1.H.1 The Claudin Tight Junction (Claudin1) Family

Epithelia form boundaries of biological compartments, creating specialized absorptive and secretive surfaces such as the kidney tubules, the intestinal tract, and the mammary gland. The ability of epithelial cells to regulate absorption and secretion of essential ions such as sodium, chloride, calcium, and magnesium is critical for the maintenance of electrolyte balance (Van Itallie and Anderson, 2006). Ion transport across an epithelial layer can be either transcellular or paracellular (Shen et al., 2011). The transcellular pathway involves the movement of ions across the cytoplasm via plasma membrane channels, carriers, and exchangers (Muto et al., 2011). The paracellular pathway involves the movement of ions through the intercellular spaces between epithelial cells. The transmembrane proteins of tight junctions include claudins, junctional adhesion molecules (JAMs), occludin and tricellulin. Chiba et al. (2008) have provided an overview of these proteins, highlighting their roles and regulation, as well as their functional significance in human diseases. Sequence analysis of claudins has led to differentiation into two groups, designated as classic claudins (1-10, 14, 15, 17, 19) and non-classic claudins (11-13, 16, 18, 20-24), according to their degree of sequence similarity (Krause et al., 2008).  Claudins have been reviewed from structural/functional standpoints (Krause et al. 2015). All of the identified tight junction transmembrane proteins can be multiply phosphorylated, but only in a few cases are the consequences of phosphorylation at specific sites well characterized (Van Itallie and Anderson 2017). Passive solute transport across primary alveolar epithelial cell monolayers can be mediated by intercellular tight junctions (Kim et al. 2021). Claudins are not expressed exclusively by epithelial cells, but also by certain types of cells of mesodermal origin (Čužić et al. 2021). Multiscale modelling of claudin-based assemblies has been reported (Berselli et al. 2022).

The architecture of tight junctions can be conceptualized into compartments with the transmembrane barrier proteins (claudins, occludin, JAM-A, etc.), linked to peripheral scaffolding proteins (such as ZO-1, afadin, MAGI1, etc.) which are in turned linked to actin and microtubules through numerous linkers (cingulin, myosins, protein 4.1, etc.) (Van Itallie and Anderson 2014). Within this complex network are associated many signaling proteins that affect the barrier and broader cell functions. The PDZ domain is a commonly used motif to specifically link individual junction protein pairs. Van Itallie and Anderson 2014 reviewed some of the key proteins defining the tight junction as well as their detailed architecture and subcompartments. Claudins 1 and 3 can form homo- and heterophilic cis and trans interactions, and at least two different cis-interaction interfaces within claudin-3 homopolymers as well as within claudin-1/claudin-3 heteropolymers have been documented (Milatz et al. 2015). The disruption of the barrier between the endolymph and perilymph in the auditory system, caused by tight junction abnormalities, can affect the microenvironment of hair cells, and this can be the reason for one type of hearing loss. This topic has been reviewed (see below; Gao et al. 2023).

Two TJ protein families can be distinguished, claudins, comprising 27 members in mammals, and TJ-associated MARVEL proteins (TAMP), comprising occludin, tricellulin, and MarvelD3 (Krug et al. 2014). They are linked to a multitude of TJ-associated regulatory and scaffolding proteins. The major TJ proteins are classified according to the physiological role they play in enabling or preventing paracellular transport. Many TJ proteins have sealing functions (claudins 1, 3, 5, 11, 14, 19, and tricellulin). In contrast, a significant number of claudins form channels across TJs which feature selectivity for cations (claudins 2, 10b, and 15), anions (claudin-10a and -17), or are permeable to water (claudin-2). For several TJ proteins, function is yet unclear as their effects on epithelial barriers are inconsistent (claudins 4, 7, 8, 16, and occludin). TJs undergo physiological and pathophysiological regulation by altering protein composition or abundance. Major pathophysiological conditions which involve changes in TJ protein composition are (1) effects of pathogens binding to TJ proteins, (2) altered TJ protein composition during inflammation and infection, and (3) altered TJ protein expression in cancers (Krug et al. 2014). CLDNs6 and 9 are almost identical, differing only with respect to three extracellular residues, but a monoclonal antibody speicific for CLDN6, which is upregulated in cancers, has been isolated (Screnci et al. 2022).

