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Q15599 (NHRF2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 138. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Na(+)/H(+) exchange regulatory cofactor NHE-RF2

Short name=NHERF-2
Alternative name(s):
NHE3 kinase A regulatory protein E3KARP
SRY-interacting protein 1
Short name=SIP-1
Sodium-hydrogen exchanger regulatory factor 2
Solute carrier family 9 isoform A3 regulatory factor 2
Tyrosine kinase activator protein 1
Short name=TKA-1
Gene names
Name:SLC9A3R2
Synonyms:NHERF2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length337 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 cAMP-mediated phosphorylation and inhibition of SLC9A3. May also act as scaffold protein in the nucleus. Ref.3 Ref.9

Subunit structure

Homodimer, and heterodimer with SLC9A3R1. Binds PDZK1. Found in a complex with EZR, PODXL and SLC9A3R2 By similarity. Interacts (via the PDZ domains) with PODXL (via the C-terminal PDZ-binding motif DTHL); interaction is detected in glomerular epithelium cells By similarity. Binds ADRB2, SLC9A3, P2RY1, P2YR2, SRY, RDX and LPAR2. Interacts with MCC and PODXL. Interacts with SGK1 and KCNJ1/ROMK1. Interacts (via the PDZ domains) with SLC26A6 isoform 4and isoform 5 Ref.1 Ref.3 Ref.5 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15

Subcellular location

Endomembrane system; Peripheral membrane protein. Nucleus. Apical cell membrane By similarity. Note: Localizes with EZR and PODXL at the apical cell membrane of glomerular epithelium cells and the sides of the food processes By similarity. Nuclear, in a punctate pattern. Ref.1

Tissue specificity

Widely expressed. Ref.1 Ref.3

Sequence similarities

Contains 2 PDZ (DHR) domains.

Sequence caution

The sequence AAH14513.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

The sequence CAA90511.1 differs from that shown. Reason: Frameshift at position 309.

Binary interactions

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q15599-1)

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: Q15599-2)

The sequence of this isoform differs from the canonical sequence as follows:
     286-296: Missing.
Isoform 3 (identifier: Q15599-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-27: MAAPEPLRPRLCRLVRGEQGYGFHLHG → MARSGSATPPARAPGAPPRSPPQRLVQ
     28-138: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 337337Na(+)/H(+) exchange regulatory cofactor NHE-RF2
PRO_0000096805

Regions

Domain11 – 9080PDZ 1
Domain150 – 23081PDZ 2

Amino acid modifications

Modified residue1831Phosphoserine Ref.14
Modified residue2541Phosphoserine Ref.14

Natural variations

Alternative sequence1 – 2727MAAPE…FHLHG → MARSGSATPPARAPGAPPRS PPQRLVQ in isoform 3.
VSP_046849
Alternative sequence28 – 138111Missing in isoform 3.
VSP_046850
Alternative sequence286 – 29611Missing in isoform 2.
VSP_009378

Experimental info

Sequence conflict511Missing in CAA90511. Ref.2
Sequence conflict1801D → Y in BM920873. Ref.8
Sequence conflict334 – 3363FSN → LQH in BM920873. Ref.8

Secondary structure

............................... 337
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified February 16, 2004. Version 2.
Checksum: 4F5D341590D22ED7

FASTA33737,414
        10         20         30         40         50         60 
MAAPEPLRPR LCRLVRGEQG YGFHLHGEKG RRGQFIRRVE PGSPAEAAAL RAGDRLVEVN 

        70         80         90        100        110        120 
GVNVEGETHH QVVQRIKAVE GQTRLLVVDQ ETDEELRRRQ LTCTEEMAQR GLPPAHDPWE 

       130        140        150        160        170        180 
PKPDWAHTGS HSSEAGKKDV SGPLRELRPR LCHLRKGPQG YGFNLHSDKS RPGQYIRSVD 

       190        200        210        220        230        240 
PGSPAARSGL RAQDRLIEVN GQNVEGLRHA EVVASIKARE DEARLLVVDP ETDEHFKRLR 

       250        260        270        280        290        300 
VTPTEEHVEG PLPSPVTNGT SPAQLNGGSA CSSRSDLPGS DKDTEDGSAW KQDPFQESGL 

       310        320        330 
HLSPTAAEAK EKARAMRVNK RAPQMDWNRK REIFSNF 

« Hide

Isoform 2 [UniParc].

