ID CLD4_HUMAN Reviewed; 209 AA. AC O14493; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 27-MAR-2024, entry version 187. DE RecName: Full=Claudin-4; DE AltName: Full=Clostridium perfringens enterotoxin receptor {ECO:0000303|PubMed:9334247}; DE Short=CPE-R {ECO:0000303|PubMed:9334247}; DE Short=CPE-receptor {ECO:0000303|PubMed:9334247}; DE AltName: Full=Williams-Beuren syndrome chromosomal region 8 protein; GN Name=CLDN4; GN Synonyms=CPER {ECO:0000303|PubMed:9334247}, CPETR1 GN {ECO:0000303|PubMed:9334247}, WBSCR8; 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] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Fetal brain; RX PubMed=9334247; DOI=10.1074/jbc.272.42.26652; RA Katahira J., Sugiyama H., Inoue N., Horiguchi Y., Matsuda M., Sugimoto N.; RT "Clostridium perfringens enterotoxin utilizes two structurally related RT membrane proteins as functional receptors in vivo."; RL J. Biol. Chem. 272:26652-26658(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Colon; 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 [4] RP INTERACTION WITH EPHA2 AND TJP1, MUTAGENESIS OF TYR-208, AND RP PHOSPHORYLATION AT TYR-208 BY EPHA2. RX PubMed=16236711; DOI=10.1074/jbc.m503786200; RA Tanaka M., Kamata R., Sakai R.; RT "EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates RT paracellular permeability."; RL J. Biol. Chem. 280:42375-42382(2005). RN [5] RP SUBCELLULAR LOCATION, AND INTERACTION WITH CLDN1. RX PubMed=20375010; DOI=10.1074/jbc.m110.104836; RA Harris H.J., Davis C., Mullins J.G., Hu K., Goodall M., Farquhar M.J., RA Mee C.J., McCaffrey K., Young S., Drummer H., Balfe P., McKeating J.A.; RT "Claudin association with CD81 defines hepatitis C virus entry."; RL J. Biol. Chem. 285:21092-21102(2010). RN [6] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [7] RP DEVELOPMENTAL STAGE. RX PubMed=24787463; DOI=10.1165/rcmb.2013-0456oc; RA LaFemina M.J., Sutherland K.M., Bentley T., Gonzales L.W., Allen L., RA Chapin C.J., Rokkam D., Sweerus K.A., Dobbs L.G., Ballard P.L., Frank J.A.; RT "Claudin-18 deficiency results in alveolar barrier dysfunction and impaired RT alveologenesis in mice."; RL Am. J. Respir. Cell Mol. Biol. 51:550-558(2014). RN [8] {ECO:0007744|PDB:5B2G} RP X-RAY CRYSTALLOGRAPHY (3.50 ANGSTROMS) OF 1-183 IN COMPLEX WITH CLOSTRIDIUM RP PERFRINGENS CPE, INTERACTION WITH CLOSTRIDIUM PERFRINGENS CPE, MUTAGENESIS RP OF PHE-35; ILE-40 AND ASN-53, AND DISULFIDE BOND. RX PubMed=27647526; DOI=10.1038/srep33632; RA Shinoda T., Shinya N., Ito K., Ohsawa N., Terada T., Hirata K., Kawano Y., RA Yamamoto M., Kimura-Someya T., Yokoyama S., Shirouzu M.; RT "Structural basis for disruption of claudin assembly in tight junctions by RT an enterotoxin."; RL Sci. Rep. 6:33632-33632(2016). CC -!- FUNCTION: Channel-forming tight junction protein that mediates CC paracellular chloride transport in the kidney. Plays a critical role in CC the paracellular reabsorption of filtered chloride in the kidney CC collecting ducts. Claudins play a major role in tight junction-specific CC obliteration of the intercellular space, through calcium-independent CC cell-adhesion activity. {ECO:0000250|UniProtKB:O35054}. CC -!- SUBUNIT: Directly interacts with TJP1/ZO-1 (PubMed:16236711). Interacts CC with TJP2/ZO-2 and TJP3/ZO-3 (By similarity). Interacts with EPHA2; CC phosphorylates CLDN4 and may regulate tight junctions CC (PubMed:16236711). Interacts with CLDN1 (PubMed:20375010). Interacts CC with CLDN8 (By similarity). {ECO:0000250|UniProtKB:O35054, CC ECO:0000269|PubMed:16236711, ECO:0000269|PubMed:20375010}. CC -!