NHRF1_RABIT
ID NHRF1_RABIT Reviewed; 358 AA.
AC Q28619;
DT 02-FEB-2004, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 25-MAY-2022, entry version 143.
DE RecName: Full=Na(+)/H(+) exchange regulatory cofactor NHE-RF1;
DE Short=NHERF-1;
DE AltName: Full=Ezrin-radixin-moesin-binding phosphoprotein 50;
DE Short=EBP50;
DE AltName: Full=Regulatory cofactor of Na(+)/H(+) exchanger;
DE AltName: Full=Sodium-hydrogen exchanger regulatory factor 1;
DE AltName: Full=Solute carrier family 9 isoform A3 regulatory factor 1;
GN Name=SLC9A3R1; Synonyms=NHERF, NHERF1;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=New Zealand white; TISSUE=Kidney cortex;
RX PubMed=7738182; DOI=10.1172/jci117903;
RA Weinman E.J., Steplock D., Wang Y., Shenolikar S.;
RT "Characterization of a protein cofactor that mediates protein kinase A
RT regulation of the renal brush border membrane Na(+)-H+ exchanger.";
RL J. Clin. Invest. 95:2143-2149(1995).
RN [2]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SLC9A3 AND ADRB2.
RX PubMed=9560162; DOI=10.1038/33458;
RA Hall R.A., Premont R.T., Chow C.-W., Blitzer J.T., Pitcher J.A., Claing A.,
RA Stoffel R.H., Barak L.S., Shenolikar S., Weinman E.J., Grinstein S.,
RA Lefkowitz R.J.;
RT "The beta2-adrenergic receptor interacts with the Na+/H+-exchanger
RT regulatory factor to control Na+/H+ exchange.";
RL Nature 392:626-630(1998).
RN [3]
RP FUNCTION, INTERACTION WITH SLC9A3, MUTAGENESIS OF SER-287 AND
RP 289-SER-SER-290, AND PHOSPHORYLATION AT SER-289 AND SER-290.
RX PubMed=10455146; DOI=10.1074/jbc.274.35.24753;
RA Zizak M., Lamprecht G., Steplock D., Tariq N., Shenolikar S., Donowitz M.,
RA Yun C.H.C., Weinman E.J.;
RT "cAMP-induced phosphorylation and inhibition of Na(+)/H(+) exchanger 3
RT (NHE3) are dependent on the presence but not the phosphorylation of NHE
RT regulatory factor.";
RL J. Biol. Chem. 274:24753-24758(1999).
RN [4]
RP DIMERIZATION, INTERACTION WITH ADRB2, AND MUTAGENESIS OF SER-289.
RX PubMed=11456497; DOI=10.1021/bi0103516;
RA Lau A.G., Hall R.A.;
RT "Oligomerization of NHERF-1 and NHERF-2 PDZ domains: differential
RT regulation by association with receptor carboxyl-termini and by
RT phosphorylation.";
RL Biochemistry 40:8572-8580(2001).
CC -!- FUNCTION: Scaffold protein that connects plasma membrane proteins with
CC members of the ezrin/moesin/radixin family and thereby helps to link
CC them to the actin cytoskeleton and to regulate their surface
CC expression. Necessary for recycling of internalized ADRB2. Was first
CC known to play a role in the regulation of the activity and subcellular
CC location of SLC9A3. Necessary for cAMP-mediated phosphorylation and
CC inhibition of SLC9A3. Involved in sperm capacitation. May participate
CC in the regulation of the chloride and bicarbonate homeostasis in
CC spermatozoa. May enhance Wnt signaling. May participate in HTR4
CC targeting to microvilli (By similarity). Involved in the regulation of
CC phosphate reabsorption in the renal proximal tubules (By similarity).
CC {ECO:0000250, ECO:0000269|PubMed:10455146, ECO:0000269|PubMed:9560162}.
