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Sodium/hydrogen exchanger 3 (Na( )/H( ) exchanger 3) (NHE-3) (Solute carrier family 9 member 3)

 SL9A3_HUMAN             Reviewed;         834 AA.
P48764; B7ZKR2; E9PF67; Q3MIW3;
01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
24-NOV-2009, sequence version 2.
28-FEB-2018, entry version 155.
RecName: Full=Sodium/hydrogen exchanger 3 {ECO:0000305};
AltName: Full=Na(+)/H(+) exchanger 3 {ECO:0000303|PubMed:7631746};
Short=NHE-3 {ECO:0000303|PubMed:7631746};
AltName: Full=Solute carrier family 9 member 3;
Name=SLC9A3 {ECO:0000312|HGNC:HGNC:11073};
Synonyms=NHE3 {ECO:0000303|PubMed:7631746};
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ARG-799.
TISSUE=Kidney cortex;
PubMed=7631746;
Brant S.R., Yun C.H., Donowitz M., Tse C.-M.;
"Cloning, tissue distribution, and functional analysis of the human
Na+/N+ exchanger isoform, NHE3.";
Am. J. Physiol. 269:C198-C206(1995).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15372022; DOI=10.1038/nature02919;
Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
"The DNA sequence and comparative analysis of human chromosome 5.";
Nature 431:268-274(2004).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
ARG-799.
TISSUE=Colon;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[4]
SUBCELLULAR LOCATION, AND INTERACTION WITH PDZD3.
PubMed=19088451; DOI=10.1159/000185553;
Zachos N.C., Hodson C., Kovbasnjuk O., Li X., Thelin W.R., Cha B.,
Milgram S., Donowitz M.;
"Elevated intracellular calcium stimulates NHE3 activity by an IKEPP
(NHERF4) dependent mechanism.";
Cell. Physiol. Biochem. 22:693-704(2008).
[5]
INTERACTION WITH AHCYL1.
PubMed=18829453; DOI=10.1074/jbc.M805534200;
He P., Zhang H., Yun C.C.;
"IRBIT, inositol 1,4,5-triphosphate (IP3) receptor-binding protein
released with IP3, binds Na+/H+ exchanger NHE3 and activates NHE3
activity in response to calcium.";
J. Biol. Chem. 283:33544-33553(2008).
[6]
INTERACTION WITH AHCYL1.
PubMed=20584908; DOI=10.1074/jbc.M110.133066;
He P., Klein J., Yun C.C.;
"Activation of Na+/H+ exchanger NHE3 by angiotensin II is mediated by
inositol 1,4,5-triphosphate (IP3) receptor-binding protein released
with IP3 (IRBIT) and Ca2+/calmodulin-dependent protein kinase II.";
J. Biol. Chem. 285:27869-27878(2010).
[7]
VARIANTS DIAR8 THR-127; THR-269; VAL-311 AND GLN-382, CHARACTERIZATION
OF VARIANTS DIAR8 THR-127; THR-269; VAL-311 AND GLN-382, FUNCTION, AND
SUBCELLULAR LOCATION.
PubMed=26358773; DOI=10.1093/hmg/ddv367;
Janecke A.R., Heinz-Erian P., Yin J., Petersen B.S., Franke A.,
Lechner S., Fuchs I., Melancon S., Uhlig H.H., Travis S., Marinier E.,
Perisic V., Ristic N., Gerner P., Booth I.W., Wedenoja S.,
Baumgartner N., Vodopiutz J., Frechette-Duval M.C., De Lafollie J.,
Persad R., Warner N., Tse C.M., Sud K., Zachos N.C., Sarker R.,
Zhu X., Muise A.M., Zimmer K.P., Witt H., Zoller H., Donowitz M.,
Mueller T.;
"Reduced sodium/proton exchanger NHE3 activity causes congenital
sodium diarrhea.";
Hum. Mol. Genet. 24:6614-6623(2015).
-!- FUNCTION: Involved in pH regulation to eliminate acids generated
by active metabolism or to counter adverse environmental
conditions. Major proton extruding system driven by the inward
sodium ion chemical gradient (PubMed:26358773). Plays an important
role in signal transduction. {ECO:0000269|PubMed:26358773}.
-!- SUBUNIT: Binds SLC9A3R1 and SLC9A3R2. Interacts with CHP1, CHP2
and SHANK2. Interacts with PDZK1 (via C-terminal PDZ domain) (By
similarity). Interacts with PDZD3 and interactions decrease in
response to elevated calcium ion levels. Interacts with AHCYL1;
the interaction is required for SLC9A3 activity (PubMed:18829453,
PubMed:20584908). {ECO:0000250|UniProtKB:P26432,
ECO:0000250|UniProtKB:P26433, ECO:0000250|UniProtKB:Q28362,
ECO:0000269|PubMed:18829453, ECO:0000269|PubMed:19088451,
ECO:0000269|PubMed:20584908}.
