Claudins are a family of proteins which, along with occludin, are the most important components of the tight junctions (zonulae occludentes). [1] [2] Tight junctions establish the paracellular barrier that controls the flow of molecules in the intercellular space between the cells of an epithelium. [1] [3] They have four transmembrane domains, with the N-terminus and the C-terminus in the cytoplasm.
Claudins are small (20–24/27 kilodalton (kDa)) [4] transmembrane proteins which are found in many organisms, ranging from nematodes to human beings. They all have a very similar structure. Claudins span the cellular membrane 4 times, with the N-terminal end and the C-terminal end both located in the cytoplasm, and two extracellular loops which show the highest degree of conservation.
Claudins have both cis and trans interactions between cell membranes. [5] Cis-interactions is when claudins on the same membrane interact, one way they interact is by transmembrane domain having molecular interactions. [6] Trans-interaction is when claudins of neighboring cells interact through their extracellular loops. [7] Cis-interactions is also known as side-to-side interactions and trans-interactions is also known as head-to-head interactions. [8]
Generally the tight junction is known for its impermeability. However, depending on the type of claudin and their interactions there is selective permeability. This includes charge selectivity and size selectivity. [6]
The N-terminal end is usually very short (1–10 amino acids) [9] [7] It is located in the cytoplasm where it is thought to help to contribute to cell signaling, cytoskeletal organization and other possible functions. [10]
The C-terminal has a longer chain and is located in the cytoplasm. It varies in length from 21 to 63 and is necessary for the localization of these proteins in the tight junctions. [9] It is thought that it may play a role in cell signaling. [10] All human claudins (with the exception of Claudin 12) have domains that let them bind to PDZ domains of scaffold proteins.
The transmembrane domain is the amino acids that cross the cellular membrane. The transmembrane domain is important for cis-interaction of claudins.
The first extracellular loop has a range of 42-56 amino acids and is longer than the second extracellular loop. It is suspected that the cysteines of found on the first extracellular loop form disulfide bonds. This loop has charged amino acids that may be the predictor for the charge selectivity of tight junctions. The first extracellular loop plays a role in trans-interaction of claudins of adjacent cells. [6]
The second extracellular loop is shorter than the first extracellular loop. In this short chain of amino acids there are three hydrophobic residues. These three residues are suspected to be a contributor to the trans-interaction of proteins between adjacent cells. [6]
Claudins were first named in 1998 by Japanese researchers Mikio Furuse and Shoichiro Tsukita at Kyoto University. [11] The name claudin comes from Latin word claudere ("to close"), suggesting the barrier role of these proteins.
A recent review discusses evidence regarding the structure and function of claudin family proteins using a systems approach to understand evidence generated by proteomics techniques. [12]
A chimeric claudin was synthesized to help enhance the understanding of both the structure and function of the tight junction. [13]
Computational modeling is also another technique being used to help enhance research into the structure and functions of claudins. [8]
| PMP22_Claudin | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | PMP22_Claudin | ||||||||
| Pfam | PF00822 | ||||||||
| Pfam clan | CL0375 | ||||||||
| InterPro | IPR004031 | ||||||||
| PROSITE | PDOC01045 | ||||||||
| TCDB | 1.H.1 | ||||||||
| OPM superfamily | 194 | ||||||||
| OPM protein | 4p79 | ||||||||
| |||||||||
There are 23 genes found in the human genome for claudin proteins [13] and there are 27 transmembrane domains across mammals. [7] [10] The conservation is not observed on a genetic level. Despite the genetic level not being conserved across claudins their structural conservation are very similar.
Cell junctions or junctional complexes, are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also maintain the paracellular barrier of epithelia and control paracellular transport. Cell junctions are especially abundant in epithelial tissues. Combined with cell adhesion molecules and extracellular matrix, cell junctions help hold animal cells together.
Tight junctions, also known as occluding junctions or zonulae occludentes, are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epithelial cells. They also play a critical role maintaining the structure and permeability of endothelial cells. Tight junctions may also serve as leaky pathways by forming selective channels for small cations, anions, or water. The corresponding junctions that occur in invertebrates are septate junctions.