- SUBUNIT: (Microbial infection) Interacts (via both extracellular CC domains) with Clostridium perfringens enterotoxin CPE; the interaction CC may disrupt claudin assembly in tight junctions. CC {ECO:0000269|PubMed:27647526}. CC -!- INTERACTION: CC O14493; Q13520: AQP6; NbExp=3; IntAct=EBI-9316372, EBI-13059134; CC O14493; Q3SXY8: ARL13B; NbExp=3; IntAct=EBI-9316372, EBI-11343438; CC O14493; Q86T13: CLEC14A; NbExp=3; IntAct=EBI-9316372, EBI-17710733; CC O14493; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-9316372, EBI-18304435; CC O14493; O15552: FFAR2; NbExp=3; IntAct=EBI-9316372, EBI-2833872; CC O14493; P48165: GJA8; NbExp=3; IntAct=EBI-9316372, EBI-17458373; CC O14493; Q8NBJ4: GOLM1; NbExp=3; IntAct=EBI-9316372, EBI-712073; CC O14493; Q7Z5P4: HSD17B13; NbExp=3; IntAct=EBI-9316372, EBI-18053395; CC O14493; P32942: ICAM3; NbExp=3; IntAct=EBI-9316372, EBI-725421; CC O14493; Q5SR56: MFSD14B; NbExp=3; IntAct=EBI-9316372, EBI-373355; CC O14493; Q8N9I0: SYT2; NbExp=3; IntAct=EBI-9316372, EBI-8032987; CC O14493; Q96Q45-2: TMEM237; NbExp=3; IntAct=EBI-9316372, EBI-10982110; CC O14493; Q4KMG9: TMEM52B; NbExp=3; IntAct=EBI-9316372, EBI-18178701; CC O14493; Q8IWR1: TRIM59; NbExp=3; IntAct=EBI-9316372, EBI-10262539; CC O14493; Q5TGU0: TSPO2; NbExp=3; IntAct=EBI-9316372, EBI-12195249; CC -!- SUBCELLULAR LOCATION: Cell junction, tight junction CC {ECO:0000250|UniProtKB:O35054}. Cell membrane CC {ECO:0000269|PubMed:20375010}; Multi-pass membrane protein CC {ECO:0000255}. Note=CLDN4 is required for tight junction localization CC in the kidney. {ECO:0000250|UniProtKB:O35054}. CC -!- DEVELOPMENTAL STAGE: Expressed in the lungs from 23 weeks of gestation CC till birth. {ECO:0000269|PubMed:24787463}. CC -!- PTM: Phosphorylated. Phosphorylation by EPHA2 is stimulated by EFNA1 CC and alters interaction with TJP1. {ECO:0000269|PubMed:16236711}. CC -!- DISEASE: Note=CLDN4 is located in the Williams-Beuren syndrome (WBS) CC critical region. WBS results from a hemizygous deletion of several CC genes on chromosome 7q11.23, thought to arise as a consequence of CC unequal crossing over between highly homologous low-copy repeat CC sequences flanking the deleted region. CC -!- SIMILARITY: Belongs to the claudin family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/42975/CLDN4"; 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; AB000712; BAA22984.1; -; mRNA. DR EMBL; BT006989; AAP35635.1; -; mRNA. DR EMBL; BC000671; AAH00671.1; -; mRNA. DR CCDS; CCDS5560.1; -. DR RefSeq; NP_001296.1; NM_001305.4. DR PDB; 5B2G; X-ray; 3.50 A; A/C/E/G=1-183. DR PDB; 7KP4; X-ray; 3.37 A; A=1-209. DR PDB; 7TDM; EM; 6.90 A; A=1-209. DR PDB; 7TDN; EM; 5.00 A; A=1-209. DR PDB; 8U4V; EM; 2.99 A; A=1-209. DR PDB; 8U5B; EM; 5.30 A; A=1-209. DR PDBsum; 5B2G; -. DR PDBsum; 7KP4; -. DR PDBsum; 7TDM; -. DR PDBsum; 7TDN; -. DR PDBsum; 8U4V; -. DR PDBsum; 8U5B; -. DR AlphaFoldDB; O14493; -. DR EMDB; EMD-25834; -. DR EMDB; EMD-25835; -. DR EMDB; EMD-41899; -. DR EMDB; EMD-41915; -. DR SMR; O14493; -. DR BioGRID; 107756; 72. DR IntAct; O14493; 16. DR STRING; 9606.ENSP00000409544; -. DR TCDB; 1.H.1.1.6; the claudin tight junction (claudin1) family. DR iPTMnet; O14493; -. DR PhosphoSitePlus; O14493; -. DR SwissPalm; O14493; -. DR BioMuta; CLDN4; -. DR EPD; O14493; -. DR