ID NHRF4_HUMAN Reviewed; 571 AA. AC Q86UT5; Q8N6R4; Q8NAW7; Q8NEX7; Q9H5Z3; DT 16-AUG-2005, integrated into UniProtKB/Swiss-Prot. DT 05-OCT-2010, sequence version 2. DT 25-MAY-2022, entry version 151. DE RecName: Full=Na(+)/H(+) exchange regulatory cofactor NHE-RF4; DE Short=NHERF-4; DE AltName: Full=Intestinal and kidney-enriched PDZ protein; DE AltName: Full=Natrium-phosphate cotransporter IIa C-terminal-associated protein 2; DE Short=Na/Pi cotransporter C-terminal-associated protein 2; DE Short=NaPi-Cap2; DE AltName: Full=PDZ domain-containing protein 2; DE AltName: Full=PDZ domain-containing protein 3; DE AltName: Full=Sodium-hydrogen exchanger regulatory factor 4; GN Name=PDZD3; Synonyms=IKEPP, NHERF4, PDZK2; ORFNames=DLNB27; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] {ECO:0000305, ECO:0000312|EMBL:AAL10686.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, INTERACTION WITH GUCY2C, RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RC TISSUE=Intestinal epithelium {ECO:0000269|PubMed:11950846}; RX PubMed=11950846; DOI=10.1074/jbc.m202434200; RA Scott R.O., Thelin W.R., Milgram S.L.; RT "A novel PDZ protein regulates the activity of guanylyl cyclase C, the RT heat-stable enterotoxin receptor."; RL J. Biol. Chem. 277:22934-22941(2002). RN [2] {ECO:0000305, ECO:0000312|EMBL:BAC76050.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Kubo T., Arai Y., Ohira M., Gamou T., Maeno G., Sakiyama T., Toyoda A., RA Hattori M., Sakaki Y., Nakagawara A., Ohki M.; RT "Identification of a 500-kb region of common allelic loss in chromosome RT 11q23 in non-MYCN amplified type of neuroblastoma."; RL Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases. RN [3] {ECO:0000305, ECO:0000312|EMBL:BAC03780.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 4 AND 5). RC TISSUE=Ileal mucosa {ECO:0000312|EMBL:BAB15474.1}, and RC Kidney {ECO:0000312|EMBL:BAC03780.1}; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [5] {ECO:0000305, ECO:0000312|EMBL:AAH29042.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SLC9A3. RX PubMed=19088451; DOI=10.1159/000185553; RA Zachos N.C., Hodson C., Kovbasnjuk O., Li X., Thelin W.R., Cha B., RA Milgram S., Donowitz M.; RT "Elevated intracellular calcium stimulates NHE3 activity by an IKEPP RT (NHERF4) dependent mechanism."; RL Cell. Physiol. Biochem. 22:693-704(2008). RN [7] {ECO:0000305, ECO:0000312|EMBL:BAC76050.1} RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 326-415. RG Structural genomics consortium (SGC); RT "Crystal structure of the 3rd PDZ domain of intestine- and kidney-enriched RT PDZ domain IKEPP (PDZD3)."; RL Submitted (JUL-2011) to the PDB data bank. RN [8] RP INTERACTION WITH USP2. RX PubMed=26756164; DOI=10.1371/journal.pone.0145155; RA Pouly D., Chenaux S., Martin V., Babis M., Koch R., Nagoshi E., RA Katanaev V.L., Gachon F., Staub O.; RT "USP2-45 is a circadian clock output effector regulating calcium absorption RT at the post-translational level."; RL PLoS ONE 11:E0145155-E0145155(2016). CC -!- FUNCTION: Acts as a regulatory protein that associates with GUCY2C and CC negatively modulates its heat-stable enterotoxin-mediated activation CC (PubMed:11950846). Stimulates SLC9A3 activity in the presence of CC elevated calcium ions (PubMed:19088451). {ECO:0000269|PubMed:11950846, CC ECO:0000269|PubMed:19088451}. CC -!