SL9A4_HUMAN
ID SL9A4_HUMAN Reviewed; 798 AA.
AC Q6AI14; Q69YK0;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 03-AUG-2022, entry version 141.
DE RecName: Full=Sodium/hydrogen exchanger 4;
DE AltName: Full=Na(+)/H(+) exchanger 4;
DE Short=NHE-4;
DE AltName: Full=Solute carrier family 9 member 4;
GN Name=SLC9A4; Synonyms=NHE4;
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 [LARGE SCALE MRNA].
RC TISSUE=Fetal skin, and Stomach;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [2]
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).
CC -!- FUNCTION: Involved in pH regulation to eliminate acids generated by
CC active metabolism or to counter adverse environmental conditions. Major
CC proton extruding system driven by the inward sodium ion chemical
CC gradient. Plays an important role in signal transduction. May play a
CC specialized role in the kidney in rectifying cell volume in response to
CC extreme fluctuations of hyperosmolar-stimulated cell shrinkage. Is
CC relatively amiloride and ethylisopropylamiloride (EIPA) insensitive.
CC Can be activated under conditions of hyperosmolar-induced cell
CC shrinkage in a sustained intracellular acidification-dependence manner.
CC Activated by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) in
CC a sustained intracellular acidification-dependence manner. Affects
CC potassium/proton exchange as well as sodium/proton and lithium/proton
CC exchange. In basolateral cell membrane, participates in homeostatic
CC control of intracellular pH, and may play a role in proton extrusion in
CC order to achieve transepithelial HCO3(-) secretion. In apical cell
CC membrane may be involved in mediating sodium absorption. Requires for
CC normal levels of gastric acid secretion, secretory membrane
CC development, parietal cell maturation and/or differentiation and at
CC least secondarily for chief cell differentiation (By similarity).
CC {ECO:0000250}.
CC -!- SUBUNIT: Interacts with CHP1 and CHP2. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Basolateral cell membrane
CC {ECO:0000250|UniProtKB:P26434}; Multi-pass membrane protein
CC {ECO:0000255}. Apical cell membrane {ECO:0000250|UniProtKB:Q8BUE1};
CC Multi-pass membrane protein {ECO:0000255}. Zymogen granule membrane
CC {ECO:0000250|UniProtKB:P26434}; Multi-pass membrane protein
CC {ECO:0000255}. Note=Enrichment at apical or basolateral membrane may be
CC tissue-dependent. {ECO:0000250|UniProtKB:P26434}.
CC -!- PTM: May be phosphorylated. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the monovalent cation:proton antiporter 1 (CPA1)
CC transporter (TC 2.A.36) family. {ECO:0000305}.
CC -!- CAUTION: The number, localization and denomination of hydrophobic
CC domains in the Na(+)/H(+) exchangers vary among authors. {ECO:0000305}.
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DR EMBL; AL833048; CAH10600.1; -; mRNA.
DR EMBL; CR627411; CAH10500.1; -; mRNA.
DR EMBL; AC007278; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS33264.1; -.
DR RefSeq; NP_001011552.2; NM_001011552.3.
DR AlphaFoldDB; Q6AI14; -.
DR SMR; Q6AI14; -.
DR BioGRID; 132934; 4.
DR STRING; 9606.ENSP00000295269; -.
DR TCDB; 2.A.36.1.18; the monovalent cation:proton antiporter-1 (cpa1) family.
DR GlyGen; Q6AI14; 1 site.
DR iPTMnet; Q6AI14; -.
DR PhosphoSitePlus; Q6AI14; -.
DR BioMuta; SLC9A4; -.
DR DMDM; 296452906; -.
DR MassIVE; Q6AI14; -.
DR PaxDb; Q6AI14; -.
DR PeptideAtlas; Q6AI14; -.
DR PRIDE; Q6AI14; -.
DR Antibodypedia; 49172; 10 antibodies from 6 providers.
DR DNASU; 389015; -.
DR Ensembl; ENST00000295269.5; ENSP00000295269.4; ENSG00000180251.5.
DR GeneID; 389015; -.
DR KEGG; hsa:389015; -.
DR MANE-Select; ENST00000295269.5; ENSP00000295269.4; NM_001011552.4; NP_001011552.2.
DR UCSC; uc002tbz.4; human.
DR CTD; 389015; -.
DR DisGeNET; 389015; -.
DR GeneCards; SLC9A4; -.
DR HGNC; HGNC:11077; SLC9A4.
DR HPA; ENSG00000180251; Tissue enriched (stomach).
DR MIM; 600531; gene.
DR neXtProt; NX_Q6AI14; -.
DR OpenTargets; ENSG00000180251; -.
DR PharmGKB; PA35933; -.
DR VEuPathDB; HostDB:ENSG00000180251; -.
DR eggNOG; KOG1966; Eukaryota.
DR GeneTree; ENSGT00940000160774; -.
DR HOGENOM; CLU_005912_4_3_1; -.
DR InParanoid; Q6AI14; -.
DR OMA; TFSPWNC; -.
DR OrthoDB; 316731at2759; -.
DR PhylomeDB; Q6AI14; -.
DR TreeFam; TF317212; -.
DR PathwayCommons; Q6AI14; -.
DR Reactome; R-HSA-425986; Sodium/Proton exchangers.
DR SignaLink; Q6AI14; -.
DR SIGNOR; Q6AI14; -.
DR BioGRID-ORCS; 389015; 8 hits in 1066 CRISPR screens.
DR GenomeRNAi; 389015; -.
DR Pharos; Q6AI14; Tdark.
DR PRO; PR:Q6AI14; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q6AI14; protein.
DR Bgee; ENSG00000180251; Expressed in stomach and 49 other tissues.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005774; C:vacuolar membrane; IEA:InterPro.
DR GO; GO:0015386; F:potassium:proton antiporter activity; IBA:GO_Central.
DR GO; GO:0015385; F:sodium:proton antiporter activity; IBA:GO_Central.
DR GO; GO:0001696; P:gastric acid secretion; IEA:Ensembl.
DR GO; GO:0002068; P:glandular epithelial cell development; IEA:Ensembl.
DR GO; GO:0006811; P:ion transport; TAS:Reactome.
DR GO; GO:0055075; P:potassium ion homeostasis; IEA:InterPro.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IBA:GO_Central.
DR GO; GO:0051453; P:regulation of intracellular pH; IBA:GO_Central.
DR GO; GO:0009651; P:response to salt stress; IEA:InterPro.
DR GO; GO:0098719; P:sodium ion import across plasma membrane; IBA:GO_Central.
DR InterPro; IPR006153; Cation/H_exchanger.
DR InterPro; IPR018422; Cation/H_exchanger_CPA1.
DR InterPro; IPR004709; NaH_exchanger.
DR InterPro; IPR001953; NHE-2/4.
DR InterPro; IPR036958; NHE-4.
DR InterPro; IPR032103; NHE_CaM-bd.
DR PANTHER; PTHR10110; PTHR10110; 1.
DR PANTHER; PTHR10110:SF103; PTHR10110:SF103; 1.
DR Pfam; PF00999; Na_H_Exchanger; 1.
DR Pfam; PF16644; NEXCaM_BD; 1.
DR PRINTS; PR01084; NAHEXCHNGR.
DR PRINTS; PR01086; NAHEXCHNGR2.
DR TIGRFAMs; TIGR00840; b_cpa1; 1.
PE 2: Evidence at transcript level;
KW Antiport; Cell membrane; Cytoplasmic vesicle; Glycoprotein; Ion transport;
KW Membrane; Phosphoprotein; Reference proteome; Sodium; Sodium transport;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..798
FT /note="Sodium/hydrogen exchanger 4"
FT /id="PRO_0000314665"
FT TOPO_DOM 1..13
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT INTRAMEM 14..28
FT /note="Name=A/M1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 29..69
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT INTRAMEM 70..90
FT /note="Name=B/M2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 91..94
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 95..115
FT /note="Helical; Name=C/M3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 116..127
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 128..148
FT /note="Helical; Name=D/M4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 149..154
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 155..175
FT /note="Helical; Name=E/M5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 176..196
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 197..217
FT /note="Helical; Name=F/M5A"
FT /evidence="ECO:0000255"
FT TOPO_DOM 218..226
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 227..247
FT /note="Helical; Name=G/M5B"
FT /evidence="ECO:0000255"
FT TOPO_DOM 248..270
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 271..291
FT /note="Helical; Name=H/M6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 292..304
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 305..325
FT /note="Helical; Name=I/M7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 326..356
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 357..373
FT /note="Helical; Name=J/M8"
FT /evidence="ECO:0000255"
FT TOPO_DOM 374..384
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 385..405
FT /note="Helical; Name=K/M9"
FT /evidence="ECO:0000255"
FT TOPO_DOM 406..420
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT INTRAMEM 421..441
FT /note="Name=L"
FT /evidence="ECO:0000255"
FT TOPO_DOM 442..450
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 451..471
FT /note="Helical; Name=M/M10"
FT /evidence="ECO:0000255"
FT TOPO_DOM 472..798
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 662..690
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 776..798
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 342
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 116
FT /note="G -> S (in dbSNP:rs17027275)"
FT /id="VAR_056209"
FT VARIANT 581
FT /note="I -> V (in dbSNP:rs6742280)"
FT /id="VAR_056210"
FT CONFLICT 429
FT /note="V -> A (in Ref. 1; CAH10500)"
FT /evidence="ECO:0000305"
FT CONFLICT 784
FT /note="G -> S (in Ref. 1; CAH10500/CAH10600)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 798 AA; 89814 MW; 757DAD603ECFF0D3 CRC64;
MALQMFVTYS PWNCLLLLVA LECSEASSDL NESANSTAQY ASNAWFAAAS SEPEEGISVF
ELDYDYVQIP YEVTLWILLA SLAKIGFHLY HRLPGLMPES CLLILVGALV GGIIFGTDHK
SPPVMDSSIY FLYLLPPIVL EGGYFMPTRP FFENIGSILW WAVLGALINA LGIGLSLYLI
CQVKAFGLGD VNLLQNLLFG SLISAVDPVA VLAVFEEARV NEQLYMMIFG EALLNDGITV
VLYNMLIAFT KMHKFEDIET VDILAGCARF IVVGLGGVLF GIVFGFISAF ITRFTQNISA
IEPLIVFMFS YLSYLAAETL YLSGILAITA CAVTMKKYVE ENVSQTSYTT IKYFMKMLSS
VSETLIFIFM GVSTVGKNHE WNWAFICFTL AFCQIWRAIS VFALFYISNQ FRTFPFSIKD
QCIIFYSGVR GAGSFSLAFL LPLSLFPRKK MFVTATLVVI YFTVFIQGIT VGPLVRYLDV
KKTNKKESIN EELHIRLMDH LKAGIEDVCG HWSHYQVRDK FKKFDHRYLR KILIRKNLPK
SSIVSLYKKL EMKQAIEMVE TGILSSTAFS IPHQAQRIQG IKRLSPEDVE SIRDILTSNM
YQVRQRTLSY NKYNLKPQTS EKQAKEILIR RQNTLRESMR KGHSLPWGKP AGTKNIRYLS
YPYGNPQSAG RDTRAAGFSD DDSSDPGSPS ITFSACSRIG SLQKQEAQEI IPMKSLHRGR
KAFSFGYQRN TSQEEYLGGV RRVALRPKPL FHAVDEEGES GGESEGKASL VEVRSRWTAD
HGHGRDHHRS HSPLLQKK
