Reviewed, UniProtKB/Swiss-Prot Q15599 (NHRF2_HUMAN)

Names and origin

Protein names

Recommended name:
    Na(+)/H(+) exchange regulatory cofactor NHE-RF2
      Short name=NHERF-2
Alternative name(s):
    Tyrosine kinase activator protein 1
      Short name=TKA-1
    SRY-interacting protein 1
      Short name=SIP-1
    Solute carrier family 9 isoform A3 regulatory factor 2
    NHE3 kinase A regulatory protein E3KARP
    Sodium-hydrogen exchanger regulatory factor 2

Gene names

Name:	SLC9A3R2
Synonyms:	NHERF2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	337 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence 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.
Subunit structure	Homodimer, and heterodimer with SLC9A3R1. Binds PODXL and PDZK1 By similarity. Binds ADRB2, SLC9A3, P2RY1, P2YR2, SRY, RDX and LPAR2.
Subcellular location	Intracytoplasmic membrane; Peripheral membrane protein. Nucleus. Note= Nuclear, in a punctate pattern.
Tissue specificity	Widely expressed.
Sequence similarities	Contains 2 PDZ (DHR) domains.
Sequence caution	The sequence CAA90511.1 differs from that shown. Reason: Frameshift at position 309.

Ontologies

Keywords
Cellular component	Membrane Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	protein complex assembly Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Inferred from direct assay. Source: HPA endomembrane system Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Ref.1 Traceable author statement. Source: ProtInc plasma membrane Inferred from direct assay. Source: UniProtKB
Molecular function	protein C-terminus binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CFTR	P13569	1	EBI-1149760,EBI-349854
LPAR2	Q9HBW0	1	EBI-1149760,EBI-765995

Alternative products

This entry describes 2 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:
     285-295: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 337

337

Na(+)/H(+) exchange regulatory cofactor NHE-RF2

PRO_0000096805

Regions

Domain

11 – 90

80

PDZ 1

Domain

150 – 230

81

PDZ 2

Amino acid modifications

Modified residue

183

1

Phosphoserine

Modified residue

254

1

Phosphoserine

Modified residue

272

1

Phosphoserine By similarity

Modified residue

275

1

Phosphoserine

Natural variations

Alternative sequence

285 – 295

11

Missing in isoform 2.

VSP_009378

Experimental info

Sequence conflict

51

1

Missing in CAA90511. Ref.2

Secondary structure

1

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337

Helix Strand Turn

Details...

Beta strand

10 – 15

6

Beta strand

23 – 27

5

Beta strand

34 – 39

6

Helix

44 – 47

4

Beta strand

54 – 59

6

Helix

69 – 77

9

Beta strand

82 – 89

8

Beta strand

150 – 155

6

Beta strand

163 – 167

5

Beta strand

169 – 179

11

Helix

184 – 188

5

Beta strand

195 – 199

5

Helix

209 – 216

8

Beta strand

219 – 228

10

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 16, 2004. Version 2. Checksum: 4F5D341590D22ED7	FASTA	337	37,414
	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
	Isoform 2 [UniParc]. Checksum: 59FB231865D896DC		326	36,152
	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 DKDTQESGLH LSPTAAEAKE 310 320 KARAMRVNKR APQMDWNRKR EIFSNF

References

	« Hide 'large scale' referencesShow '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: 9054412] [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: 9314537] [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: 9096337] [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: 9831664] [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: 9671706] [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. , 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: 15616553] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Kidney and Testis.
[8]	"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: 10455146] [Abstract] Cited for: FUNCTION, INTERACTION WITH SLC9A3.
[9]	"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: 15143197] [Abstract] Cited for: INTERACTION WITH LPAR2.
[10]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-275, MASS SPECTROMETRY. Tissue: Epithelium.
[11]	"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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-183 AND SER-254, MASS SPECTROMETRY.
[12]	"Structural basis for NHERF recognition by ERM proteins." Terawaki S., Maesaki R., Hakoshima T. Structure 14:777-789(2006) [PubMed: 16615918] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) OF 310-337 IN COMPLEX WITH RDX.
[13]	"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

EMBLGenBankDDBJ

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.
BC014513 mRNA. Translation: AAH14513.2. Different initiation.
BC106001 mRNA. Translation: AAI06002.1.

PIR

G01158.

RefSeq

NP_001123484.1.
NP_004776.3.

UniGene

Hs.440896

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2D11	X-ray	2.81	E/F/G/H	310-337	[»]
2HE4	X-ray	1.45	A	147-232	[»]
2OCS	X-ray	1.50	A	9-91	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:29093N.

IntAct

Q15599.

PTM databases

PhosphoSite

Q15599.

Genome annotation databases

Ensembl

ENSG00000065054. Homo sapiens. [Contig view]

GeneID

9351.

KEGG

hsa:9351.

Organism-specific databases

H-InvDB

HIX0012710.

HGNC

HGNC:11076. SLC9A3R2.

HPA

HPA001672.

MIM

606553. gene.

PharmGKB

PA35932.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOVERGEN

Q15599.

Gene expression databases

CleanEx

HS_SLC9A3R2.

GermOnline

ENSG00000065054. Homo sapiens.

Family and domain databases

InterPro

IPR015098. EBP50_C-term.
IPR017300. NaH_exchngr_reg_CF_NHE-RF.
IPR001478. PDZ.
[Graphical view]

Pfam

PF09007. EBP50_C-term. 1 hit.
PF00595. PDZ. 2 hits.
[Graphical view]

PIRSF

PIRSF037866. EBP50. 1 hit.

SMART

SM00228. PDZ. 2 hits.
[Graphical view]

PROSITE

PS50106. PDZ. 2 hits.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

35017.

SOURCE

Search...

Entry information

Entry name

NHRF2_HUMAN

Accession

Primary (citable) accession number: Q15599
Secondary accession number(s): O00272, O00556, Q3KQY7

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 16, 2004
Last sequence update:	February 16, 2004
Last modified:	November 25, 2008
This is version 82 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)