- SUBUNIT: Interacts with the C-terminal region of GUCY2C CC (PubMed:11950846). Interacts with the C-terminal region SLC9A3 and the CC interactions decrease in response to elevated calcium ion levels CC (PubMed:19088451). Interacts with the C-terminal region of SLC34A1 (By CC similarity). Interacts with USP2 isoform 4 (PubMed:26756164). CC {ECO:0000250|UniProtKB:Q99MJ6, ECO:0000269|PubMed:11950846, CC ECO:0000269|PubMed:19088451, ECO:0000269|PubMed:26756164}. CC -!- INTERACTION: CC Q86UT5; Q8TDY4: ASAP3; NbExp=3; IntAct=EBI-8744528, EBI-2609717; CC Q86UT5; Q13698: CACNA1S; NbExp=3; IntAct=EBI-8744528, EBI-5329490; CC Q86UT5; Q96GZ6: SLC41A3; NbExp=3; IntAct=EBI-8744528, EBI-7225508; CC Q86UT5; Q5W111: SPRYD7; NbExp=3; IntAct=EBI-8744528, EBI-10248098; CC Q86UT5-2; P25092: GUCY2C; NbExp=4; IntAct=EBI-8299496, EBI-2816795; CC Q86UT5-3; Q8TDY4: ASAP3; NbExp=3; IntAct=EBI-12092811, EBI-2609717; CC Q86UT5-3; Q9NYW2: TAS2R8; NbExp=3; IntAct=EBI-12092811, EBI-12092809; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11950846, CC ECO:0000269|PubMed:19088451}; Peripheral membrane protein CC {ECO:0000269|PubMed:11950846, ECO:0000269|PubMed:19088451}. Cytoplasm CC {ECO:0000269|PubMed:19088451}. Note=Preferentially accumulates at the CC apical surface and ileal brush border of intestinal epithelial cells CC (PubMed:11950846, PubMed:19088451). {ECO:0000269|PubMed:11950846, CC ECO:0000269|PubMed:19088451}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1 {ECO:0000269|Ref.2}; CC IsoId=Q86UT5-1; Sequence=Displayed; CC Name=2 {ECO:0000269|PubMed:11950846}; CC IsoId=Q86UT5-2; Sequence=VSP_051786, VSP_051787; CC Name=3 {ECO:0000305}; CC IsoId=Q86UT5-3; Sequence=VSP_051786, VSP_051787, VSP_051788; CC Name=4 {ECO:0000305}; CC IsoId=Q86UT5-4; Sequence=VSP_051790, VSP_051791; CC Name=5 {ECO:0000305}; CC IsoId=Q86UT5-5; Sequence=VSP_051786, VSP_051787, VSP_051789; CC -!- TISSUE SPECIFICITY: Expressed in kidney and the gastrointestinal tract. CC Not detected in brain, heart, skeletal muscle or cells of hematopoietic CC origin. {ECO:0000269|PubMed:11950846}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY047359; AAL10686.1; -; mRNA. DR EMBL; AB094096; BAC76050.1; -; mRNA. DR EMBL; AK026409; BAB15474.1; -; mRNA. DR EMBL; AK091966; BAC03780.1; -; mRNA. DR EMBL; AP002956; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC029042; AAH29042.1; -; mRNA. DR CCDS; CCDS53719.1; -. [Q86UT5-2] DR CCDS; CCDS8417.1; -. [Q86UT5-3] DR RefSeq; NP_001161940.1; NM_001168468.1. [Q86UT5-2] DR RefSeq; NP_079067.3; NM_024791.3. [Q86UT5-3] DR RefSeq; XP_011541302.1; XM_011543000.2. [Q86UT5-1] DR RefSeq; XP_011541303.1; XM_011543001.2. [Q86UT5-1] DR RefSeq; XP_011541304.1; XM_011543002.2. [Q86UT5-1] DR PDB; 2V90; X-ray; 2.00 A; A/B/C/D/E/F=326-415. DR PDBsum; 2V90; -. DR AlphaFoldDB; Q86UT5; -. DR SMR; Q86UT5; -. DR BioGRID; 122940; 10. DR IntAct; Q86UT5; 8. DR MINT; Q86UT5; -. DR STRING; 9606.ENSP00000347742; -. DR iPTMnet; Q86UT5; -. DR PhosphoSitePlus; Q86UT5; -. DR BioMuta; PDZD3; -. DR DMDM; 308153467; -. DR MassIVE; Q86UT5; -. DR MaxQB; Q86UT5; -. DR PaxDb; Q86UT5; -. DR PeptideAtlas; Q86UT5; -. DR