhosphoserineCombined sources1
Modified residuei1064PhosphoserineCombined sources1
Modified residuei1078PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylation of Ser-1026 by PKA increases the binding of CA2 and changes the Na+:HCO3- stoichiometry of the transporter from 3:1 to 2:1. Phosphorylated in presence of STK39 and dephosphorylated in presence of PP1 phosphatase; phosphorylation seems to inhibit SLC4A4 activity.By similarity
N-glycosylation is not necessary for the transporter basic functions.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei636Not glycosylated1

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ9JI66.
PRIDEiQ9JI66.

PTM databases

iPTMnetiQ9JI66.
PhosphoSitePlusiQ9JI66.
SwissPalmiQ9JI66.

Expressioni

Tissue specificityi

Specifically expressed in kidney and to a lower extent in liver, lung, spleen, brain, skeletal muscle and heart. In kidney, expressed in proximal tubules at the corticomedullary junction. Isoform 2 is specifically expressed in kidney. Isoform 1 is expressed in kidney and pancreas while isoform 3 is specifically expressed in brain (at protein level). In brain, isoform 1 is expressed in astrocytes while isoform 3 is expressed in neurons (at protein level). In the eye, isoform 1 is expressed in cornea, conjunctiva, lens epithelium, ciliary bodies and retina while isoform 2 is detected only in the conjunctiva.7 Publications

Developmental stagei

Expression is first detected at E17 in spinal cord and starts in forebrain at birth. Higher expression in brain is detected at postnatal day 15 and persists throughout adulthood.1 Publication

Inductioni

Down-regulated after cadmium-intoxication and sodium or bicarbonate loading (at protein level). Down-regulated by HCO3[-] loading.3 Publications

Gene expression databases

BgeeiENSRNOG00000003134.
ExpressionAtlasiQ9JI66. baseline and differential.
GenevisibleiQ9JI66. RN.

Interactioni

Subunit structurei

Interacts with CA2/carbonic anhydrase 2 and CA4/carbonic anhydrase 4 which may regulate transporter activity. Isoform 1 but not isoform 2 interacts with AHCYL1 (via PEST domain when phosphorylated); the interaction increases SLC4A4 isoform 1 activity. Interacts with AHCYL2.By similarity

Protein-protein interaction databases

BioGridi249983. 1 interactor.
STRINGi10116.ENSRNOP00000004391.

Structurei

3D structure databases

ProteinModelPortaliQ9JI66.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 62Required for interaction with AHCYL1By similarityAdd BLAST62
Regioni748 – 779Interaction with CA4By similarityAdd BLAST32
Regioni1002 – 1004CA2-bindingBy similarity3
Regioni1030 – 1033CA2-bindingBy similarity4
Regioni1057 – 1059Required for basolateral targetingBy similarity3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi1009 – 1024Lys-richAdd BLAST16

Sequence similaritiesi

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1172. Eukaryota.
ENOG410XPHD. LUCA.
GeneTreeiENSGT00760000119021.
HOGENOMiHOG000280684.
HOVERGENiHBG004326.
InParanoidiQ9JI66.
KOiK13575.
OrthoDBiEOG091G01FT.
PhylomeDBiQ9JI66.
TreeFamiTF313630.

Family and domain databases

Gene3Di3.40.1100.10. 1 hit.
InterProiIPR013769. Band3_cytoplasmic_dom.
IPR011531. HCO3_transpt_C.
IPR003020. HCO3_transpt_euk.
IPR003024. Na/HCO3_transpt.
IPR016152. PTrfase/Anion_transptr.
[Graphical view]
PANTHERiPTHR11453. PTHR11453. 2 hits.
PfamiPF07565. Band_3_cyto. 1 hit.
PF00955. HCO3_cotransp. 1 hit.
[Graphical view]
PRINTSiPR01231. HCO3TRNSPORT.
PR01232. NAHCO3TRSPRT.
SUPFAMiSSF55804. SSF55804. 1 hit.
TIGRFAMsiTIGR00834. ae. 1 hit.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9JI66-1) [UniParc]FASTAAdd to basket
Also known as: bNBC1, NBCe1-B, pNBC1, pNBC-1, rb1NBC

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.