The gatekeeper of the paracellular pathway is the tight junction, which is located at apical cell-cell interactions of adjacent epithelial cells. Three known inherited disorders, familial hypomagnesemia (Simon et al., 1999), hypertension (Wilson et al., 2001), and autosomal recessive deafness (Wilcox et al. 2001) have been linked to proteins that localize at the tight junction. Transmembrane proteins of tight junctions include claudins, junctional adhesion molecules (JAMS), occludin and tricellulin. The cytoplasmic scaffolding proteins include Z0-1, -2 and -3 (Hartsock and Nelson, 2008).Their study has led to insights into the molecular nature of tight junctions (Chiba et al., 2008). Neurological diseases (Bednarczyk and Lukasiuk, 2011) and renal diseases (Li et al., 2011) have been reviewed. High concentrations (>200 μM) of Zn2+ can affect TJ integrity in a polarized manner. Thus, the basolateral addition of Zn2+ leads to reversible TJ opening with pore paths of r ∼ 2 nm or more, depending on the Zn2+ concentration.  Zn2+-induced paracelluar channels favour efflux especially for macromolecules (Xiao et al. 2018). Even bacterial outer membrane vesicles have been shown to pass through 'leaky' junctions (Jones et al. 2020).

Tight junctions of epithelial cells exclude macromolecules but allows permeation of ions. It has not been clear whether this ion-conducting property is mediated by aqueous pores or by ion channels. To investigate the permeability properties of the tight junction, Tang & Goodenough (2003) developed paracellular ion flux assays for four major extracellular ions, Na+, Cl-, Ca2+, and Mg2+. Tight junctions share biophysical properties with conventional ion channels, including size and charge selectivity, dependency of permeability on ion concentration, competition between permeant molecules, anomalous mole-fraction effects, and sensitivity to pH. Their results support the hypothesis that discrete ion channels are present at the tight junction. Unlike conventional ion channels, which mediate ion transport across lipid bilayers, the tight junction channels must orient parallel to the plane of the plasma membranes to support paracellular ion movements. This new class of paracellular-tight junction channels facilitates the transport of ions between separate extracellular compartments (Balkovetz, 2009). Claudin-2 forms highly cation-selective paracellular pores (Yu, 2009). The basis of this charge selectivity is likely to be the presence of a negatively charged binding site within the lumen of the pore.  Paracellin-1 may be a Mg2+ transporter (Brandao et al. 2012).

Heterotypic (head-to-head) binding between different claudin isoforms plays a role in regulating paracellular permeability. Claudin-3 and claudin-4 do not heterotypically interact despite having highly conserved extracellular loop (EL) domains (Daugherty et al., 2007). Claudin-1 and -5, which are heterotypically compatible with claudin-3, do not bind to claudin-4. In contrast, claudin-4 chimeras containing either the first EL domain or the second EL domain of claudin-3, do bind to claudin-1, claudin-3, and claudin-5. Moreover, a single point mutation in the first extracellular loop domain of claudin-3, converting Asn44 to the corresponding amino acid in claudin-4 (Thr) produced a claudin capable of heterotypic binding to claudin-4 while still retaining the ability to bind to claudin-1 and -5. Thus, control of heterotypic claudin-claudin interactions is sensitive to small changes in the EL domains (Daugherty et al., 2007). Claudin-1, - 3, - 4, and - 7 are expressed mainly in the lateral plasmamembrane of serous glandular cells. In the ducts, claudin-1, - 4, and - 7 were detected at the basal cell layer; claudin-7 was found at the lateral cytomembrane (Stoeckelhuber et al. 2023).