PRIDE; Q86UT5; -. DR ProteomicsDB; 69882; -. [Q86UT5-1] DR ProteomicsDB; 69883; -. [Q86UT5-2] DR ProteomicsDB; 69884; -. [Q86UT5-3] DR ProteomicsDB; 69885; -. [Q86UT5-4] DR ProteomicsDB; 69886; -. [Q86UT5-5] DR TopDownProteomics; Q86UT5-4; -. [Q86UT5-4] DR Antibodypedia; 32648; 180 antibodies from 24 providers. DR DNASU; 79849; -. DR Ensembl; ENST00000322712.4; ENSP00000327107.4; ENSG00000172367.16. [Q86UT5-3] DR Ensembl; ENST00000355547.10; ENSP00000347742.5; ENSG00000172367.16. [Q86UT5-2] DR Ensembl; ENST00000531114.5; ENSP00000431164.1; ENSG00000172367.16. DR GeneID; 79849; -. DR KEGG; hsa:79849; -. DR MANE-Select; ENST00000355547.10; ENSP00000347742.5; NM_001168468.2; NP_001161940.1. [Q86UT5-2] DR UCSC; uc001pvy.4; human. [Q86UT5-1] DR CTD; 79849; -. DR DisGeNET; 79849; -. DR GeneCards; PDZD3; -. DR HGNC; HGNC:19891; PDZD3. DR HPA; ENSG00000172367; Group enriched (intestine, kidney). DR MIM; 607146; gene. DR neXtProt; NX_Q86UT5; -. DR OpenTargets; ENSG00000172367; -. DR PharmGKB; PA134911718; -. DR VEuPathDB; HostDB:ENSG00000172367; -. DR eggNOG; KOG3528; Eukaryota. DR GeneTree; ENSGT00950000182849; -. DR InParanoid; Q86UT5; -. DR OMA; LPAKPRC; -. DR OrthoDB; 880632at2759; -. DR PhylomeDB; Q86UT5; -. DR TreeFam; TF350449; -. DR PathwayCommons; Q86UT5; -. DR Reactome; R-HSA-8942233; Intestinal infectious diseases. DR SignaLink; Q86UT5; -. DR BioGRID-ORCS; 79849; 34 hits in 1063 CRISPR screens. DR EvolutionaryTrace; Q86UT5; -. DR GenomeRNAi; 79849; -. DR Pharos; Q86UT5; Tbio. DR PRO; PR:Q86UT5; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q86UT5; protein. DR Bgee; ENSG00000172367; Expressed in duodenum and 102 other tissues. DR ExpressionAtlas; Q86UT5; baseline and differential. DR Genevisible; Q86UT5; HS. DR GO; GO:0043296; C:apical junction complex; IDA:UniProtKB. DR GO; GO:0045177; C:apical part of cell; IDA:UniProtKB. DR GO; GO:0016324; C:apical plasma membrane; IBA:GO_Central. DR GO; GO:0005903; C:brush border; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:UniProtKB. DR GO; GO:0030251; F:guanylate cyclase inhibitor activity; IDA:UniProtKB. DR GO; GO:0008200; F:ion channel inhibitor activity; TAS:UniProtKB. DR GO; GO:0008022; F:protein C-terminus binding; IPI:UniProtKB. DR GO; GO:0043495; F:protein-membrane adaptor activity; IBA:GO_Central. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:UniProtKB. DR GO; GO:0006811; P:ion transport; NAS:UniProtKB. DR GO; GO:0010754; P:negative regulation of cGMP-mediated signaling; IDA:UniProtKB. DR GO; GO:0072659; P:protein localization to plasma membrane; IBA:GO_Central. DR GO; GO:0007168; P:receptor guanylyl cyclase signaling pathway; IC:UniProtKB. DR GO; GO:0009636; P:response to toxic substance; TAS:UniProtKB. DR GO; GO:0006833; P:water transport; NAS:UniProtKB. DR Gene3D; 2.30.42.10; -; 4. DR InterPro; IPR031200; NHERF-4. DR InterPro; IPR001478; PDZ. DR InterPro; IPR041489; PDZ_6. DR InterPro; IPR036034; PDZ_sf. DR PANTHER; PTHR14191:SF20; PTHR14191:SF20; 1. DR Pfam; PF00595; PDZ; 3. DR Pfam; PF17820; PDZ_6; 1. DR SMART; SM00228; PDZ; 4. DR SUPFAM; SSF50156; SSF50156; 4. DR PROSITE; PS50106; PDZ; 4. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cytoplasm; Membrane; KW Reference proteome; Repeat. FT CHAIN 1..571 FT /note="Na(+)/H(+) exchange regulatory cofactor NHE-RF4" FT /id="PRO_0000058292" FT DOMAIN 115..196 FT /note="PDZ 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143" FT DOMAIN 223..301 FT /note="PDZ 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143" FT DOMAIN 329..412 FT /note="PDZ 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143" FT DOMAIN 467..548 FT /note="PDZ 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143" FT REGION 52..72 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 432..459 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 434..459 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 1..66 FT /note="Missing (in isoform 2, isoform 3 and isoform 5)" FT /evidence="ECO:0000303|PubMed:11950846, FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334" FT /id="VSP_051786" FT VAR_SEQ 67..105 FT /note="TRQKLPSTLSGHRVCQAHGEPVLGLCPLLPLFCCPPHPP -> MEKAADLQD FT TASLTLKFKFNPKLGIDNPVLSLAEDHDPY (in isoform 2, isoform 3 and FT isoform 5)" FT /evidence="ECO:0000303|PubMed:11950846, FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334" FT /id="VSP_051787" FT VAR_SEQ 272..285 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:11950846, FT ECO:0000303|PubMed:15489334" FT /id="VSP_051788" FT VAR_SEQ 287..571 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:11950846, FT ECO:0000303|PubMed:14702039" FT /id="VSP_051789" FT VAR_SEQ 355..386 FT /note="QFLWEVDPGLPAKKAGMQAGDRLVAVAGESVE -> EWEPWGRWGKVGLGVG FT TQAYIHLSVHRRGVPV (in isoform 4)" FT /evidence="ECO:0000303|PubMed:11950846, FT ECO:0000303|PubMed:14702039" FT /id="VSP_051790" FT VAR_SEQ 387..571 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:11950846, FT ECO:0000303|PubMed:14702039" FT /id="VSP_051791" FT CONFLICT 112 FT /note="R -> P (in Ref. 3; BAB15474)" FT /evidence="ECO:0000305" FT CONFLICT 125 FT /note="S -> G (in Ref. 3; BAC03780)" FT /evidence="ECO:0000305" FT CONFLICT 286 FT /note="L -> V (in Ref. 3; BAB15474)" FT /evidence="ECO:0000305" FT CONFLICT 438 FT /note="R -> Q (in Ref. 2; BAC76050 and 5; AAH29042)" FT /evidence="ECO:0000305" FT STRAND 328..333 FT /evidence="ECO:0007829|PDB:2V90" FT STRAND 341..347 FT /evidence="ECO:0007829|PDB:2V90" FT STRAND 353..360 FT /evidence="ECO:0007829|PDB:2V90" FT HELIX 365..368 FT /evidence="ECO:0007829|PDB:2V90" FT STRAND 375..380 FT /evidence="ECO:0007829|PDB:2V90" FT HELIX 390..398 FT /evidence="ECO:0007829|PDB:2V90" FT TURN 399..402 FT /evidence="ECO:0007829|PDB:2V90" FT STRAND 403..409 FT /evidence="ECO:0007829|PDB:2V90" SQ SEQUENCE 571 AA; 61032 MW; B56CDC91348EE592 CRC64; MVTPSPPGNH SLSLEAPRLH TASDLLGNHS LGLPLITALV GSRDRRGRVF SPVPVPLPTN PTTQHPTRQK LPSTLSGHRV CQAHGEPVLG LCPLLPLFCC PPHPPDPWSL ERPRFCLLSK EEGKSFGFHL QQELGRAGHV VCRVDPGTSA QRQGLQEGDR ILAVNNDVVE HEDYAVVVRR IRASSPRVLL TVLARHAHDV ARAQLGEDAH LCPTLGPGVR PRLCHIVKDE GGFGFSVTHG NQGPFWLVLS TGGAAERAGV PPGARLLEVN GVSVEKFTHN QLTRKLWQSG QQVTLLVAGP EVEEQCRQLG LPLAAPLAEG WALPTKPRCL HLEKGPQGFG FLLREEKGLD GRPGQFLWEV DPGLPAKKAG MQAGDRLVAV AGESVEGLGH EETVSRIQGQ GSCVSLTVVD PEADRFFSMV RLSPLLFLEN TEAPASPRGS SSASLVETED PSLEDTSVPS VPLGSRQCFL YPGPGGSYGF RLSCVASGPR LFISQVTPGG SAARAGLQVG DVILEVNGYP VGGQNDLERL QQLPEAEPPL CLKLAARSLR GLEAWIPPGA AEDWALASDL L //