TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
1.H.1.1.1









Claudin 16 (CLDN16; Paracellin) (defects in CLDN16 are the cause of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) (primary hypomagnesemia) (Hou et al., 2007; Ikari et al., 2008).  Forms a Mg2+/Ca2+-selective pore together with Claudin-3 and Claudin-19 (Brandao et al. 2012; Milatz et al. 2017).  The tight junction archetecture and constituent proteins have been reviewed (Van Itallie and Anderson 2014). Claudin-16 and -19 form a stable dimer through cis-association of transmembrane domains 3 and 4, and mutations disrupting the claudin-16/19 cis-interaction increase tight junction ultrastructural complexity but reduce tight junction permeability (Gong et al. 2015).

Eukaryota
Metazoa, Chordata
Cldn 16 of Homo sapiens
(Q9Y5I7)
1.H.1.1.2









Claudin 7 (anion selective; Angelow et al., 2008).  25% identity with Cldn 16; down regulated in breast cancer. In urothelial tumors, REG1A expression and loss of claudin 7 may be markers of prognosis that predict tumor recurrence (Yamuç et al. 2022).

Eukaryota
Metazoa, Chordata
Cldn 7 of Homo sapiens
(O95471)
1.H.1.1.3









Claudin 22 (function unknown; distantly related to most claudins)
Eukaryota
Metazoa, Chordata
Cldn 22 of Homo sapiens
(Q8N7P3)
1.H.1.1.4









Claudin 23 (function unknown; distantly related to most claudins including Cldn 22). Related to cancer invasion/metastasis; it may regulate these phenomena through activation of the MEK signalling pathway in pancreatic cancer (Wang et al., 2010). Shows reduced levels in atopic dermatitis (De Benedetto et al., 2011).

Eukaryota
Metazoa, Chordata
Cldn 23 of Homo sapiens
(Q96B33)
1.H.1.1.5









Claudin-19 (Cldn19) (interacts with Cldn3 and Cldn16 to form divalent cation (Mg2+ and Ca2+)-selective tight junctions; mutations in both proteins can give rise to hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), an inherited disorder (Hou et al., 2008). Claudins 16 and 19 belong to the PMP22-Claudin subfamily.  The structure of Claudin 19 with Clostridium perfringens enterotoxin bound (3.7Å resolution) revelaed interactions with the two extracellular loops of the claudin giving rise to helix displacement as the mechanism of tight junction disruption (Saitoh et al. 2015).  Claudin-16 and -19 form a stable dimer through cis-association of transmembrane domains 3 and 4, and mutations disrupting the claudin-16/19 cis-interaction increase tight junction ultrastructural complexity but reduce its permeability (Gong et al. 2015).

Eukaryota
Metazoa, Chordata
Cldn19 of Homo sapiens (Q8N6F1)
1.H.1.1.6









Claudin 4 (209aas) forms paracellular chloride channels in the kidney collecting duct and requires Claudin 8 for tight junctions localization (Hou et al., 2010).

Eukaryota
Metazoa, Chordata
Cldn4 of Homo sapiens (O14493)
1.H.1.1.7









Claudin 8 (225aas) is required for localization of Claudin 4 (TC# 1.H.1.1.6) to the kidney tight junctions (Hou et al., 2010). Bartter's syndrome patients have a single nucleotide substitution of C for T at position 451 of the claudin-8 gene sequence that changes the amino acid residue from serine to proline at position 151 in the second extracellular domain of the claudin-8 gene (Chen et al., 2009). Interactions between epithelial sodium channel gamma-subunit and claudin-8 modulates paracellular sodium permeability in the renal collecting duct (Sassi et al. 2020).

Eukaryota
Metazoa, Chordata
Cldn8 of Homo sapiens (P56748)
1.H.1.1.8









PM22_Claudin family (CLDN_18A2.1; CRA_C; 264 aas). It is 88% identical to the human ortholog, CLDN18 of 261 aas and 4 TMSs (P56856). The human CLDN18.1 attenuates malignant properties including xenograft tumor growth in vivo as well as cell proliferation, migration, invasion and anchorage-independent colony formation in vitro (Luo et al. 2018). A transmembrane scaffold from CD20 helps recombinant expression of a chimeric claudin 18.2 in an in vitro coupled transcription and translation system (Wang et al. 2024).

Eukaryota
Metazoa, Chordata
Claudin-18A2.1 of Mus musculus (P56857)
1.H.1.1.9









Claudin 15 (with a cation selective paracellular channel (Angelow et al., 2008).  Claudin-15 is highly expressed in the intestine where it forms efficient Na+ channels and Cl- barriers. The permeation process of Na+, K+, and Cl- ions inside a refined structural model of a claudin-15 paracellular channel was investigated using all-atom molecular dynamics simulations in a double-bilayer (Alberini et al. 2018). The channel allows the passage of the two physiological cations while excluding chloride with 30x selectivity. These features are generated by the action of several acidic residues, in particular, the ring of D55 residues which is located at the narrowest region of the pore, in correspondence with the energy minimum for cations and the peak for chloride. Claudin-15 thus regulates tight junction selectivity by invoking the experimentally determined role of the acidic residues (Alberini et al. 2018). Water and small cations can pass through the channel, but larger cations, such as tetramethylammonium, do not (Samanta et al. 2018). TMS 3 plays a role in claudin-15 strand flexibility (Fuladi et al. 2022). Specifically, the kink in TMS 3 skews the rotational flexibility of claudin-15 in the strands and limits their fluctuation (Fuladi et al. 2022).

Eukaryota
Metazoa, Chordata
Cldn15 of Homo sapiens (P56746)
1.H.1.1.10









Claudin 10a (Claudin-10a; isoform 1) has an anion-selective paracellular channel (Angelow et al., 2008) while Claudin 10b (Claudin-10b; isoform 2) has a cation-selective paracellular channel (Milatz and Breiderhoff 2017).

Eukaryota
Metazoa, Chordata
Cldn10a of Mus musculus (Q9Z0S6)
1.H.1.1.11









Claudin 2 (Claudin-2; CLDN2) (forms narrow, fluid filled, water-permeable cation-selective paracellular pores) (Angelow et al., 2008; Yu et al., 2009).  It is a dimer in a high molecular weight protein complex (Van Itallie et al. 2011; Krug et al. 2014). Transports Na+, K+, Ca2+ smal organic molecules and water through the paracellular channel (Fromm et al. 2017). Site-specific distributions of claudin-2- and claudin-15-based paracellular channels drive their organ-specific functions in the liver, kidney, and intestine (Tanaka et al. 2017). Disruption of the gastrointestinal epithelial barrier is a hallmark of chronic inflammatory bowel diseases (IBDs), and in the intestines of patients with IBDs, the expression of CLDN2 is upregulated (Takigawa et al. 2017). Leu increases Ca2+ flux through cellular redistribution of Cldn-2 to the tight junction membrane (Gaffney-Stomberg et al. 2018).

Eukaryota
Metazoa, Chordata
Cldn2 of Mus musculus (O88552)
1.H.1.1.12









Claudin-15 of 227 aas and 4 TMSs, Cldn15.  Suzuki et al. 2013 reported the crystal structure of mouse claudin-15 at a resolution of 2.4 angstroms. The structure revealed a characteristic β-sheet fold consisting of two extracellular segments anchored to a transmembrane four-helix bundle by a consensus motif. Potential paracellular pathways with distinctive charges on the extracellular surface provided insight into the molecular basis of ion homeostasis across tight junctions. Site-specific distributions of claudin-2- and claudin-15-based paracellular channels drive their organ-specific functions in the liver, kidney, and intestine (Tanaka et al. 2017). A model of the claudin-15-based paracellular channel has been presented (Alberini et al. 2017).

Eukaryota
Metazoa, Chordata
Cldn15 of Mus musculus
1.H.1.1.13









Claudin 17 (Cluadin-17; CLDN17) of 224 aas and 4 TMSs.  Selectively permeable to anions (Krug et al. 2014).