CC -!- SUBUNIT: Homodimer, and heterodimer with SLC9A3R2. Binds the N-termini
CC of EZR, RDX and MSN. Binds the C-termini of PDGFRA, PDGFRB, ADRB2, NOS2
CC and CFTR. Binds ARHGAP17, EPI64, RACK1, OPRK1, GNAQ, CTNNB1 and PLCB3.
CC Binds PDZK1 (By similarity). Interacts with CLCN3. Binds the C-terminus
CC of PAG1. In resting T-cells, part of a PAG1-SLC9A3R1-MSN complex which
CC is disrupted upon TCR activation. Forms a complex with CFTR and SLC4A7.
CC Forms a complex with SLC4A7 and ATP6V1B1. Interacts with TRPC4 (via the
CC PDZ-binding domain). Directly interacts with HTR4 (By similarity).
CC Interacts (via the PDZ 1 domain) with PODXL (via the C-terminal PDZ-
CC binding motif DTHL); interaction is not detected in glomerular
CC epithelium cells. Interacts (via the PDZ 1 domain) with PODXL (via the
CC C-terminal PDZ-binding motif DTHL); the interaction take place early in
CC the secretory pathway and is necessary for its apical membrane sorting
CC (By similarity). Interacts with SLC26A3 (By similarity). Interacts with
CC MCC. Interacts with SLC34A1. Interacts (via the PDZ domains) with
CC SLC26A6 isoform 4 and isoform 5 (By similarity). Interacts (via PDZ
CC domains) with ACE2 (via PDZ-binding motif); the interaction may enhance
CC ACE2 membrane residence (By similarity). {ECO:0000250|UniProtKB:O14745,
CC ECO:0000250|UniProtKB:P70441}.
CC -!- INTERACTION:
CC Q28619; O70293-1: Grk6; Xeno; NbExp=5; IntAct=EBI-7073613, EBI-7073604;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Apical cell membrane
CC {ECO:0000250}. Cell projection, filopodium {ECO:0000250}. Cell
CC projection, ruffle {ECO:0000250}. Cell projection, microvillus
CC {ECO:0000250}. Endomembrane system {ECO:0000250}; Peripheral membrane
CC protein {ECO:0000250}. Note=Colocalizes with actin in microvilli-rich
CC apical regions of the syncytiotrophoblast. Present in lipid rafts of T-
CC cells. Translocates from the cytoplasm to the apical cell membrane in a
CC PODXL-dependent manner (By similarity). Colocalizes with CFTR at the
CC midpiece of sperm tail (By similarity). {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Detected in ileum, duodenum and in kidney, where it
CC is found in the glomerulus, the proximal tubule, the thick ascending
CC limb of Henle's loop and the cortical collecting duct.
CC {ECO:0000269|PubMed:7738182}.
CC -!- PTM: Phosphorylated on serine residues. {ECO:0000269|PubMed:10455146}.
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DR EMBL; U19815; AAA80218.1; -; mRNA.
DR PIR; I46532; I46532.
DR RefSeq; NP_001075814.1; NM_001082345.1.
DR AlphaFoldDB; Q28619; -.
DR SMR; Q28619; -.
DR BioGRID; 1172218; 1.
DR IntAct; Q28619; 3.
DR MINT; Q28619; -.
DR STRING; 9986.ENSOCUP00000001351; -.
DR iPTMnet; Q28619; -.
DR PRIDE; Q28619; -.
DR GeneID; 100009196; -.
DR KEGG; ocu:100009196; -.
DR CTD; 9368; -.
DR InParanoid; Q28619; -.
DR OrthoDB; 880632at2759; -.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0071944; C:cell periphery; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0012505; C:endomembrane system; IEA:UniProtKB-SubCell.
DR GO; GO:0030175; C:filopodium; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0005902; C:microvillus; ISS:UniProtKB.
DR GO; GO:0031528; C:microvillus membrane; ISS:UniProtKB.
DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
DR GO; GO:0097225; C:sperm midpiece; ISS:UniProtKB.
DR GO; GO:0017081; F:chloride channel regulator activity; ISS:UniProtKB.
