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Protein

Na(+)/H(+) exchange regulatory cofactor NHE-RF1

Gene

SLC9A3R1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for recycling of internalized ADRB2. Was first known to play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. May participate in HTR4 targeting to microvilli (By similarity). Involved in the regulation of phosphate reabsorption in the renal proximal tubules. Involved in sperm capacitation. May participate in the regulation of the chloride and bicarbonate homeostasis in spermatozoa.By similarity4 Publications

GO - Molecular functioni

  • beta-2 adrenergic receptor binding Source: UniProtKB
  • beta-catenin binding Source: UniProtKB
  • chloride channel regulator activity Source: UniProtKB
  • dopamine receptor binding Source: Ensembl
  • growth factor receptor binding Source: UniProtKB
  • myosin II binding Source: Ensembl
  • PDZ domain binding Source: UniProtKB
  • phosphatase binding Source: UniProtKB
  • protein complex binding Source: Ensembl
  • protein complex scaffold activity Source: Ensembl
  • protein self-association Source: UniProtKB
  • receptor binding Source: UniProtKB

GO - Biological processi

  • actin cytoskeleton organization Source: Ensembl
  • adenylate cyclase-activating dopamine receptor signaling pathway Source: Ensembl
  • auditory receptor cell stereocilium organization Source: Ensembl
  • bile acid secretion Source: UniProtKB
  • cAMP-mediated signaling Source: Ensembl
  • cellular phosphate ion homeostasis Source: Ensembl
  • establishment of epithelial cell apical/basal polarity Source: UniProtKB
  • establishment of Golgi localization Source: UniProtKB
  • establishment of nucleus localization Source: UniProtKB
  • establishment of protein localization to plasma membrane Source: UniProtKB
  • gland morphogenesis Source: UniProtKB
  • glutathione transport Source: UniProtKB
  • microvillus assembly Source: UniProtKB
  • negative regulation of catenin import into nucleus Source: UniProtKB
  • negative regulation of cell migration Source: Ensembl
  • negative regulation of cell proliferation Source: UniProtKB
  • negative regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • negative regulation of mitotic cell cycle Source: UniProtKB
  • negative regulation of phosphatidylinositol 3-kinase signaling Source: UniProtKB
  • negative regulation of platelet-derived growth factor receptor signaling pathway Source: UniProtKB
  • negative regulation of protein kinase B signaling Source: UniProtKB
  • negative regulation of sodium:proton antiporter activity Source: Ensembl
  • phospholipase C-activating dopamine receptor signaling pathway Source: Ensembl
  • positive regulation of intrinsic apoptotic signaling pathway Source: UniProtKB
  • protein complex assembly Source: ProtInc
  • regulation of cell shape Source: UniProtKB
  • regulation of cell size Source: UniProtKB
  • regulation of excretion Source: Ensembl
  • regulation of protein kinase activity Source: UniProtKB
  • regulation of sodium:proton antiporter activity Source: UniProtKB
  • renal absorption Source: UniProtKB
  • renal phosphate ion absorption Source: UniProtKB
  • renal sodium ion transport Source: Ensembl
  • sensory perception of sound Source: Ensembl
  • Wnt signaling pathway Source: UniProtKB-KW

Keywordsi

Biological processWnt signaling pathway

Enzyme and pathway databases

SignaLinkiO14745.
SIGNORiO14745.

Protein family/group databases

TCDBi8.A.24.1.1. the ezrin/radixin/moesin-binding phosphoprotein 50 (ebp50) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Na(+)/H(+) exchange regulatory cofactor NHE-RF1
Short name:
NHERF-1
Alternative name(s):
Ezrin-radixin-moesin-binding phosphoprotein 50
Short name:
EBP50
Regulatory cofactor of Na(+)/H(+) exchanger
Sodium-hydrogen exchanger regulatory factor 1
Solute carrier family 9 isoform A3 regulatory factor 1
Gene namesi
Name:SLC9A3R1
Synonyms:NHERF, NHERF1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000109062.9.
HGNCiHGNC:11075. SLC9A3R1.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Membrane