jPOST; O14493; -. DR MassIVE; O14493; -. DR PaxDb; 9606-ENSP00000409544; -. DR PeptideAtlas; O14493; -. DR ProteomicsDB; 48036; -. DR Pumba; O14493; -. DR ABCD; O14493; 3 sequenced antibodies. DR Antibodypedia; 3618; 655 antibodies from 38 providers. DR DNASU; 1364; -. DR Ensembl; ENST00000340958.4; ENSP00000342445.2; ENSG00000189143.10. DR Ensembl; ENST00000431918.1; ENSP00000388639.1; ENSG00000189143.10. DR Ensembl; ENST00000435050.1; ENSP00000409544.1; ENSG00000189143.10. DR GeneID; 1364; -. DR KEGG; hsa:1364; -. DR MANE-Select; ENST00000340958.4; ENSP00000342445.2; NM_001305.5; NP_001296.1. DR AGR; HGNC:2046; -. DR CTD; 1364; -. DR DisGeNET; 1364; -. DR GeneCards; CLDN4; -. DR HGNC; HGNC:2046; CLDN4. DR HPA; ENSG00000189143; Tissue enhanced (esophagus, urinary bladder). DR MIM; 602909; gene. DR neXtProt; NX_O14493; -. DR OpenTargets; ENSG00000189143; -. DR PharmGKB; PA26572; -. DR VEuPathDB; HostDB:ENSG00000189143; -. DR eggNOG; ENOG502QSCN; Eukaryota. DR GeneTree; ENSGT00940000154762; -. DR HOGENOM; CLU_076370_1_2_1; -. DR InParanoid; O14493; -. DR OMA; NCMDDEA; -. DR OrthoDB; 4040914at2759; -. DR PhylomeDB; O14493; -. DR TreeFam; TF331936; -. DR PathwayCommons; O14493; -. DR Reactome; R-HSA-420029; Tight junction interactions. DR SignaLink; O14493; -. DR SIGNOR; O14493; -. DR BioGRID-ORCS; 1364; 15 hits in 1146 CRISPR screens. DR ChiTaRS; CLDN4; human. DR GeneWiki; CLDN4; -. DR GenomeRNAi; 1364; -. DR Pharos; O14493; Tbio. DR PRO; PR:O14493; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; O14493; Protein. DR Bgee; ENSG00000189143; Expressed in mucosa of transverse colon and 146 other cell types or tissues. DR ExpressionAtlas; O14493; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl. DR GO; GO:0016327; C:apicolateral plasma membrane; IEA:Ensembl. DR GO; GO:0009925; C:basal plasma membrane; IEA:Ensembl. DR GO; GO:0005923; C:bicellular tight junction; IDA:UniProtKB. DR GO; GO:0005911; C:cell-cell junction; IDA:ARUK-UCL. DR GO; GO:0034707; C:chloride channel complex; IEA:UniProtKB-KW. DR GO; GO:0016328; C:lateral plasma membrane; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0070160; C:tight junction; IDA:ARUK-UCL. DR GO; GO:0005254; F:chloride channel activity; ISS:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro. DR GO; GO:0004888; F:transmembrane signaling receptor activity; TAS:ProtInc. DR GO; GO:0070830; P:bicellular tight junction assembly; IBA:GO_Central. DR GO; GO:0016338; P:calcium-independent cell-cell adhesion via plasma membrane cell-adhesion molecules; ISS:UniProtKB. DR GO; GO:0007155; P:cell adhesion; IBA:GO_Central. DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl. DR GO; GO:0061436; P:establishment of skin barrier; IMP:UniProtKB. DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl. DR GO; GO:0030335; P:positive regulation of cell migration; IMP:ARUK-UCL. DR GO; GO:1905050; P:positive regulation of metallopeptidase activity; IMP:ARUK-UCL. DR GO; GO:0090303; P:positive regulation of wound healing; IMP:ARUK-UCL. DR GO; GO:0022604; P:regulation of cell morphogenesis; IMP:ARUK-UCL. DR GO; GO:0070293; P:renal absorption; ISS:UniProtKB. DR GO; GO:0032570; P:response to progesterone; IEA:Ensembl. DR Gene3D; 1.20.140.150; -; 1. DR InterPro; IPR006187; Claudin. DR InterPro; IPR003550; Claudin4. DR InterPro; IPR017974; Claudin_CS. DR InterPro; IPR004031; PMP22/EMP/MP20/Claudin. DR PANTHER; PTHR12002; CLAUDIN; 1. DR