Eukaryota
Metazoa, Chordata
CLDN17 of Homo sapiens
1.H.1.1.14









Claudin-1 (CLDN1) of 211 aas.  Forms homoligomers as well as heterooligomers with Claudin-3 (Milatz et al. 2015). Claudins function as major constituents of the tight junction complexes that regulate the permeability of epithelia. While some claudin family members play essential roles in the formation of impermeable barriers, others mediate the permeability to ions and small molecules. Often, several claudin family members are coexpressed and interact with each other, and this determines the overall permeability. CLDN1 is required to prevent the paracellular diffusion of small molecules through tight junctions in the epidermis and is required for the normal barrier function of the skin (Kirschner et al. 2013). It influences stratum corneum (SC) proteins important for SC water barrier function, and is crucial for TJ barrier formation for allergen-sized macromolecules (Kirschner et al. 2013).

Eukaryota
Metazoa, Chordata
Claudin-1 of Homo sapiens
1.H.1.1.15









Claudin-3 (CLDN3) of 220 aas.  Forms homooligomers as well as heterooligomers with CLNVN1 (Milatz et al. 2015). Also forms hetero-oligomers with Claudin-16 and Claudin-19 which are divalent cation (Ca2+ and Mg2+)-selective (Milatz et al. 2017). The crystal structure of claudin-3 at 3.6 A resolution reveals that the third TMS is bent compared with that of other subtypes, and strand formation - straight or curvy strands - observed in native epithelia results in different morphologies (Nakamura et al. 2019).

.

Eukaryota
Metazoa, Chordata
CLDN3 of Homo sapiens
1.H.1.1.16









Claudin 5 of 218 aas and 4 TMSs.  Plays an important role in the tight junctions that comprise the blood-brain barrier (BBB) (Irudayanathan et al. 2015). Polyinosinic-polycytidylic acid [Poly(I:C)], a synthetic analog of viral double-stranded RNA (dsRNA) commonly used to simulate viral infections, decreases the expression of claudin-5, and gives rise to increased endothelial permeability (Huang et al. 2016). DNA methylation plays an important role in regulating BBB repair after stroke, through regulating processes associated with BBB restoration and prevalently with processes enhancing BBB injury (Phillips et al. 2023). It may have 4 C-terminal TMSs. Wine-processed Chuanxiong Rhizoma enhances efficacy of aumolertinib against EGFR mutant non-small cell lung cancer xenografts in nude mouse brain (Niu et al. 2023).

Eukaryota
Metazoa, Chordata
Claudin-5 of Homo sapiens
1.H.1.1.17









Claudin 10b of 233 aas and 4 TMSs with a monovalent cation-selective paracellular channel (Milatz and Breiderhoff 2017).

Eukaryota
Metazoa, Chordata
Claudin 10b of Danio rerio (Zebrafish) (Brachydanio rerio)
1.H.1.1.18









Claudin 18-like protein of 411 aas and 5 or 6 TMSs in a 1 + 2 + 2 +1 or 1 + 1 + 2 + 1 TMS arrangement, respectively.

Eukaryota
Metazoa, Chordata
Claudn-18-like protein of Scleropages formosus (Asian bonytongue)
1.H.1.1.19









Claudin-9, CLDN9, of 217 aas and 4 or 5 TMSs. It plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. It acts as a receptor for hepatitis C virus (HCV) entry into hepatic cells. It's expression in breast cancer has been evaluated, and its signifucabce with respect to its impact on drug resistance has been reported (Zhuang et al. 2023).

Eukaryota
Metazoa, Chordata
CDN9 of Homo sapiens
1.H.1.2.1









Epithelial membrane protein2 EMP2. This protein interconnects the Claudin superfamily with the LACC (SUR7) family (1.A.81) of mating-dependent 4TMS Ca2+ channels in fungi and the 4TMS Ca2+ channel auxiliary subunit γ1-γ8 (CCAγ) family of animals (8.A.16).

Eukaryota
Metazoa, Chordata
EMP2 of Mus musculus (Q8CGC1)
1.H.1.2.2









Peripheral myelin protein 22, PMP22 of 160 aas and 4 TMSs.  May be involved in growth regulation and myelinization in the peripheral nervous system (Magyar et al. 1997). PMP22 associates with MPZ via their transmembrane domains, and disrupting this interaction causes a loss-of-function phenotype similar to hereditary neuropathy associated with liability to pressure palsies
(Pashkova et al. 2023).
Eukaryota
Metazoa, Chordata
PMP22 of Homo sapiens
1.H.1.3.1









Claudin family protein (related to Sur7; TC# 1.A.81)

Eukaryota
Fungi, Basidiomycota
Sur7 family protein of Cryptococcus formans
1.H.1.4.1









Putative 5 TMS Claudin family member, distantly related to Sur7 in family 1.A.81.