Pathology & Biotechi

Involvement in diseasei

Nephrolithiasis/osteoporosis, hypophosphatemic, 2 (NPHLOP2)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disease characterized by decreased renal phosphate absorption, renal phosphate wasting, hypophosphatemia, hyperphosphaturia, hypercalciuria, nephrolithiasis and osteoporosis.
See also OMIM:612287
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06766168E → A in NPHLOP2; impairs the interaction with SLC34A1; causes a reduction of SLC34A1 amount on cell membrane and affects SLC34A1-dependent phosphate uptake. 1 PublicationCorresponds to variant dbSNP:rs139622189Ensembl.1
Natural variantiVAR_034899110L → V in NPHLOP2; the mutant expressed in cultured renal cells increases the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibits phosphate transport. 1 PublicationCorresponds to variant dbSNP:rs35910969Ensembl.1
Natural variantiVAR_048021153R → Q in NPHLOP2; the mutant expressed in cultured renal cells increases the generation of cAMP by PTH and inhibits phosphate transport. 1 PublicationCorresponds to variant dbSNP:rs41282065Ensembl.1
Natural variantiVAR_048022225E → K in NPHLOP2; the mutant expressed in cultured renal cells increases the generation of cAMP by PTH and inhibits phosphate transport. 1 PublicationCorresponds to variant dbSNP:rs119486097Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi355F → R: Loss of MSX binding. 1 Publication1
Mutagenesisi358Missing : Reduces MSX binding. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi9368.
MalaCardsiSLC9A3R1.
MIMi612287. phenotype.
OpenTargetsiENSG00000109062.
Orphaneti244305. Dominant hypophosphatemia with nephrolithiasis or osteoporosis.
PharmGKBiPA35931.

Polymorphism and mutation databases

BioMutaiSLC9A3R1.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources2 Publications
ChainiPRO_00000967992 – 358Na(+)/H(+) exchange regulatory cofactor NHE-RF1Add BLAST357

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineCombined sources1 Publication1
Modified residuei2PhosphoserineCombined sources1
Modified residuei46PhosphoserineCombined sources1
Modified residuei162PhosphoserineCombined sources1
Modified residuei269PhosphoserineCombined sources1
Modified residuei280PhosphoserineCombined sources1
Modified residuei290PhosphoserineBy similarity1
Modified residuei291PhosphoserineBy similarity1
Modified residuei293PhosphothreonineBy similarity1
Modified residuei294PhosphoserineCombined sources1
Modified residuei299PhosphoserineBy similarity1
Modified residuei302PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated on serine residues.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiO14745.
MaxQBiO14745.
PaxDbiO14745.
PeptideAtlasiO14745.
PRIDEiO14745.

PTM databases

iPTMnetiO14745.
PhosphoSitePlusiO14745.

Expressioni

Tissue specificityi

Detected in liver, kidney, pancreas, prostate, spleen, small intestine and placenta, in particular in the syncytiotrophoblast.2 Publications

Inductioni

By estrogen.1 Publication

Gene expression databases

BgeeiENSG00000109062.
CleanExiHS_SLC9A3R1.
ExpressionAtlasiO14745. baseline and differential.
GenevisibleiO14745. HS.

Organism-specific databases

HPAiCAB001962.
HPA009672.
HPA027247.

Interactioni

Subunit structurei

Homodimer, and heterodimer with SLC9A3R2. Binds the N-termini of EZR, RDX and MSN. Binds the C-termini of PDGFRA, PDGFRB, ADRB2, NOS2 and CFTR. Binds ARHGAP17, EPI64, RACK1, OPRK1, GNAQ, CTNNB1 and PLCB3. Binds PDZK1 (By similarity). Interacts with CLCN3. Binds the C-terminus of PAG1. In resting T-cells, part of a PAG1-SLC9A3R1-MSN complex which is disrupted upon TCR activation. Forms a complex with CFTR and SLC4A7. Forms a complex with SLC4A7 and ATP6V1B1. Interacts with TRPC4 (via the PDZ-binding domain). Directly interacts with HTR4 (By similarity). Interacts (via the PDZ 1 domain) with PODXL (via the C-terminal PDZ-binding motif DTHL); interaction is not detected in glomerular epithelium cells. Interacts (via the PDZ 1 domain) with PODXL (via the C-terminal PDZ-binding motif DTHL); the interaction take place early in the secretory pathway and is necessary for its apical membrane sorting (By similarity). Interacts with SLC26A3 (By similarity). Interacts with MCC. Interacts with SLC34A1. Interacts (via the PDZ domains) with SLC26A6 isoform 4 and isoform 5.By similarity22 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • beta-2 adrenergic receptor binding Source: UniProtKB
  • beta-catenin binding Source: UniProtKB
  • dopamine receptor binding Source: Ensembl
  • growth factor receptor binding Source: UniProtKB
  • myosin II binding Source: Ensembl
  • PDZ domain binding Source: UniProtKB
  • phosphatase binding Source: UniProtKB
  • protein complex binding Source: Ensembl
  • protein complex scaffold activity Source: Ensembl
  • protein self-association Source: UniProtKB
  • receptor binding Source: UniProtKB