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a human disorder caused by mutations in the tight junction protein claudin-16 (Hou et al., 2007). Claudin-16 plays a key role in maintaining the paracellular cation selectivity of the thick ascending limbs of the nephron. Claudin-16-deficient mice exhibit chronic renal wasting of magnesium and calcium and develop renal nephrocalcinosis. Claudin-16 apparently forms a non-selective paracellular cation channel, rather than a selective Mg2+/Ca2+channel as previously proposed (Hou et al., 2007). Claudin-16 increases transepithelial electrical resistance and transepithelial magnesium transport (Ikari et al., 2008). The activation of polyvalent extracellular cation (Ca2+)-sensing receptor (CaSR; P41180) decreased the resistance and magnesium transport, which were recovered by co-treatment with dibutyryl cAMP. Activation of CaSR may thus decrease PKA activity, resulting in a decrease in phosphorylated claudin-16, the translocation of claudin-16 to lysosomes and a consequent decrease in magnesium reabsorption (Ikari et al., 2008).

Claudins comprise the primary constituents of tight junctions and determine paracellular permeability. Ion selectivity of the paracellular conductance is a complex function of claudin subtype and cellular context (Hou et al., 2007). These 4 TMS proteins have been characterized from structural standpoints and may have arisen from an early intragenic duplication event (Hua et al., 2003).  There are 27 claudin paralogues in mice and humans (Mineta et al. 2011).  Permselective paracellular claudin channels are specific for certain ions and non-ionic solutes. Recent studies using claudin knockout mice revealed that the loss of claudins' specific paracellular barrier and/or channel functions affects particular biological functions and leads to pathological states (Tamura and Tsukita 2014). Palmitoylation of claudins is required for efficient tight-junction localization (Van Itallie et al. 2005). Human peritoneal tight junctions, transporters and channels are expressed differentially in health and kidney failure, and are described by Levai et al. 2023.

As reviewed by Angelow et al. (2007;2008), the structure of claudin-based paracellular pores is largely unknown, but it is probably composed of homo- and hetero-typic claudin digomers. Both the proteins involved and the cell type determine the selectivity of paracellular transport. Claudins 2, 106 and 15 act preferentially as cation pores while claudins 10a and 7 are the only claudins that have significant anion pore properties (Angelow et al., 2008). However, claudins 4 and 7 have been reported to act as cation pores in MDCK II cells but as anion pores in LLC-PK 1 cells (Hou et al., 2006). They can pass neutral as well as charged small molecules. Their pore diameters are 8-15 Å. The first extracellular loop may line the paracellular pathways and determine the charge selectivity, but the C-terminal tail, which is modified by phosphorylation and palmitoylation and interacts with cytoskeletal proteins, may also play a role.

Claudin-2 pores are narrow, fluid filled, and cation selective (Yu et al., 2009). Charge selectivity is mediated by the electrostatic interaction of partially dehydrated permeating cations with a negatively charged site within the pore that is formed by the side chain carboxyl group of aspartate-65. Thus, paracellular pores use intrapore electrostatic binding sites to achieve a high conductance with a high degree of charge selectivity. Post-translational modifications, PTMs of TJ proteins directly contributes to epithelial barrier changes in permeability to ions and macromolecules (Reiche and Huber 2020).

The control of claudin assembly into tight junctions requires a complex interplay between several classes of claudins, other transmembrane proteins and scaffold proteins (Findley and Koval, 2009). Claudins are also subject to regulation by post-translational modifications including phosphorylation and palmitoylation. Several human diseases have been linked to claudin mutations. Roles for claudins in regulating cell phenotype and growth control suggest a multifaceted role for claudins in regulation of cells beyond serving as a simple structural element of tight junctions. Claudins (Cldns) promote the formation of either barriers or ion-selective channels at the interface between two facing cells, across the paracellular space (Berselli et al. 2022). Multiple Cldn subunits form complexes that include cis- (intracellular) interactions along the membrane of a single cell and trans- (intercellular) interactions across adjacent cells.  The recent implementation of computer-based techniques contributed to the elucidation of Cldn properties. Molecular dynamics simulations and docking calculations were extensively used to refine the first Cldn multimeric model postulated from the crystal structure of Cldn15, and contributed to the introduction of a novel alternative arrangement. Both these multimeric assemblies were found to account for the physiological properties of some family members. Berselli et al. 2022 illustrated the major findings on Cldn-based systems that were achieved by using state-of-the-art computational methodologies.