Checksum: 59EB725D61D896DC
Show »

FASTA32636,153
Isoform 3 [UniParc].

Checksum: 51D77F534CB2328A
Show »

FASTA22624,718

References

« Hide 'large scale' references
[1]"The human testis determining factor SRY binds a nuclear factor containing PDZ protein interaction domains."
Poulat F., de Santa Barbara P., Desclozeaux M., Soullier S., Moniot B., Bonneaud N., Boizet B., Berta P.
J. Biol. Chem. 272:7167-7172(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), INTERACTION WITH SRY, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
Tissue: Cervix carcinoma, Fetal brain and Testis.
[2]"Identification of EBP50: a PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family."
Reczek D., Berryman M., Bretscher A.
J. Cell Biol. 139:169-179(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Placenta.
[3]"cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein."
Yun C.H.C., Oh S., Zizak M., Steplock D., Tsao S., Tse C.-M., Weinman E.J., Donowitz M.
Proc. Natl. Acad. Sci. U.S.A. 94:3010-3015(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH SLC9A3, TISSUE SPECIFICITY.
Tissue: Embryo.
[4]"Genomic structure and sequence of a human homologue (NTHL1/NTH1) of Escherichia coli endonuclease III with those of the adjacent parts of TSC2 and SLC9A3R2 genes."
Imai K., Sarker A.H., Akiyama K., Ikeda S., Yao M., Tsutsui K., Shohmori T., Seki S.
Gene 222:287-295(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]"A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins."
Hall R.A., Ostedgaard L.S., Premont R.T., Blitzer J.T., Rahman N., Welsh M.J., Lefkowitz R.J.
Proc. Natl. Acad. Sci. U.S.A. 95:8496-8501(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH ADRB2; P2RY1 AND P2YR2.
Tissue: Lung.
[6]"The sequence and analysis of duplication-rich human chromosome 16."
Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. expand/collapse author list , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A.
Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
Tissue: Kidney and Testis.
[9]"cAMP-induced phosphorylation and inhibition of Na(+)/H(+) exchanger 3 (NHE3) are dependent on the presence but not the phosphorylation of NHE regulatory factor."
Zizak M., Lamprecht G., Steplock D., Tariq N., Shenolikar S., Donowitz M., Yun C.H.C., Weinman E.J.
J. Biol. Chem. 274:24753-24758(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SLC9A3.
[10]"Isoforms of SLC26A6 mediate anion transport and have functional PDZ interaction domains."
Lohi H., Lamprecht G., Markovich D., Heil A., Kujala M., Seidler U., Kere J.
Am. J. Physiol. 284:C769-C779(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SLC26A6.
[11]"Molecular requirements for the regulation of the renal outer medullary K(+) channel ROMK1 by the serum- and glucocorticoid-inducible kinase SGK1."
Palmada M., Embark H.M., Yun C., Bohmer C., Lang F.
Biochem. Biophys. Res. Commun. 311:629-634(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SGK1 AND KCNJ1/ROMK1.
[12]"NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation."
Oh Y.-S., Jo N.W., Choi J.W., Kim H.S., Seo S.-W., Kang K.-O., Hwang J.-I., Heo K., Kim S.-H., Kim Y.-H., Kim I.-H., Kim J.H., Banno Y., Ryu S.H., Suh P.-G.
Mol. Cell. Biol. 24:5069-5079(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LPAR2.
[13]"Gp135/podocalyxin and NHERF-2 participate in the formation of a preapical domain during polarization of MDCK cells."
Meder D., Shevchenko A., Simons K., Fuellekrug J.
J. Cell Biol. 168:303-313(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PODXL.
[14]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-183 AND SER-254, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[15]"MCC, a new interacting protein for Scrib, is required for cell migration in epithelial cells."
Arnaud C., Sebbagh M., Nola S., Audebert S., Bidaut G., Hermant A., Gayet O., Dusetti N.J., Ollendorff V., Santoni M.J., Borg J.P., Lecine P.
FEBS Lett. 583:2326-2332(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MCC.
[16]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]"Structural basis for NHERF recognition by ERM proteins."
Terawaki S., Maesaki R., Hakoshima T.
Structure 14:777-789(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) OF 310-337 IN COMPLEX WITH RDX.
[18]"The crystal structure of the first and second PDZ domain of human NHERF-2 (SLC9A3R2) interacting with a mode 1 PDZ binding motif."
Structural genomics consortium (SGC)
Submitted (JAN-2007) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 9-232.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U82108 mRNA. Translation: AAB53042.1.
Z50150 mRNA. Translation: CAA90511.1. Frameshift.
AF004900 mRNA. Translation: AAC63061.1.
AF035771 mRNA. Translation: AAC52090.1.
AB014460 Genomic DNA. Translation: BAA32696.1.
AB016243 Genomic DNA. Translation: BAA33216.1.
AC005600 Genomic DNA. Translation: AAC34208.1.
AC093513 Genomic DNA. No translation available.
CH471112 Genomic DNA. Translation: EAW85563.1.
CH471112 Genomic DNA. Translation: EAW85564.1.
CH471112 Genomic DNA. Translation: EAW85565.1.
CH471112 Genomic DNA. Translation: EAW85566.1.
BC014513 mRNA. Translation: AAH14513.2. Different initiation.
BC106001 mRNA. Translation: AAI06002.1.
BM920873 mRNA. No translation available.
PIRG01158.
RefSeqNP_001123484.1. NM_001130012.2.
NP_001239002.1. NM_001252073.1.
NP_004776.3. NM_004785.5.
UniGeneHs.440896.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2D11X-ray2.81E/F/G/H310-337[»]
2HE4X-ray1.45A147-228[»]
2OCSX-ray1.50A9-91[»]
ProteinModelPortalQ15599.
SMRQ15599. Positions 9-337.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114754. 41 interactions.
DIPDIP-29093N.
IntActQ15599. 20 interactions.
MINTMINT-126664.
STRING9606.ENSP00000408005.