Protein-protein interaction databases

BioGridi114769. 106 interactors.
CORUMiO14745.
DIPiDIP-29092N.
ELMiO14745.
IntActiO14745. 40 interactors.
MINTiMINT-4998796.
STRINGi9606.ENSP00000262613.

Structurei

Secondary structure

1358
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi13 – 18Combined sources6
Beta strandi23 – 25Combined sources3
Beta strandi27 – 30Combined sources4
Beta strandi32 – 40Combined sources9
Helixi47 – 50Combined sources4
Beta strandi58 – 62Combined sources5
Helixi72 – 81Combined sources10
Beta strandi82 – 91Combined sources10
Turni93 – 95Combined sources3
Turni101 – 103Combined sources3
Turni106 – 108Combined sources3
Helixi109 – 112Combined sources4
Beta strandi115 – 118Combined sources4
Beta strandi153 – 158Combined sources6
Turni160 – 162Combined sources3
Beta strandi166 – 170Combined sources5
Beta strandi172 – 182Combined sources11
Beta strandi184 – 186Combined sources3
Helixi187 – 190Combined sources4
Beta strandi198 – 202Combined sources5
Helixi212 – 221Combined sources10
Turni222 – 224Combined sources3
Beta strandi225 – 231Combined sources7
Helixi233 – 238Combined sources6
Helixi248 – 251Combined sources4
Beta strandi286 – 289Combined sources4
Helixi297 – 299Combined sources3
Beta strandi300 – 302Combined sources3
Beta strandi313 – 315Combined sources3
Helixi323 – 328Combined sources6
Helixi329 – 333Combined sources5
Helixi348 – 355Combined sources8

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1G9OX-ray1.50A11-99[»]
1GQ4X-ray1.90A11-94[»]
1GQ5X-ray2.20A11-94[»]
1I92X-ray1.70A11-94[»]
1SGHX-ray3.50B321-358[»]
2D10X-ray2.50E/F/G/H331-358[»]
2JXONMR-A150-240[»]
2KJDNMR-A150-270[»]
2KRGNMR-A150-358[»]
2M0TNMR-A11-120[»]
2M0UNMR-A11-120[»]
2M0VNMR-A150-270[»]
2OZFX-ray1.50A150-235[»]
4JL7X-ray1.16A11-95[»]
4LMMX-ray1.10A11-94[»]
4MPAX-ray1.10A11-94[»]
4N6XX-ray1.05A11-94[»]
4PQWX-ray1.47A11-94[»]
4Q3HX-ray1.44A/B150-234[»]
ProteinModelPortaliO14745.
SMRiO14745.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO14745.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini14 – 94PDZ 1PROSITE-ProRule annotationAdd BLAST81
Domaini154 – 234PDZ 2PROSITE-ProRule annotationAdd BLAST81

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiENOG410ITAB. Eukaryota.
ENOG4110SZZ. LUCA.
GeneTreeiENSGT00530000062999.
HOGENOMiHOG000089940.
HOVERGENiHBG052616.
InParanoidiO14745.
KOiK13365.
OMAiLCAMKKG.
OrthoDBiEOG091G086H.
PhylomeDBiO14745.
TreeFamiTF350449.