Epithelial transport relies on the proper function and regulation of the tight junction (TJ); otherwise, uncontrolled paracellular leakage of solutes and water would occur. They also act as a fence against mixing of membrane proteins of the apical and basolateral side. The proteins determining paracellular transport consist of four transmembrane regions, intracellular N and C terminals, one intracellular and two extracellular loops (ECLs). The ECLs interact laterally and with counterparts of the neighboring cell and thereby achieve a general sealing function. Two TJ protein families can be distinguished, claudins, comprising 27 members in mammals, and TJ-associated MARVEL proteins (TAMP), comprising occludin, tricellulin, and MarvelD3. They are linked to a multitude of TJ- associated regulatory and scaffolding proteins (Günzel and Fromm 2012). The major TJ proteins are classified according to the physiological role they play in enabling or preventing paracellular transport. Many TJ proteins have sealing functions (claudins 1, 3, 5, 11, 14, 19, and tricellulin). In contrast, a significant number of claudins form channels across TJs which feature selectivity for cations (claudins 2, 10b, and 15), anions (claudin-10a and -17), or are permeable to water (claudin-2). For several TJ proteins, their functions are unclear as their effects on epithelial barriers are inconsistent (claudins 4, 7, 8, 16, and occludin). TJs undergo physiological and pathophysiological regulation by altering protein composition or abundance. Major pathophysiological conditions which involve changes in TJ protein composition are (1) effects of pathogens binding to TJ proteins, (2) altered TJ protein composition during inflammation and infection, and (3) altered TJ protein expression in cancers (Günzel and Fromm 2012). 

The electric property of claudin pertains to two important organ functions: the renal and sensorineural functions. The kidney consists of three major segments of epithelial tubules with different paracellular permeabilities: the proximal tubule (PT), the thick acending limb of Henle's loop (TALH) and the collecting duct (CD). Claudins act as ion channels allowing selective permeation of Na+ in the PT, Ca2+ and Mg2+ in the TALH and Cl- in the CD. The inner ear, on the other hand, expresses claudins as a barrier to block K+ permeation between endolymph and perilymph. The permeability properties of claudins in different organs can be attributed to claudin interactions within the cell membrane and between neighboring cells. The first extracellular loop of claudins contains determinants of paracellular ionic permeability (Hou 2013).

The thick ascending limb (TAL) of Henle's loop drives paracellular Na+, Ca2+, and Mg2+ reabsorption via the tight junction (TJ). The TJ is composed of claudins with two extracellular segments (ECS1 and -2), and one intracellular loop. Claudins interact within the same (cis) and opposing (trans) plasma membranes. Claudins Cldn10b, -16, and -19 facilitate cation reabsorption in the TAL, and their absence leads to disturbances of renal ion homeostasis. Milatz et al. 2017 showed that (i) TAL TJs show a mosaic expression pattern of either cldn10b or cldn3/cldn16/cldn19 in a complex; (ii) TJs dominated by cldn10b prefer Na+ over Mg2+, whereas TJs dominated by Cldn16 favor Mg2+ over Na+; (iii) Cldn10b does not interact with other TAL claudins, whereas Cldn3 and Cldn16 can interact with Cldn19 to form joint strands; and (iv) further claudin segments in addition to ECS2 are crucial for trans interaction. Milatz et al. 2017 suggested the existence of at least two spatially distinct types of paracellular channels in TAL: a Cldn10b-based channel for monovalent cations such as Na+ and a spatially distinct site for reabsorption of divalent cations such as Ca2+ and Mg2+