Occludin is a transmembrane protein that regulates the permeability of epithelial and endothelial barriers. It was first identified in epithelial cells as a 65 kDa integral plasma-membrane protein localized at the tight junctions. Together with Claudins, and zonula occludens-1 (ZO-1), occludin has been considered a staple of tight junctions, and although it was shown to regulate the formation, maintenance, and function of tight junctions, its precise mechanism of action remained elusive and most of its actions were initially attributed to conformational changes following selective phosphorylation, and its redox-sensitive dimerization. However, mounting evidence demonstrated that occludin is not only present in epithelial/endothelial cells, but is also expressed in large quantities in cells that do not have tight junctions but have very active metabolism: pericytes, neurons and astrocytes, oligodendrocytes, dendritic cells, monocytes/macrophages lymphocytes, and myocardium. Recent work, using molecular modeling, supported by biochemical and live-cell experiments in human cells demonstrated that occludin is a NADH oxidase that influences critical aspects of cell metabolism like glucose uptake, ATP production and gene expression. Furthermore, manipulation of occludin content in human cells is capable of influencing the expression of glucose transporters, and the activation of transcription factors like NFkB, and histone deacetylases like sirtuins, which proved capable of diminishing HIV replication rates in infected human macrophages under laboratory conditions.
Claudin-1 is a protein that in humans is encoded by the CLDN1 gene. It belongs to the group of claudins.
Claudin 4, also known as CLDN4, is a protein which in humans is encoded by the CLDN4 gene. It belongs to the group of claudins.
Claudin-5 is a protein that in humans is encoded by the CLDN5 gene. It belongs to the group of claudins.
Claudin 3, also known as CLDN3, is a protein which in humans is encoded by the CLDN3 gene. It is a member of the claudin protein family.
Claudin-7 is a protein that in humans is encoded by the CLDN7 gene. It belongs to the group of claudins.
Claudin-6 is a protein that in humans is encoded by the CLDN6 gene. It belongs to the group of claudins. The knockout mice of mouse homolog exhibit no phenotype, indicating that claudin-6 is dispensable for normal development and homeostasis.
Claudin-2 is a protein that in humans is encoded by the CLDN2 gene. It belongs to the group of claudins.
Claudin-12 is a protein that in humans is encoded by the CLDN12 gene. It belongs to the group of claudins.
Claudin-8 is a protein that in humans is encoded by the CLDN8 gene. It belongs to the group of claudins.
Claudin-11 is a protein that in humans is encoded by the CLDN11 gene. It belongs to the group of claudins and was the first member of the family to be knocked out in mice, thereby demonstrating the central role of claudins for intramembranous strands observed in freeze-fracture images.
Claudin-16 is a protein that in humans is encoded by the CLDN16 gene. It belongs to the group of claudins.
Claudin-14 is a protein that in humans is encoded by the CLDN14 gene. It belongs to a related family of proteins called claudins.
Claudin-17 is a protein that in humans is encoded by the CLDN17 gene. It belongs to the group of claudins; claudins are cell-cell junction proteins that keep that maintains cell- and tissue-barrier function. It forms anion-selective paracellular channels and is localized mainly in kidney proximal tubules.
Claudin-10 is a protein that in humans is encoded by the CLDN10 gene. It belongs to the group of claudins.
Claudin-15 is a protein that in humans is encoded by the CLDN15 gene. It belongs to the group of claudins. Among its related pathways are Blood-Brain Barrier and Immune Cell Transmigration: VCAM-1/CD106 Signaling Pathways and Tight junction. GO annotations related to this gene include identical protein binding and structural molecule activity. An important paralog of this gene is CLDN10.
The intestinal epithelium is the single cell layer that form the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelial cells, it serves two main functions: absorbing useful substances into the body and restricting the entry of harmful substances. As part of its protective role, the intestinal epithelium forms an important component of the intestinal mucosal barrier. Certain diseases and conditions are caused by functional defects in the intestinal epithelium. On the other hand, various diseases and conditions can lead to its dysfunction which, in turn, can lead to further complications.
Tight junction proteins are molecules situated at the tight junctions of epithelial, endothelial and myelinated cells. This multiprotein junctional complex has a regulatory function in passage of ions, water and solutes through the paracellular pathway. It can also coordinate the motion of lipids and proteins between the apical and basolateral surfaces of the plasma membrane. Thereby tight junction conducts signaling molecules, that influence the differentiation, proliferation and polarity of cells. So tight junction plays a key role in maintenance of osmotic balance and trans-cellular transport of tissue specific molecules. Nowadays is known more than 40 different proteins, that are involved in these selective TJ channels.
| Authority control databases: National |
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