PANTHER; PTHR12002:SF89; CLAUDIN-4; 1. DR Pfam; PF00822; PMP22_Claudin; 1. DR PRINTS; PR01077; CLAUDIN. DR PRINTS; PR01379; CLAUDIN4. DR PROSITE; PS01346; CLAUDIN; 1. DR Genevisible; O14493; HS. PE 1: Evidence at protein level; KW 3D-structure; Cell junction; Cell membrane; Chloride; Chloride channel; KW Disulfide bond; Ion channel; Ion transport; Membrane; Phosphoprotein; KW Reference proteome; Tight junction; Transmembrane; Transmembrane helix; KW Transport; Williams-Beuren syndrome. FT CHAIN 1..209 FT /note="Claudin-4" FT /id="PRO_0000144743" FT TOPO_DOM 1..7 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 8..28 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 29..81 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 82..102 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 103..117 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 118..138 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 139..160 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 161..181 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 182..209 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 1..103 FT /note="Interaction with EPHA2" FT /evidence="ECO:0000269|PubMed:16236711" FT REGION 208..209 FT /note="Interactions with TJP1, TJP2 and TJP3" FT /evidence="ECO:0000250|UniProtKB:O35054" FT MOD_RES 208 FT /note="Phosphotyrosine; by EPHA2" FT /evidence="ECO:0000269|PubMed:16236711" FT DISULFID 54..64 FT /evidence="ECO:0000269|PubMed:27647526, FT ECO:0007744|PDB:5B2G" FT MUTAGEN 35 FT /note="F->A: Decreases interaction with Clostridium FT perfringens CPE." FT /evidence="ECO:0000269|PubMed:27647526" FT MUTAGEN 35 FT /note="F->D: Abolishes interaction with Clostridium FT perfringens CPE." FT /evidence="ECO:0000269|PubMed:27647526" FT MUTAGEN 40 FT /note="I->A: No effect on interaction with Clostridium FT perfringens CPE." FT /evidence="ECO:0000269|PubMed:27647526" FT MUTAGEN 40 FT /note="I->D: Strongly decreases interaction with FT Clostridium perfringens CPE." FT /evidence="ECO:0000269|PubMed:27647526" FT MUTAGEN 53 FT /note="N->A,D: Decreases interaction with Clostridium FT perfringens CPE." FT /evidence="ECO:0000269|PubMed:27647526" FT MUTAGEN 208 FT /note="Y->F: Loss of phosphorylation by EPHA2." FT /evidence="ECO:0000269|PubMed:16236711" FT STRAND 1..3 FT /evidence="ECO:0007829|PDB:5B2G" FT HELIX 8..26 FT /evidence="ECO:0007829|PDB:7KP4" FT STRAND 30..34 FT /evidence="ECO:0007829|PDB:7KP4" FT STRAND 45..48 FT /evidence="ECO:0007829|PDB:7KP4" FT STRAND 50..56 FT /evidence="ECO:0007829|PDB:7KP4" FT STRAND 58..60 FT /evidence="ECO:0007829|PDB:7KP4" FT STRAND 63..67 FT /evidence="ECO:0007829|PDB:7KP4" FT TURN 68..71 FT /evidence="ECO:0007829|PDB:7KP4" FT HELIX 75..98 FT /evidence="ECO:0007829|PDB:7KP4" FT STRAND 103..105 FT /evidence="ECO:0007829|PDB:7KP4" FT HELIX 111..144 FT /evidence="ECO:0007829|PDB:7KP4" FT HELIX 145..147 FT /evidence="ECO:0007829|PDB:7KP4" FT STRAND 158..160 FT /evidence="ECO:0007829|PDB:7KP4" FT HELIX 162..178 FT /evidence="ECO:0007829|PDB:7KP4" FT TURN 179..181 FT /evidence="ECO:0007829|PDB:7KP4" FT STRAND 182..184 FT /evidence="ECO:0007829|PDB:7KP4" SQ SEQUENCE 209 AA; 22077 MW; 0659A93AA5F0E4C5 CRC64; MASMGLQVMG IALAVLGWLA VMLCCALPMW RVTAFIGSNI VTSQTIWEGL WMNCVVQSTG QMQCKVYDSL LALPQDLQAA RALVIISIIV AALGVLLSVV GGKCTNCLED ESAKAKTMIV AGVVFLLAGL MVIVPVSWTA HNIIQDFYNP LVASGQKREM GASLYVGWAA SGLLLLGGGL LCCNCPPRTD KPYSAKYSAA RSAAASNYV //