« Hide

        10         20         30         40         50
MEDEAVLDRG ASFLKHVCDE EEVEGHHTIY IGVHVPKSYR RRRRHKRKAG
60 70 80 90 100
HKEKKEKERI SENYSDKSDV ENADESSSSI LKPLISPAAE RIRFILGEED
110 120 130 140 150
DSPAPPQLFT ELDELLAVDG QEMEWKETAR WIKFEEKVEQ GGERWSKPHV
160 170 180 190 200
ATLSLHSLFE LRTCMEKGSI MLDREASSLP QLVEMIADHQ IETGLLKPDL
210 220 230 240 250
KDKVTYTLLR KHRHQTKKSN LRSLADIGKT VSSASRMFSN PDNGSPAMTH
260 270 280 290 300
RNLTSSSLND ISDKPEKDQL KNKFMKKLPR DAEASNVLVG EVDFLDTPFI
310 320 330 340 350
AFVRLQQAVM LGALTEVPVP TRFLFILLGP KGKAKSYHEI GRAIATLMSD
360 370 380 390 400
EVFHDIAYKA KDRHDLIAGI DEFLDEVIVL PPGEWDPAIR IEPPKSLPSS
410 420 430 440 450
DKRKNMYSGG ENVQMNGDTP HDGGHGGGGH GDCEELQRTG RFCGGLIKDI
460 470 480 490 500
KRKAPFFASD FYDALNIQAL SAILFIYLAT VTNAITFGGL LGDATDNMQG
510 520 530 540 550
VLESFLGTAV SGAIFCLFAG QPLTILSSTG PVLVFERLLF NFSKDHSFDY
560 570 580 590 600
LEFRLWIGLW SAFMCLILVA TDASFLVQYF TRFTEEGFSS LISFIFIYDA
610 620 630 640 650
FKKMIKLADY YPINSDFRVG YNTHFSCACL PPDPVNLSVS NDTTLAPEDL
660 670 680 690 700
PTVSSTDMYH NATFDWAYLS KKECVKFGGK LVGNNCDFVP DITLMSFILF
710 720 730 740 750
LGTYTSSMAM KKFKTSRYFP TTARKLISDF AIILSILIFC VIDALVGVDT
760 770 780 790 800
PKLIVPSEFK PTSPHRGWFV PPFGGNPWWV CLAAAIPALL VTILIFMDQQ
810 820 830 840 850
ITAVIVNRKE HKLKKGAGYH LDLFWVAILM VVCSFMALPW YVAATVISIA
860 870 880 890 900
HIDSLKMETE TSAPGEQPKF LGVREQRVTG TLVFILTGLS VFMAPILKFI
910 920 930 940 950
PMPVLYGVFL YMGVASLNGV QFMDRLKLLL MPLKHQPDFI YLRHVPLRRV
960 970 980 990 1000
HLFTSLQVLC LALLWILKST VAAIIFPVMI LALVAVRKGM DYLFSQHDLS
1010 1020 1030 1040 1050
FLDDVIPEKD KKKKEDEKKK KKKKGSLDSD NDDSDCPYSE KVPSIKIPMD
1060 1070
ITEQQPFLSD NKPLDRERSS TFLERHTSC
Length:1,079
Mass (Da):121,343
Last modified:October 1, 2000 - v1
Checksum:iF5A187AFE41BA5B4
GO
Isoform 2 (identifier: Q9JI66-2) [UniParc]FASTAAdd to basket
Also known as: kNBC1, kNBC-1, NBCe1-A, rkNBC, rkNBC1

The sequence of this isoform differs from the canonical sequence as follows:
     1-44: Missing.
     45-85: HKRKAGHKEK...SSSSILKPLI → MSTENVEGKP...FNHSIFTSAV

Note: Mutagenesis of Asn-33 into Gln has no effect on N-glycosylation.Combined sources
Show »
Length:1,035
Mass (Da):116,042
Checksum:i5BAB6B0152DE31FD
GO
Isoform 3 (identifier: Q9JI66-3) [UniParc]FASTAAdd to basket
Also known as: NBCe1-C, rb2NBC

The sequence of this isoform differs from the canonical sequence as follows:
     1034-1079: SDCPYSEKVP...STFLERHTSC → EKDPQHSLNA...WRNKGTETTL

Show »
Length:1,094
Mass (Da):122,962
Checksum:i1DD46D615F650311
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti284 – 285AS → VP in AAB83997 (PubMed:9841505).Curated2
Sequence conflicti284 – 285AS → VP in AAF21040 (PubMed:10648705).Curated2
Sequence conflicti479A → G in AAB83997 (PubMed:9841505).Curated1
Sequence conflicti479A → G in AAF21040 (PubMed:10648705).Curated1
Sequence conflicti640S → Y in AAB83997 (PubMed:9841505).Curated1
Sequence conflicti655S → F in AAB83997 (PubMed:9841505).Curated1
Sequence conflicti803A → P in AAB83997 (PubMed:9841505).Curated1
Sequence conflicti803A → P in AAF21040 (PubMed:10648705).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0167171 – 44Missing in isoform 2. 2 PublicationsAdd BLAST44
Alternative sequenceiVSP_01671845 – 85HKRKA…LKPLI → MSTENVEGKPNNLGERGRAR SSTFLRVFQPMFNHSIFTSA V in isoform 2. 2 PublicationsAdd BLAST41
Alternative sequenceiVSP_0167191034 – 1079SDCPY…RHTSC → EKDPQHSLNATHHADKIPFL ESLGLPSPPRSPVKVVPQIR IELESEDNDYLWRNKGTETT L in isoform 3. 1 PublicationAdd BLAST46