Protein family/group databases

TCDB8.A.24.1.2. the ezrin/radixin/moesin-binding phosphoprotein 50 (ebp50) family.

PTM databases

PhosphoSiteQ15599.

Polymorphism databases

DMDM42559433.

Proteomic databases

PaxDbQ15599.
PRIDEQ15599.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000424542; ENSP00000408005; ENSG00000065054. [Q15599-1]
ENST00000432365; ENSP00000402857; ENSG00000065054. [Q15599-2]
ENST00000566198; ENSP00000456895; ENSG00000065054. [Q15599-3]
GeneID9351.
KEGGhsa:9351.
UCSCuc002coi.3. human. [Q15599-1]

Organism-specific databases

CTD9351.
GeneCardsGC16P002075.
HGNCHGNC:11076. SLC9A3R2.
HPAHPA001672.
MIM606553. gene.
neXtProtNX_Q15599.
PharmGKBPA35932.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG319972.
HOGENOMHOG000089940.
HOVERGENHBG052616.
InParanoidQ15599.
KOK13358.
OMATDEYFKR.
PhylomeDBQ15599.
TreeFamTF350449.

Gene expression databases

ArrayExpressQ15599.
BgeeQ15599.
CleanExHS_SLC9A3R2.
GenevestigatorQ15599.

Family and domain databases

Gene3D2.30.42.10. 2 hits.
InterProIPR015098. EBP50_C-term.
IPR017300. NaH_exchngr_reg_CF_NHE-RF.
IPR001478. PDZ.
[Graphical view]
PfamPF09007. EBP50_C-term. 1 hit.
PF00595. PDZ. 2 hits.
[Graphical view]
PIRSFPIRSF037866. EBP50. 1 hit.
ProDomPD283022. EBP50_C-term. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SMARTSM00228. PDZ. 2 hits.
[Graphical view]
SUPFAMSSF50156. SSF50156. 2 hits.
PROSITEPS50106. PDZ. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ15599.
GenomeRNAi9351.
NextBio35017.
PROQ15599.
SOURCESearch...

Entry information

Entry nameNHRF2_HUMAN
AccessionPrimary (citable) accession number: Q15599
Secondary accession number(s): D3DU84 expand/collapse secondary AC list , D3DU85, H3BSV6, O00272, O00556, Q3KQY7
Entry history
Integrated into UniProtKB/Swiss-Prot: February 16, 2004
Last sequence update: February 16, 2004
Last modified: April 16, 2014
This is version 138 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 16

Human chromosome 16: entries, gene names and cross-references to MIM