Claudin Proteins


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 Claudin Proteins Background

Claudin protein (Cldn)

Claudins were discovered in 1998 by M. Furuse as a part of a tight junction complex distinct from earlier known occludin proteins. Claudins are tetraspan membrane proteins with molecular weight ranging from 20 -30 kDa. They have four transmembrane domains and two extracellular loops (ECL). The first extracellular loop was shown to be responsible for charge selectivity. The C-terminus of claudins contains putative regulatory sites.

Claudins as an integral part of tight junction complexes of the epithelial cells

Fig. 1 Claudins as an integral part of tight junction complexes of the epithelial cells.

Claudins are represented by numerous isoforms numbering reaches 24 in mammals and up to 56 in some fish. expression of different claudin isoforms appeared to be tissue-specific. For instance, the highest expression of Claudin-9 was found in cochlea while claudin-10a expression was restricted mainly to the kidney in mammals. Some claudins, however, exhibit a more ubiquitous pattern of expression. Claudin-1, similarly to Claudin-5 has been found in most epithelial tissues. Different claudin isoforms were shown to have distinct properties, crucial in defining permeability characteristics of epithelium. Based on studies using cultured epithelial cell lines, expression of claudin-2, -10b or 15 caused an increase in epithelial permeability to sodium, leading to the conclusion that these isoforms create cation-selective pores. In contrast, Claudin-3, -4 or -5 were shown to form barriers that seal the epithelium layer. Therefore, claudin composition corresponds to tight or leaky epithelium. Recent findings demonstrated that distinct charge-selective properties of claudins are determined by the arrangement of charged amino acids on the first extracellular loop (ECL-1). The role of the shorter second loop is not so clear. So far, it has been shown that the second extracellular loop of some claudins contains a binding site for Clostridium perfringens enterotoxin and may be involved in strand formation between claudins from adjacent cells. Furthermore, it was reported that the cytoplasmic C-terminus tail possesses sites that can be phosphorylated or palmitoylated suggesting that it may affect the regulation of claudins.

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.