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF004017 mRNA. Translation: AAC40034.1.
AF027362 mRNA. Translation: AAB83997.1.
AF124441 mRNA. Translation: AAF87312.1.
AF254802 mRNA. Translation: AAF87553.1.
AF210250 mRNA. Translation: AAF21040.1.
PIRiT13962.
T14110.
RefSeqiNP_445876.1. NM_053424.1. [Q9JI66-1]
XP_006250853.1. XM_006250791.3. [Q9JI66-3]
UniGeneiRn.11114.
Rn.8739.

Genome annotation databases

EnsembliENSRNOT00000033806; ENSRNOP00000035006; ENSRNOG00000003134. [Q9JI66-1]
GeneIDi84484.
KEGGirno:84484.
UCSCiRGD:68936. rat. [Q9JI66-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF004017 mRNA. Translation: AAC40034.1.
AF027362 mRNA. Translation: AAB83997.1.
AF124441 mRNA. Translation: AAF87312.1.
AF254802 mRNA. Translation: AAF87553.1.
AF210250 mRNA. Translation: AAF21040.1.
PIRiT13962.
T14110.
RefSeqiNP_445876.1. NM_053424.1. [Q9JI66-1]
XP_006250853.1. XM_006250791.3. [Q9JI66-3]
UniGeneiRn.11114.
Rn.8739.

3D structure databases

ProteinModelPortaliQ9JI66.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi249983. 1 interactor.
STRINGi10116.ENSRNOP00000004391.

Protein family/group databases

TCDBi2.A.31.2.2. the anion exchanger (ae) family.

PTM databases

iPTMnetiQ9JI66.
PhosphoSitePlusiQ9JI66.
SwissPalmiQ9JI66.

Proteomic databases

PaxDbiQ9JI66.
PRIDEiQ9JI66.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000033806; ENSRNOP00000035006; ENSRNOG00000003134. [Q9JI66-1]
GeneIDi84484.
KEGGirno:84484.
UCSCiRGD:68936. rat. [Q9JI66-1]

Organism-specific databases

CTDi8671.
RGDi68936. Slc4a4.

Phylogenomic databases

eggNOGiKOG1172. Eukaryota.
ENOG410XPHD. LUCA.
GeneTreeiENSGT00760000119021.
HOGENOMiHOG000280684.
HOVERGENiHBG004326.
InParanoidiQ9JI66.
KOiK13575.
OrthoDBiEOG091G01FT.
PhylomeDBiQ9JI66.
TreeFamiTF313630.

Enzyme and pathway databases

ReactomeiR-RNO-425381. Bicarbonate transporters.

Miscellaneous databases

PROiQ9JI66.

Gene expression databases

BgeeiENSRNOG00000003134.
ExpressionAtlasiQ9JI66. baseline and differential.
GenevisibleiQ9JI66. RN.

Family and domain databases

Gene3Di3.40.1100.10. 1 hit.
InterProiIPR013769. Band3_cytoplasmic_dom.
IPR011531. HCO3_transpt_C.
IPR003020. HCO3_transpt_euk.
IPR003024. Na/HCO3_transpt.
IPR016152. PTrfase/Anion_transptr.
[Graphical view]
PANTHERiPTHR11453. PTHR11453. 2 hits.
PfamiPF07565. Band_3_cyto. 1 hit.
PF00955. HCO3_cotransp. 1 hit.
[Graphical view]
PRINTSiPR01231. HCO3TRNSPORT.
PR01232. NAHCO3TRSPRT.
SUPFAMiSSF55804. SSF55804. 1 hit.
TIGRFAMsiTIGR00834. ae. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiS4A4_RAT
AccessioniPrimary (citable) accession number: Q9JI66
Secondary accession number(s): O35422
, O54815, Q9JJ32, Q9QXH6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 20, 2005
Last sequence update: October 1, 2000
Last modified: November 2, 2016
This is version 110 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.