Eukaryota
Fungi, Ascomycota
Claudin-like protein of Neurospora crassa
1.H.1.4.2









Protein up-regulated during nitrogen stress 1, PUN1 (YLR414c).  Colocalizes with Sur7 in punctate patches of the plasma membrane.

Eukaryota
Fungi, Ascomycota
PUN1 of Saccharomyces cerevisiae
1.H.1.4.3









Uncharacterized protein

Eukaryota
Fungi, Ascomycota
UP of Aspergillus niger
1.H.1.4.4









4 TMS uncharacterized protein

Eukaryota
Fungi, Ascomycota
UP of Saccharomyces cerevisiae
1.H.1.4.5









Uncharacterized protein

Eukaryota
Fungi, Ascomycota
UP of Aspergillus oryzae
1.H.1.4.6









Ecm7, (448aas; 4 TMS), is a member of the PMP-22/EMP/MP20 Claudin superfamily of transmembrane proteins that includes gamma-subunits of voltage-gated calcium channels.  It appears to interact with Mid1 and regulate the activity of the Cch1/Mid1 channel (TC# 1.A.1.11.10; Martin et al., 2011). Ecm7p is related to members of TC families 1.H.1, 1.H.2 and 1.A.81.

Eukaryota
Fungi, Ascomycota
Ecm7 of Saccharomyces cerevisiae
1.H.1.5.1









β-type IP39 protein of 264 aas and 4 TMSs in a 1 3 TMS arrangement.  Euglenoid flagellates have striped surface structures comprising pellicles, which allow the cell shape to vary from rigid to flexible during the characteristic movement of the flagellates. In Euglena gracilis, the pellicular strip membranes are covered with paracrystalline arrays of a major integral membrane protein, IP39, a four TMS protein with the conserved sequence motif of the PMP-22/EMP/MP20/Claudin superfamily. Suzuki et al. 2013 reported the three-dimensional structure of Euglena IP39 determined by electron crystallography. Two-dimensional crystals of IP39 formed a striated pattern of antiparallel double-rows in which trimeric IP39 units are longitudinally polymerised, resulting in continuously extending zigzag-shaped lines. Structural analysis revealed an asymmetric molecular arrangement in the trimer, suggesting that at least four different interactions between neighbouring protomers are involved. A combination of such multiple interactions would be important for linear strand formation of membrane proteins in a lipid bilayer (Suzuki et al. 2013).

Eukaryota
Euglenozoa
IP39 of Euglena gracilis
1.H.1.5.2









α-type IP39 protein of 263 aas.  Nearly identical to 1.H.1.5.1. The low resolution 3-d structure is available (Suzuki et al. 2013).

Eukaryota
Euglenozoa
IP39 of Euglena gracilis
1.H.1.6.1









Claudin-like protein (shows similarity to members of both 1.H.1 and 1.H.2). 

Eukaryota
Metazoa, Chordata
Claudin-like protein of Ciona intestinalis (sea squirt) (F6YNZ8)
1.H.1.6.2









Epithelial membrane protein 1-like of 164 aas and 4 TMSs in a 1 + 3 TMS arrangement.

Eukaryota
Metazoa, Mollusca
EMP1 of Pomacea canaliculata
1.H.1.7.1









Sur7p Ca2+ channel (4TMSs); affects sphingolipid metabolism and is involved in sporulation (Young et al., 2002). Related proteins contribute to secretion, biofilm formation and macrophage killing (see 1.A.81.3.2; Bernardo and Lee, 2010).

Eukaryota
Fungi, Ascomycota
Sur7p of Saccharomyces cerevisiae (P54003)
1.H.1.7.2









4TMS Sur7 family cortical patch protein. Contributes to secretion, biofilm formation and macrophage killing (Bernardo and Lee, 2010).  

Eukaryota
Fungi, Ascomycota
Sur7p of Candida albicans (Q5A4M8)