Family and domain databases

InterProiView protein in InterPro
IPR015098. EBP50_C-term.
IPR031199. NHERF-1.
IPR017300. NHERF-1/NHERF-2.
IPR001478. PDZ.
PANTHERiPTHR14191:SF14. PTHR14191:SF14. 1 hit.
PfamiView protein in Pfam
PF09007. EBP50_C. 1 hit.
PF00595. PDZ. 2 hits.
PIRSFiPIRSF037866. EBP50. 1 hit.
ProDomiView protein in ProDom or Entries sharing at least one domain
PD283022. EBP50_C-term. 1 hit.
SMARTiView protein in SMART
SM00228. PDZ. 2 hits.
SUPFAMiSSF50156. SSF50156. 2 hits.
PROSITEiView protein in PROSITE
PS50106. PDZ. 2 hits.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O14745-1) [UniParc]FASTAAdd to basket

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
MSADAAAGAP LPRLCCLEKG PNGYGFHLHG EKGKLGQYIR LVEPGSPAEK
60 70 80 90 100
AGLLAGDRLV EVNGENVEKE THQQVVSRIR AALNAVRLLV VDPETDEQLQ
110 120 130 140 150
KLGVQVREEL LRAQEAPGQA EPPAAAEVQG AGNENEPREA DKSHPEQREL
160 170 180 190 200
RPRLCTMKKG PSGYGFNLHS DKSKPGQFIR SVDPDSPAEA SGLRAQDRIV
210 220 230 240 250
EVNGVCMEGK QHGDVVSAIR AGGDETKLLV VDRETDEFFK KCRVIPSQEH
260 270 280 290 300
LNGPLPVPFT NGEIQKENSR EALAEAALES PRPALVRSAS SDTSEELNSQ
310 320 330 340 350
DSPPKQDSTA PSSTSSSDPI LDFNISLAMA KERAHQKRSS KRAPQMDWSK

KNELFSNL
Length:358
Mass (Da):38,868
Last modified:January 23, 2007 - v4
Checksum:iE33AF87016D37A65
GO
Isoform 2 (identifier: O14745-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-156: Missing.

Note: No experimental confirmation available.
Show »
Length:202
Mass (Da):22,034
Checksum:i544A8F15B453C859
GO

Sequence cautioni

The sequence AAH49220 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06766168E → A in NPHLOP2; impairs the interaction with SLC34A1; causes a reduction of SLC34A1 amount on cell membrane and affects SLC34A1-dependent phosphate uptake. 1 PublicationCorresponds to variant dbSNP:rs139622189Ensembl.1
Natural variantiVAR_034899110L → V in NPHLOP2; the mutant expressed in cultured renal cells increases the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibits phosphate transport. 1 PublicationCorresponds to variant dbSNP:rs35910969Ensembl.1
Natural variantiVAR_048021153R → Q in NPHLOP2; the mutant expressed in cultured renal cells increases the generation of cAMP by PTH and inhibits phosphate transport. 1 PublicationCorresponds to variant dbSNP:rs41282065Ensembl.1
Natural variantiVAR_048022225E → K in NPHLOP2; the mutant expressed in cultured renal cells increases the generation of cAMP by PTH and inhibits phosphate transport. 1 PublicationCorresponds to variant dbSNP:rs119486097Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0554971 – 156Missing in isoform 2. 1 PublicationAdd BLAST156

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF015926 mRNA. Translation: AAC52084.1.
AF036241 mRNA. Translation: AAC04572.1.
AK128474 mRNA. Translation: BAG54683.1.
AC016888 Genomic DNA. No translation available.
CH471099 Genomic DNA. Translation: EAW89189.1.
BC001443 mRNA. Translation: AAH01443.1.
BC003361 mRNA. Translation: AAH03361.1.
BC011777 mRNA. Translation: AAH11777.1.
BC049220 mRNA. Translation: AAH49220.1. Different initiation.
BC053350 mRNA. Translation: AAH53350.1.
CCDSiCCDS11705.1. [O14745-1]
RefSeqiNP_004243.1. NM_004252.4. [O14745-1]
UniGeneiHs.724482.
Hs.744126.

Genome annotation databases

EnsembliENST00000262613; ENSP00000262613; ENSG00000109062. [O14745-1]
ENST00000413388; ENSP00000464982; ENSG00000109062. [O14745-2]
GeneIDi9368.
KEGGihsa:9368.
UCSCiuc002jlo.5. human. [O14745-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiNHRF1_HUMAN
AccessioniPrimary (citable) accession number: O14745
Secondary accession number(s): B3KY21, O43552, Q86WQ5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 2, 2004
Last sequence update: January 23, 2007
Last modified: September 27, 2017
This is version 186 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references