Tight junctions (TJ) play a central role in the homeostasis of epithelial and endothelial tissues, by providing a semipermeable barrier to ions and solutes, by contributing to the maintenance of cell polarity, and by functioning as signaling platforms. TJ are associated with the actomyosin and microtubule cytoskeletons, and the crosstalk with the cytoskeleton is fundamental for junction biogenesis and physiology. TJ are spatially and functionally connected to adherens junctions (AJ), which are essential for the maintenance of tissue integrity. Mechano-sensing and mechano-transduction properties of several AJ proteins have been characterized during the last decade. Citi 2019 reviews how mechanical forces act on TJ and their proteins, how TJ control the mechanical properties of cells and tissues, and what the underlying molecular mechanisms are. Interactions among the adherence junctional proteins is influenced by phosphorylation (Wang et al. 2019).

Tight junctions act as a barrier between epithelial cells to limit the transport of paracellular substances, which is a required function in various tissues to sequestrate diverse microenvironments and maintain a normal physiological state (Gao et al. 2023). Tight junctions are complexes that contain various proteins, like transmembrane proteins, scaffolding proteins, signaling proteins, etc. Defects in these tight junction-related proteins can lead to hearing loss which is also recapitulated in model organisms. The disruption of the barrier between the endolymph and perilymph caused by tight junction abnormalities affect the microenvironment of hair cells, and this may be the reason for some types of hearing loss. Besides their functions as a typical barrier and channel, tight junctions are also involved in many signaling networks to regulate gene expression, cell proliferation, and differentiation. Gao et al. 2023 summarized the structures, localization, and signaling pathways of hearing-related tight junction proteins and their potential contributions to the hearing disorder.

The paracellular transport reactions proposed to be catalyzed by claudinins are:

Ions (Lumen) Ions (Tissues).

This family belongs to the Tetraspan Junctional Complex Protein or MARVEL (4JC) Superfamily.



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TC#NameOrganismal TypeExample

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).


Cldn 16 of Homo sapiens


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).


Cldn10a of Mus musculus (Q9Z0S6)


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).


Cldn2 of Mus musculus (O88552)


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).


Cldn15 of Mus musculus


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

CLDN17 of Homo sapiens


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).

Claudin-1 of Homo sapiens


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).


CLDN3 of Homo sapiens


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).

Claudin-5 of Homo sapiens


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

Claudin 10b of Danio rerio (Zebrafish) (Brachydanio rerio)


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.

Claudn-18-like protein of Scleropages formosus (Asian bonytongue)


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).


Cldn 7 of Homo sapiens

1.H.1.1.3Claudin 22 (function unknown; distantly related to most claudins)AnimalsCldn 22 of Homo sapiens

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).


Cldn 23 of Homo sapiens


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).


Cldn19 of Homo sapiens (Q8N6F1)


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


Cldn4 of Homo sapiens (O14493)


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).


Cldn8 of Homo sapiens (P56748)


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).


Claudin-18A2.1 of Mus musculus (P56857)


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).


Cldn15 of Homo sapiens (P56746)


TC#NameOrganismal TypeExample

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).


EMP2 of Mus musculus (Q8CGC1)

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).

PMP22 of Homo sapiens


TC#NameOrganismal TypeExample

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


Sur7 family protein of Cryptococcus formans


TC#NameOrganismal TypeExample

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


Claudin-like protein of Neurospora crassa


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


PUN1 of Saccharomyces cerevisiae


Uncharacterized protein


UP of Aspergillus niger


4 TMS uncharacterized protein


UP of Saccharomyces cerevisiae


Uncharacterized protein


UP of Aspergillus oryzae


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.


Ecm7 of Saccharomyces cerevisiae


TC#NameOrganismal TypeExample

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).


IP39 of Euglena gracilis


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).


IP39 of Euglena gracilis


TC#NameOrganismal TypeExample

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

Ascidians (Chordate invertebrates)

Claudin-like protein of Ciona intestinalis (sea squirt) (F6YNZ8)


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

EMP1 of Pomacea canaliculata


TC#NameOrganismal TypeExample

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).


Sur7p of Saccharomyces cerevisiae (P54003)


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


Sur7p of Candida albicans (Q5A4M8)


TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample