OCLN | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | OCLN , BLCPMG, PPP1R115, occludin, PTORCH1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 602876 MGI: 106183 HomoloGene: 1905 GeneCards: OCLN | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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. [5] 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, [6] and its redox-sensitive dimerization. [7] [8] 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, [9] neurons and astrocytes, [10] oligodendrocytes, [11] dendritic cells, [12] monocytes/macrophages [13] lymphocytes, [14] and myocardium. [15] 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. [16] Furthermore, manipulation of occludin content in human cells is capable of influencing the expression of glucose transporters, [16] 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. [9]
In humans is encoded by the OCLN gene [17] [18] located on the long (q) arm of chromosome 5 at position q13.1. The canonical gene is 65,813 base pairs long, spanning base pairs 69,492,292 to 69,558,104. [19] Its product is 522 amino acids long.
Occludin's structure can be broken down into 9 domains. These domains are separated into two groups. 5 of the domains are located intracellularly and extracellularly. These 5 domains are separated by the 4 transmembrane domains of the protein. The nine domains are as follows:
The C-terminus domain has been shown experimentally to be required for correct assembly of tight junction barrier function. [20] The C-terminus also interacts with several cytoplasmic proteins of the junctional plaque and interacts with signaling molecules responsible for cell survival. [21] The N-terminus of occludin experimentally has been linked to involvement in tight junction sealing/barrier properties. [21] The extracellular loops are thought to be involved in the regulation of paracellualr permeability and the second extracellular has been shown to be involved in the localization of occludin at the tight junction. [21]
Occludin is an important protein in tight junction function. Studies have shown that rather than being important in tight junction assembly, occludin is important in tight junction stability and barrier function. Indeed, MDCK cells lacking occludin and its homolog tricellulin exhibit less complex tight junction strand network and impaired barrier function. [22] Furthermore, studies in which mice were deprived of occludin expression showed morphological stability in several epithelial tissues but also found chronic inflammation and hyperplasia in the gastric epithelium, calcification in the brain, testicular atrophy, loss of cytoplasmic granules in straited duct cells of salivary gland, and thinning of the compact bone. The phenotypical response of these mice to the lack of occludin suggest that the function of occludin is more complex than thought and requires more work. [23]
Occludin plays a critical role in maintaining the barrier properties of a tight junction. Thus, mutation or absence of occludin increases epithelial leakiness which is an important barrier in preventing metastasis of cancer. Loss of occludin or abnormal expression of occludin has been shown to cause increased invasion, reduced adhesion and significantly reduced tight junction function in breast cancer tissues. Furthermore, patients with metastatic disease displayed significantly lower levels of occludin suggesting that the loss of occludin and thereby loss of tight junction integrity is important in metastatic development of breast cancer. [24]
Occludin also plays an important role in the apoptosis. The C-terminus of occludin is important in receiving and transmitting cell survival signals. In standard cells, loss or disruption of occludin and other tight junction proteins leads to initiation of apoptosis through extrinsic pathways. [25] Studies involving high levels of expression of occludin in cancer cells have shown that occludin mitigates several important cancer proliferation properties. The presence of occludin decreased cellular invasiveness and motility, enhanced cellular sensitivity to apoptogenic factors and lowered tumorigenesis and metastasis of the cancer cells. Specifically, occludin has a strong inhibitory effect on Raf1-induced tumorigenesis. Still, the exact mechanism of how occludin prevents the progression of cancer is not known but it has been shown that cancer progression is linked to the loss of occludin or the silencing of the OCLN gene. [26]
Disruption of occludin regulation is an important aspect of a number of diseases. Strategies to prevent and/or reverse occludin downregulation may be an important therapeutic target. Mutation of occludin are thought to be a cause of band-like calcification with simple gyration and polymicrogyria (BLC-PMG). BLC-PMG is an autosomal recessive neurologic disorder.
Occludin has been shown to interact with Tight junction protein 2, [27] [28] [29] YES1 [30] and Tight junction protein 1 (ZO-1). [31] [32]
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.
Claudins are a family of proteins which, along with occludin, are the most important components of the tight junctions. Tight junctions establish the paracellular barrier that controls the flow of molecules in the intercellular space between the cells of an epithelium. They have four transmembrane domains, with the N-terminus and the C-terminus in the cytoplasm.
Zonula occludens-1 ZO-1, also known as Tight junction protein-1 is a 220-kD peripheral membrane protein that is encoded by the TJP1 gene in humans. It belongs to the family of zonula occludens proteins, which are tight junction-associated proteins and of which, ZO-1 is the first to be cloned. It was first isolated in 1986 by Stevenson and Goodenough using a monoclonal antibody raised in rodent liver to recognise a 225-kD polypeptide in whole liver homogenates and in tight junction-enriched membrane fractions. It has a role as a scaffold protein which cross-links and anchors Tight Junction (TJ) strand proteins, which are fibril-like structures within the lipid bilayer, to the actin cytoskeleton.
Claudin-1 is a protein that in humans is encoded by the CLDN1 gene. It belongs to the group of claudins.
Tight junction protein ZO-2 is a protein that in humans is encoded by the TJP2 gene.
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.
Junctional adhesion molecule A is a protein that in humans is encoded by the F11R gene. It has also been designated as CD321.
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-14 is a protein that in humans is encoded by the CLDN14 gene. It belongs to a related family of proteins called claudins.
Cingulin is a cytosolic protein encoded by the CGN gene in humans localized at tight junctions (TJs) of vertebrate epithelial and endothelial cells.
Claudin-18 is a protein that in humans is encoded by the CLDN18 gene. It belongs to the group of claudins.
Tight junction protein ZO-3 is a protein that in humans is encoded by the TJP3 gene.
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.
OCEL1, also called Occludin//ELL Domain Containing 1, is a protein encoding gene located at chromosome 19p13.11 in the human genome. Other aliases for the gene include FLJ22709, FWP009, and S863-9. The function of OCEL1 has not yet been identified.
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