Claudins are a class of proteins that, together with occludin, are the most important component of zonulae occludentes. The tight junction establishes a paracellular barrier that controls the flow of molecules in the intercellular space between epithelial cells. They have four transmembrane domains with an N-terminus and a C-terminus in the cytoplasm. Claudins is represented by a number of isoforms, numbering up to 24 in mammals and up to 56 in some fish. Expression of different claudin isoforms appears to be tissue specific. For example, the highest expression of Claudin-9 is found in the mammalian cochlea, whereas in mammals the expression of claudin-10a is primarily restricted to the kidney. However, some claudins show a more general expression. Claudin-1 similar to Claudin-5 was found in most epithelial tissues. Different claudin isoforms have been shown to have different properties, which is essential for defining the permeability characteristics of the epithelium. Based on studies using cultured epithelial cell lines, expression of claudin-2, -10b or 15 caused an increase in the permeability of the epithelium to sodium, and concluded that these isoforms produced cation selective pores. Instead, it is shown that Claudin-3, -4 or -5 forms a barrier to form a sealed epithelial layer. Thus, the claudin component corresponds to a tight or leaky epithelium. Recent findings indicate that the unique charge-selective properties of claudins are determined by the arrangement of charged amino acids on the first extracellular loop (ECL-1). The effect of the shorter second cycle is unclear. To date, it has been shown that the second extracellular loop of certain claudin contains a binding site for Clostridium perfringens enterotoxin and may be involved in strand formation between adjacent cell claudin. Furthermore, it has been reported that the cytoplasmic C-terminal tail has sites that can be phosphorylated or palmitoylated, suggesting that it may affect the regulation of claudins.
Claudins are small (20–27 kilodalton (kDa)) transmembrane proteins found in many organisms, from nematodes to humans, whose structures are very similar, although this conservation was not observed at the genetic level. Sex. Claudins spanned the cell membrane 4 times, both N-terminally and C-terminally located in the cytoplasm, and the two extracellular loops showed the highest degree of conservation. The first extracellular loop consists of an average of 53 amino acids, and the second, slightly smaller, second loop consists of 24 amino acids. The N-terminus is usually very short (4-10 amino acids) and the length of the C-terminus varies between 21 and 63, which is necessary for localizing these proteins in tight junctions. It is suspected that the cysteine of a single or individual claudins forms a disulfide bond. All human claudins (except Claudin 12) have domains that bind them to the PDZ domain of the scaffold protein.
Claudins was first named in 1998 by Japanese researchers Mikio Furuse and Tsuca Tsukita of Kyoto University. The name claudin comes from the Latin claudere ("close"), suggesting a barrier to these proteins. A recent review used systematic methods to discuss evidence about the structure and function of the claudin family of proteins to understand the evidence generated by proteomics techniques.
Claudin proteins in physiology
Charge-selective and size-selective claudins constitute the main element of tight junctions which are responsible for regulation of the cellular microenvironment. Disruption of the claudin-based ‘barrier’ leads to several disorders and diseases in vertebrates. Recent studies showed that claudins are required in proper early development. It has been shown that a knock-down of the claudin-e and claudin-b in zebrafish embryos leads to developmental abnormalities, such as delay of epiboly, and physiological defects impairing, for instance, sodium handling. Furthermore, claudins were documented to be involved in the creation of body compartments, ligand-receptor segregation, immunity and tumorogenesis. Claudin proteins were also shown to be an important element responsible for proper function of several organs including kidneys, the gastrointestinal tract, blood-brain barrier, lungs and skin. Also, claudin gene mutations were associated with several diseases, such as ichtyosis (cldn-1 mutation), nonsyndromic deafness (cldn-14 mutations) or hypomagnesemia hypercalciuria with nephrocalcinosis (mutations of and cldn-16 and cldn-19 respectively). Recent studies suggested that claudins may be involved in regulating acid-base balance in kidney and in the formation of paracellular channels permeable to water.
1. Rüffer C.; et al. The C-terminal cytoplasmic tail of claudins 1 and 5 but not its PDZ-binding motif is required for apical localization at epithelial and endothelial tight junctions. Eur. J. Cell Biol. 2004,83 (4): 135-44.
2. Furuse M.; et al. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J. Cell Biol. 1998,141 (7): 1539-50.