DR GO; GO:0060090; F:molecular adaptor activity; IEA:InterPro.
DR GO; GO:0032782; P:bile acid secretion; ISS:UniProtKB.
DR GO; GO:0034635; P:glutathione transport; ISS:UniProtKB.
DR GO; GO:2000146; P:negative regulation of cell motility; ISS:UniProtKB.
DR GO; GO:0014067; P:negative regulation of phosphatidylinositol 3-kinase signaling; ISS:UniProtKB.
DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:0045859; P:regulation of protein kinase activity; ISS:UniProtKB.
DR GO; GO:0070293; P:renal absorption; ISS:UniProtKB.
DR GO; GO:0097291; P:renal phosphate ion absorption; ISS:UniProtKB.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR Gene3D; 2.30.42.10; -; 2.
DR InterPro; IPR015098; EBP50_C-term.
DR InterPro; IPR031199; NHERF-1.
DR InterPro; IPR017300; NHERF-1/NHERF-2.
DR InterPro; IPR001478; PDZ.
DR InterPro; IPR036034; PDZ_sf.
DR PANTHER; PTHR14191:SF7; PTHR14191:SF7; 1.
DR Pfam; PF09007; EBP50_C; 1.
DR Pfam; PF00595; PDZ; 2.
DR PIRSF; PIRSF037866; EBP50; 1.
DR SMART; SM00228; PDZ; 2.
DR SUPFAM; SSF50156; SSF50156; 2.
DR PROSITE; PS50106; PDZ; 2.
PE 1: Evidence at protein level;
KW Acetylation; Cell membrane; Cell projection; Cytoplasm; Membrane;
KW Phosphoprotein; Reference proteome; Repeat; Wnt signaling pathway.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:O14745"
FT CHAIN 2..358
FT /note="Na(+)/H(+) exchange regulatory cofactor NHE-RF1"
FT /id="PRO_0000096801"
FT DOMAIN 14..94
FT /note="PDZ 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143"
FT DOMAIN 154..234
FT /note="PDZ 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143"
FT REGION 114..151
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 247..358
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 134..151
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 303..322
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 331..349
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:O14745"
FT MOD_RES 2
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14745"
FT MOD_RES 46
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14745"
FT MOD_RES 279
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14745"
FT MOD_RES 289
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:10455146"
FT MOD_RES 290
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:10455146"
FT MOD_RES 292
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P70441"
FT MOD_RES 293
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14745"
FT MOD_RES 298
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70441"
FT MOD_RES 301
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70441"
FT MUTAGEN 287
FT /note="S->A: Abolishes phosphorylation; when associated
FT with A-289 and A-290."
FT /evidence="ECO:0000269|PubMed:10455146"
FT MUTAGEN 289..290
FT /note="SS->AA: Abolishes phosphorylation; when associated
FT with A-287."
FT /evidence="ECO:0000269|PubMed:10455146"
FT MUTAGEN 289
FT /note="S->D: Enhances dimerization."
FT /evidence="ECO:0000269|PubMed:11456497"
SQ SEQUENCE 358 AA; 38562 MW; F55E6D6FFA01B991 CRC64;
MSADAAAGAP LPRLCCLEKG PNGYGFHLHG EKGKVGQYIR LVEPGSPAEK AGLLAGDRLV
EVNGENVEKE THQQVVSRIR AALNAVRLLV VDPDTDEQFR KLGVQIRGEL LRAQAGPEQA
GPPAAPGEQG PAGENEPREV EKSHPERREL RPRLCAMKKG PNGYGFNLHS DKSRPGQFIR
AVDPDSPAEA SGLREQDRIV EVNGVCVEGK QHGDVVTAIK AGGDEAKLLV VDKETDEFFK
KCKVVPSSEH LNGPLPEPFT NGEIQKNNPE TLAPAASESP RPALARSASS DTSEELASQD
SPKKEDSTAP SSTSSSSDPI LDFSISLAVA KERAHQKRSS RRAPQMDWSE KKELFSNL