-!- INTERACTION:
Q6P0Q8:MAST2; NbExp=2; IntAct=EBI-7816923, EBI-493777;
-!- SUBCELLULAR LOCATION: Apical cell membrane
{ECO:0000269|PubMed:19088451, ECO:0000269|PubMed:26358773}; Multi-
pass membrane protein {ECO:0000269|PubMed:19088451}. Note=In
intestinal epithelial cells, localizes to the ileal brush border.
Phosphorylation at Ser-663 by SGK1 is associated with increased
abundance at the cell membrane. Angiotensin-2 enhances apical
expression (By similarity). {ECO:0000250|UniProtKB:Q28362}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1;
IsoId=P48764-1; Sequence=Displayed;
Name=2;
IsoId=P48764-2; Sequence=VSP_053989;
Note=No experimental confirmation available.;
-!- PTM: Phosphorylated by PKA, which inhibits activity.
Phosphorylation at Ser-663 by SGK1 is associated with increased
abundance at the cell membrane. {ECO:0000250|UniProtKB:P26432,
ECO:0000250|UniProtKB:P26433}.
-!- DISEASE: Diarrhea 8, secretory sodium, congenital (DIAR8)
[MIM:616868]: A disease characterized by watery secretory diarrhea
with prenatal onset, prominent abdominal distension after birth
due to dilated fluid-filled loops of intestine, elevated fecal
sodium concentrations and low urinary sodium concentrations.
{ECO:0000269|PubMed:26358773}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- SIMILARITY: Belongs to the monovalent cation:proton antiporter 1
(CPA1) transporter (TC 2.A.36) family. {ECO:0000305}.
-!- CAUTION: The number, localization and denomination of hydrophobic
domains in the Na(+)/H(+) exchangers vary among authors.
{ECO:0000305}.
-----------------------------------------------------------------------
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EMBL; U28043; AAB48990.1; -; mRNA.
EMBL; AC010442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC106772; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; BC101669; AAI01670.1; -; mRNA.
EMBL; BC101671; AAI01672.1; -; mRNA.
EMBL; BC143328; AAI43329.1; -; mRNA.
CCDS; CCDS3855.1; -. [P48764-1]
CCDS; CCDS64116.1; -. [P48764-2]
PIR; B40205; B40205.
RefSeq; NP_001271280.1; NM_001284351.2. [P48764-2]
RefSeq; NP_004165.2; NM_004174.3. [P48764-1]
UniGene; Hs.658120; -.
ProteinModelPortal; P48764; -.
SMR; P48764; -.
BioGrid; 112440; 9.
CORUM; P48764; -.
IntAct; P48764; 1.
MINT; P48764; -.
STRING; 9606.ENSP00000264938; -.
BindingDB; P48764; -.
ChEMBL; CHEMBL3273; -.
TCDB; 2.A.36.1.15; the monovalent cation:proton antiporter-1 (cpa1) family.
iPTMnet; P48764; -.
PhosphoSitePlus; P48764; -.
BioMuta; SLC9A3; -.
DMDM; 269849652; -.
PaxDb; P48764; -.
PeptideAtlas; P48764; -.
PRIDE; P48764; -.
Ensembl; ENST00000264938; ENSP00000264938; ENSG00000066230. [P48764-1]
Ensembl; ENST00000514375; ENSP00000422983; ENSG00000066230. [P48764-2]
GeneID; 6550; -.
KEGG; hsa:6550; -.
UCSC; uc003jbe.3; human. [P48764-1]
CTD; 6550; -.
DisGeNET; 6550; -.
EuPathDB; HostDB:ENSG00000066230.10; -.
GeneCards; SLC9A3; -.
H-InvDB; HIX0004707; -.
H-InvDB; HIX0032039; -.
HGNC; HGNC:11073; SLC9A3.
HPA; HPA036493; -.
HPA; HPA036669; -.
MalaCards; SLC9A3; -.
MIM; 182307; gene.
MIM; 616868; phenotype.
neXtProt; NX_P48764; -.
OpenTargets; ENSG00000066230; -.
PharmGKB; PA316; -.
eggNOG; KOG1966; Eukaryota.
eggNOG; COG0025; LUCA.
GeneTree; ENSGT00760000119074; -.
HOGENOM; HOG000247044; -.
HOVERGEN; HBG052615; -.
InParanoid; P48764; -.
KO; K12040; -.
OMA; YTMKMLA; -.
OrthoDB; EOG091G02Q0; -.
PhylomeDB; P48764; -.
TreeFam; TF317212; -.
Reactome; R-HSA-425986; Sodium/Proton exchangers.
SIGNOR; P48764; -.
ChiTaRS; SLC9A3; human.
GeneWiki; Sodium%E2%80%93hydrogen_antiporter_3; -.
GenomeRNAi; 6550; -.
PRO; PR:P48764; -.
Proteomes; UP000005640; Chromosome 5.
Bgee; ENSG00000066230; -.
CleanEx; HS_SLC9A3; -.
Genevisible; P48764; HS.
GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
GO; GO:0005903; C:brush border; ISS:UniProtKB.
GO; GO:0031526; C:brush border membrane; ISS:UniProtKB.
GO; GO:0009986; C:cell surface; ISS:UniProtKB.
GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
GO; GO:0030165; F:PDZ domain binding; ISS:UniProtKB.
GO; GO:0015386; F:potassium:proton antiporter activity; IBA:GO_Central.
GO; GO:0015385; F:sodium:proton antiporter activity; IDA:UniProtKB.
GO; GO:0006811; P:ion transport; TAS:Reactome.
GO; GO:0071805; P:potassium ion transmembrane transport; IBA:GO_Central.
GO; GO:0051453; P:regulation of intracellular pH; IBA:GO_Central.
GO; GO:0098719; P:sodium ion import across plasma membrane; IDA:UniProtKB.
InterPro; IPR006153; Cation/H_exchanger.
InterPro; IPR018422; Cation/H_exchanger_CPA1.
InterPro; IPR018410; Na/H_exchanger_3/5.
InterPro; IPR004709; NaH_exchanger.
PANTHER; PTHR10110; PTHR10110; 1.
Pfam; PF00999; Na_H_Exchanger; 1.
PRINTS; PR01084; NAHEXCHNGR.
PRINTS; PR01087; NAHEXCHNGR3.
TIGRFAMs; TIGR00840; b_cpa1; 1.
1: Evidence at protein level;
Alternative splicing; Antiport; Cell membrane; Complete proteome;
Disease mutation; Glycoprotein; Ion transport; Membrane;
Phosphoprotein; Polymorphism; Reference proteome; Sodium;
Sodium transport; Transmembrane; Transmembrane helix; Transport.
CHAIN 1 834 Sodium/hydrogen exchanger 3.
/FTId=PRO_0000052356.
TOPO_DOM 1 12 Cytoplasmic. {ECO:0000255}.
INTRAMEM 13 24 Name=A/M1. {ECO:0000255}.
TOPO_DOM 25 54 Cytoplasmic. {ECO:0000255}.
INTRAMEM 55 73 Name=B/M2. {ECO:0000255}.
TOPO_DOM 74 79 Cytoplasmic. {ECO:0000255}.
TRANSMEM 80 99 Helical; Name=C/M3. {ECO:0000255}.
TOPO_DOM 100 112 Extracellular. {ECO:0000255}.
TRANSMEM 113 133 Helical; Name=D/M4. {ECO:0000255}.
TOPO_DOM 134 139 Cytoplasmic. {ECO:0000255}.
TRANSMEM 140 160 Helical; Name=E/M5. {ECO:0000255}.
TOPO_DOM 161 180 Extracellular. {ECO:0000255}.
TRANSMEM 181 202 Helical; Name=F/M5A. {ECO:0000255}.
TOPO_DOM 203 210 Cytoplasmic. {ECO:0000255}.
TRANSMEM 211 232 Helical; Name=G/M5B. {ECO:0000255}.
TOPO_DOM 233 252 Extracellular. {ECO:0000255}.
TRANSMEM 253 274 Helical; Name=H/M6. {ECO:0000255}.
TOPO_DOM 275 290 Cytoplasmic. {ECO:0000255}.
TRANSMEM 291 309 Helical; Name=I/M7. {ECO:0000255}.
TOPO_DOM 310 340 Extracellular. {ECO:0000255}.
TRANSMEM 341 362 Helical; Name=J/M8. {ECO:0000255}.
TOPO_DOM 363 369 Cytoplasmic. {ECO:0000255}.
TRANSMEM 370 390 Helical; Name=K/M9. {ECO:0000255}.
TOPO_DOM 391 405 Extracellular. {ECO:0000255}.
INTRAMEM 406 426 Name=L. {ECO:0000255}.
TOPO_DOM 427 435 Extracellular. {ECO:0000255}.
TRANSMEM 436 456 Helical; Name=M/M10. {ECO:0000255}.
TOPO_DOM 457 834 Cytoplasmic. {ECO:0000255}.
REGION 590 667 Interaction with PDZD3. {ECO:0000250}.
MOD_RES 555 555 Phosphoserine.
{ECO:0000250|UniProtKB:P26433}.
MOD_RES 563 563 Phosphoserine.
{ECO:0000250|UniProtKB:P26433}.
MOD_RES 592 592 Phosphoserine.
{ECO:0000250|UniProtKB:G3X939}.
MOD_RES 607 607 Phosphoserine.
{ECO:0000250|UniProtKB:P26433}.
MOD_RES 663 663 Phosphoserine; by SGK1.
{ECO:0000250|UniProtKB:P26432}.
MOD_RES 810 810 Phosphoserine.
{ECO:0000250|UniProtKB:G3X939}.
MOD_RES 813 813 Phosphoserine.
{ECO:0000250|UniProtKB:G3X939}.
CARBOHYD 241 241 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 326 326 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
VAR_SEQ 452 460 Missing (in isoform 2).
{ECO:0000303|PubMed:15489334}.
/FTId=VSP_053989.
VARIANT 127 127 A -> T (in DIAR8; unknown pathological
significance; does not affect cell
membrane localization; reduces weakly
Na(+)/H(+) exchange activity;
dbSNP:rs1047334552).
{ECO:0000269|PubMed:26358773}.
/FTId=VAR_076419.
VARIANT 269 269 A -> T (in DIAR8; decreases cell membrane
expression; reduces Na(+)/H(+) exchange
activity; dbSNP:rs869312807).
{ECO:0000269|PubMed:26358773}.
/FTId=VAR_076420.
VARIANT 311 311 A -> V (in DIAR8; decreases cell membrane
expression; reduces strongly Na(+)/H(+)
exchange activity; dbSNP:rs869312806).
{ECO:0000269|PubMed:26358773}.
/FTId=VAR_076421.
VARIANT 382 382 R -> Q (in DIAR8; decreases cell membrane
localization; reduces strongly Na(+)/H(+)
exchange activity; dbSNP:rs766076524).
{ECO:0000269|PubMed:26358773}.
/FTId=VAR_076422.
VARIANT 799 799 C -> R (in dbSNP:rs2247114).
{ECO:0000269|PubMed:15489334,
ECO:0000269|PubMed:7631746}.
/FTId=VAR_060593.
SEQUENCE 834 AA; 92855 MW; 3E7CE3267F6E86F7 CRC64;
MWGLGARGPD RGLLLALALG GLARAGGVEV EPGGAHGESG GFQVVTFEWA HVQDPYVIAL
WILVASLAKI GFHLSHKVTS VVPESALLIV LGLVLGGIVW AADHIASFTL TPTVFFFYLL
PPIVLDAGYF MPNRLFFGNL GTILLYAVVG TVWNAATTGL SLYGVFLSGL MGDLQIGLLD
FLLFGSLMAA VDPVAVLAVF EEVHVNEVLF IIVFGESLLN DAVTVVLYNV FESFVALGGD
NVTGVDCVKG IVSFFVVSLG GTLVGVVFAF LLSLVTRFTK HVRIIEPGFV FIISYLSYLT
SEMLSLSAIL AITFCGICCQ KYVKANISEQ SATTVRYTMK MLASSAETII FMFLGISAVN
PFIWTWNTAF VLLTLVFISV YRAIGVVLQT WLLNRYRMVQ LEPIDQVVLS YGGLRGAVAF
ALVVLLDGDK VKEKNLFVST TIIVVFFTVI FQGLTIKPLV QWLKVKRSEH REPRLNEKLH
GRAFDHILSA IEDISGQIGH NYLRDKWSHF DRKFLSRVLM RRSAQKSRDR ILNVFHELNL
KDAISYVAEG ERRGSLAFIR SPSTDNVVNV DFTPRSSTVE ASVSYLLREN VSAVCLDMQS
LEQRRRSIRD AEDMVTHHTL QQYLYKPRQE YKHLYSRHEL TPTEDEKQDR EIFHRTMRKR
LESFKSTKLG LNQNKKAAKL YKRERAQKRR NSSIPNGKLP MESPAQNFTI KEKDLELSDT
EEPPNYDEEM SGGIEFLASV TKDTASDSPA GIDNPVFSPD EALDRSLLAR LPPWLSPGET
VVPSQRARTQ IPYSPGTFCR LMPFRLSSKS VDSFLQADGP EERPPAALPE STHM


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