CLDN6 (claudin-6) is a tetraspan tight-junction protein: four transmembrane helices, two extracellular loops and cytoplasmic termini ending in a PDZ-binding motif that engages the ZO scaffolds ZO-1, ZO-2 and ZO-3. Like other claudins it polymerizes into tight-junction strands and interacts in trans with claudins on the neighbouring cell, obliterating the intercellular space and establishing paracellular barrier properties. CLDN6 is an oncofetal protein: it is widely expressed in embryonic and fetal epithelia, essentially silent in normal adult tissue, and re-expressed in germ cell tumours, ovarian, endometrial, testicular and some lung and gastric cancers, which has made its exposed extracellular loops a target for antibodies and CAR-T cells. Its first extracellular loop also makes it one of the receptor-active claudins that associate with the tetraspanin CD81 and support hepatitis C virus entry.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001618 virus receptor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CLDN6 is one of the receptor-active claudins that support hepatitis C virus entry. Reason: Directly supported: receptor activity tracks with first-extracellular-loop residues that permit CD81 association, and CLDN6 can substitute for CLDN1 in entry assays. This is an exploited host-factor role rather than the physiological function of the protein, so it is retained as non-core. Supporting Evidence: PMID:20375010 Mutation of residues 32 and 48 in the Claudin-1 first extracellular loop ablates CD81 association and HCV receptor activity file:human/CLDN6/CLDN6-uniprot.txt Acts as a receptor for hepatitis C |
| GO:0001618 virus receptor activity | IMP PMID:20375010 Claudin association with CD81 defines hepatitis C virus entr... | KEEP AS NON CORE | Summary: CLDN6 is one of the receptor-active claudins that support hepatitis C virus entry. Reason: Directly supported: receptor activity tracks with first-extracellular-loop residues that permit CD81 association, and CLDN6 can substitute for CLDN1 in entry assays. This is an exploited host-factor role rather than the physiological function of the protein, so it is retained as non-core. Supporting Evidence: PMID:20375010 Mutation of residues 32 and 48 in the Claudin-1 first extracellular loop ablates CD81 association and HCV receptor activity file:human/CLDN6/CLDN6-uniprot.txt Acts as a receptor for hepatitis C |
| GO:0005198 structural molecule activity | IEA GO_REF:0000002 | ACCEPT | Summary: Claudin-6 is a structural component of tight-junction strands. Reason: Claudins polymerize into the intramembrane strands that form the paracellular seal; structural molecule activity is the appropriate molecular function for the family. Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt Plays a major role in tight junction-specific obliteration of |
| GO:0005515 protein binding | IPI PMID:20375010 Claudin association with CD81 defines hepatitis C virus entr... | REMOVE | Summary: Association of CLDN6 with CD81 and occludin in HCV entry studies. Reason: Generic protein binding is uninformative here, and the functional content of these interactions is already captured by the virus receptor activity annotation the gene carries; no better-supported specific binding term applies. Removal does not assert the interactions are false. Supporting Evidence: PMID:20375010 we demonstrate an essential role for Claudin-CD81 complexes in HCV infection file:human/CLDN6/CLDN6-uniprot.txt Interacts with CLDN1, CD81 and OCLN (PubMed:20375010). |
| GO:0005515 protein binding | IPI PMID:20375010 Claudin association with CD81 defines hepatitis C virus entr... | REMOVE | Summary: Association of CLDN6 with CD81 and occludin in HCV entry studies. Reason: Generic protein binding is uninformative here, and the functional content of these interactions is already captured by the virus receptor activity annotation the gene carries; no better-supported specific binding term applies. Removal does not assert the interactions are false. Supporting Evidence: PMID:20375010 we demonstrate an essential role for Claudin-CD81 complexes in HCV infection file:human/CLDN6/CLDN6-uniprot.txt Interacts with CLDN1, CD81 and OCLN (PubMed:20375010). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary two-hybrid and affinity interactions from systematic interactome screens. Reason: Generic protein binding from large-scale screens (MUC1, IGFBP5, PMP22, TMEM179B, SLC30A8, MS4A3, MAPK8) with no follow-up establishing a CLDN6 function. Removal does not assert that the assay results are false. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome file:human/CLDN6/CLDN6-uniprot.txt P56747; P45983: MAPK8; NbExp=3; IntAct=EBI-12955011, EBI-286483; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary two-hybrid and affinity interactions from systematic interactome screens. Reason: Generic protein binding from large-scale screens (MUC1, IGFBP5, PMP22, TMEM179B, SLC30A8, MS4A3, MAPK8) with no follow-up establishing a CLDN6 function. Removal does not assert that the assay results are false. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome file:human/CLDN6/CLDN6-uniprot.txt P56747; P45983: MAPK8; NbExp=3; IntAct=EBI-12955011, EBI-286483; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary two-hybrid and affinity interactions from systematic interactome screens. Reason: Generic protein binding from large-scale screens (MUC1, IGFBP5, PMP22, TMEM179B, SLC30A8, MS4A3, MAPK8) with no follow-up establishing a CLDN6 function. Removal does not assert that the assay results are false. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome file:human/CLDN6/CLDN6-uniprot.txt P56747; P45983: MAPK8; NbExp=3; IntAct=EBI-12955011, EBI-286483; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary two-hybrid and affinity interactions from systematic interactome screens. Reason: Generic protein binding from large-scale screens (MUC1, IGFBP5, PMP22, TMEM179B, SLC30A8, MS4A3, MAPK8) with no follow-up establishing a CLDN6 function. Removal does not assert that the assay results are false. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome file:human/CLDN6/CLDN6-uniprot.txt P56747; P45983: MAPK8; NbExp=3; IntAct=EBI-12955011, EBI-286483; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary two-hybrid and affinity interactions from systematic interactome screens. Reason: Generic protein binding from large-scale screens (MUC1, IGFBP5, PMP22, TMEM179B, SLC30A8, MS4A3, MAPK8) with no follow-up establishing a CLDN6 function. Removal does not assert that the assay results are false. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome file:human/CLDN6/CLDN6-uniprot.txt P56747; P45983: MAPK8; NbExp=3; IntAct=EBI-12955011, EBI-286483; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary two-hybrid and affinity interactions from systematic interactome screens. Reason: Generic protein binding from large-scale screens (MUC1, IGFBP5, PMP22, TMEM179B, SLC30A8, MS4A3, MAPK8) with no follow-up establishing a CLDN6 function. Removal does not assert that the assay results are false. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome file:human/CLDN6/CLDN6-uniprot.txt P56747; P45983: MAPK8; NbExp=3; IntAct=EBI-12955011, EBI-286483; |
| GO:0005515 protein binding | IPI PMID:36935496 CLDN6 inhibits breast cancer metastasis through WIP-dependen... | REMOVE | Summary: Binary two-hybrid and affinity interactions from systematic interactome screens. Reason: Generic protein binding from large-scale screens (MUC1, IGFBP5, PMP22, TMEM179B, SLC30A8, MS4A3, MAPK8) with no follow-up establishing a CLDN6 function. Removal does not assert that the assay results are false. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome file:human/CLDN6/CLDN6-uniprot.txt P56747; P45983: MAPK8; NbExp=3; IntAct=EBI-12955011, EBI-286483; |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Claudin-6 is a multi-pass plasma membrane protein. Reason: Directly observed at the plasma membrane in the HCV entry work and expected from its four-transmembrane claudin topology; in polarized hepatoma cells receptor-active claudin pools are at the basolateral surface as well as at junctions. Supporting Evidence: PMID:20375010 Claudin-1 associated with CD81 at the basolateral membrane of polarized HepG2 cells file:human/CLDN6/CLDN6-uniprot.txt Cell membrane |
| GO:0005886 plasma membrane | IDA PMID:20375010 Claudin association with CD81 defines hepatitis C virus entr... | ACCEPT | Summary: Claudin-6 is a multi-pass plasma membrane protein. Reason: Directly observed at the plasma membrane in the HCV entry work and expected from its four-transmembrane claudin topology; in polarized hepatoma cells receptor-active claudin pools are at the basolateral surface as well as at junctions. Supporting Evidence: PMID:20375010 Claudin-1 associated with CD81 at the basolateral membrane of polarized HepG2 cells file:human/CLDN6/CLDN6-uniprot.txt Cell membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Claudin-6 is a multi-pass plasma membrane protein. Reason: Directly observed at the plasma membrane in the HCV entry work and expected from its four-transmembrane claudin topology; in polarized hepatoma cells receptor-active claudin pools are at the basolateral surface as well as at junctions. Supporting Evidence: PMID:20375010 Claudin-1 associated with CD81 at the basolateral membrane of polarized HepG2 cells file:human/CLDN6/CLDN6-uniprot.txt Cell membrane |
| GO:0005923 bicellular tight junction | IBA GO_REF:0000033 | ACCEPT | Summary: Claudin-6 localizes to bicellular tight junctions. Reason: The defining location of a claudin, supported by the phylogenetic assignment, the UniProt location and orthologue data; its extracellular loops interact in trans across the paracellular space. Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt SUBCELLULAR LOCATION: Cell junction, tight junction file:human/CLDN6/CLDN6-uniprot.txt Plays a major role in tight junction-specific obliteration of |
| GO:0005923 bicellular tight junction | IEA GO_REF:0000120 | ACCEPT | Summary: Claudin-6 localizes to bicellular tight junctions. Reason: The defining location of a claudin, supported by the phylogenetic assignment, the UniProt location and orthologue data; its extracellular loops interact in trans across the paracellular space. Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt SUBCELLULAR LOCATION: Cell junction, tight junction file:human/CLDN6/CLDN6-uniprot.txt Plays a major role in tight junction-specific obliteration of |
| GO:0005923 bicellular tight junction | ISS GO_REF:0000024 | ACCEPT | Summary: Claudin-6 localizes to bicellular tight junctions. Reason: The defining location of a claudin, supported by the phylogenetic assignment, the UniProt location and orthologue data; its extracellular loops interact in trans across the paracellular space. Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt SUBCELLULAR LOCATION: Cell junction, tight junction file:human/CLDN6/CLDN6-uniprot.txt Plays a major role in tight junction-specific obliteration of |
| GO:0007155 cell adhesion | IBA GO_REF:0000033 | MODIFY | Summary: Inherited role in cell adhesion. Reason: Correct but less specific than supported; claudin trans-interaction is calcium-independent cell-cell adhesion, which the gene already carries. Proposed replacements: calcium-independent cell-cell adhesion Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt Plays a major role in tight junction-specific obliteration of |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: PMP-22/claudin family mapping to membrane. Reason: Membrane is true but uninformative; claudin-6 is a multi-pass plasma membrane protein concentrated at tight junctions. Proposed replacements: plasma membrane bicellular tight junction Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt Cell membrane |
| GO:0016327 apicolateral plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred localization to the apicolateral plasma membrane. Reason: Consistent with tight junctions lying at the apicolateral border of polarized epithelial cells; the specific junctional term is the informative one, so this is retained as non-core. Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt SUBCELLULAR LOCATION: Cell junction, tight junction |
| GO:0016338 calcium-independent cell-cell adhesion | ISS GO_REF:0000024 | ACCEPT | Summary: Claudin-6 mediates calcium-independent adhesion between epithelial cells. Reason: Trans interaction of claudin extracellular loops joins the membranes of adjacent cells without a calcium requirement; this is the adhesive aspect of strand formation. Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt Plays a major role in tight junction-specific obliteration of |
| GO:0042802 identical protein binding | ISS GO_REF:0000024 | ACCEPT | Summary: Claudin-6 self-associates, as claudins do when polymerizing into strands. Reason: Homotypic cis and trans interaction is the mechanism of tight-junction strand formation, supported by the characterized orthologue. Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt Plays a major role in tight junction-specific obliteration of |
| GO:0046718 symbiont entry into host cell | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: CLDN6 is one of the receptor-active claudins that support hepatitis C virus entry. Reason: Directly supported: receptor activity tracks with first-extracellular-loop residues that permit CD81 association, and CLDN6 can substitute for CLDN1 in entry assays. This is an exploited host-factor role rather than the physiological function of the protein, so it is retained as non-core. Supporting Evidence: PMID:20375010 Mutation of residues 32 and 48 in the Claudin-1 first extracellular loop ablates CD81 association and HCV receptor activity file:human/CLDN6/CLDN6-uniprot.txt Acts as a receptor for hepatitis C |
| GO:0070830 bicellular tight junction assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Claudin-6 participates in assembly of bicellular tight junctions. Reason: As a strand-forming claudin that binds the ZO scaffolds, it builds the junction rather than merely residing in it; the PAINT node assigns this across the family. Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3 (By file:human/CLDN6/CLDN6-uniprot.txt Plays a major role in tight junction-specific obliteration of |
| GO:0098632 cell-cell adhesion mediator activity | IBA GO_REF:0000033 | ACCEPT | Summary: Claudin-6 acts as a cell-cell adhesion mediator through its extracellular loops. Reason: The inherited molecular function matches the trans-interaction that joins adjacent cell membranes at the junction. Supporting Evidence: file:human/CLDN6/CLDN6-uniprot.txt Plays a major role in tight junction-specific obliteration of |
Loading supporting content…
Download this section (compressed HTML)Q: What are the paracellular selectivity properties conferred by CLDN6-containing strands, and how do they differ from the adult claudins that replace CLDN6 after development?
Q: In tumours that re-express CLDN6, how much of the protein is in sealed junctions versus freely accessible on the basolateral or free surface, which determines antibody and CAR-T accessibility?
Experiment: Compare surface labelling of CLDN6 with extracellular-loop-directed antibodies on intact polarized versus non-polarized tumour lines, with junctional and non-junctional pools resolved by super-resolution imaging and by calcium-switch experiments.
Hypothesis: Re-expressed CLDN6 in tumour cells is substantially outside assembled tight junctions and therefore accessible to extracellular binders.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)