CLD4_HUMAN
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 03-AUG-2022, entry version 178.
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},
GN CPETR1 {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] {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 -!- 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="http://atlasgeneticsoncology.org/Genes/CLDN4ID42975ch7q11.html";
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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 PDBsum; 5B2G; -.
DR PDBsum; 7KP4; -.
DR PDBsum; 7TDM; -.
DR PDBsum; 7TDN; -.
DR AlphaFoldDB; O14493; -.
DR SMR; O14493; -.
DR BioGRID; 107756; 18.
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; O14493; -.
DR PeptideAtlas; O14493; -.
DR PRIDE; O14493; -.
DR ProteomicsDB; 48036; -.
DR ABCD; O14493; 3 sequenced antibodies.
DR Antibodypedia; 3618; 577 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 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; RSNDKPY; -.
DR OrthoDB; 1231389at2759; -.
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; 14 hits in 1068 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 144 other tissues.
DR ExpressionAtlas; O14493; baseline and differential.
DR Genevisible; O14493; HS.
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:0005887; C:integral component of plasma membrane; IMP:UniProtKB.
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 InterPro; IPR006187; Claudin.
DR InterPro; IPR003550; Claudin4.
DR InterPro; IPR017974; Claudin_CS.
DR InterPro; IPR004031; PMP22/EMP/MP20/Claudin.
DR PANTHER; PTHR12002; PTHR12002; 1.
DR Pfam; PF00822; PMP22_Claudin; 1.
DR PRINTS; PR01379; CLAUDIN4.
DR PROSITE; PS01346; CLAUDIN; 1.
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
