Tight junction proteins

Last updated May 16, 2024

Tight junction proteins (TJ 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.^[1]

Structure of tight junction

The morphology of tight junction is formed by transmembrane strands in the inner side of plasma membrane with complementary grooves on the outer side. This TJ strand network is composed by transmembrane proteins, that interact with the actin in cytoskeleton and with submembrane proteins, which send a signal into the cell. The complexity of the network structure depends on the cell type and it can be visualized and analyzed by freeze-fracture electron microscopy, which shows the individual strands of the tight junction.^[2]^[3]

Function of tight junction proteins

TJ proteins could be divided in different groups according to their function or localization in tight junction. TJ proteins are mostly described in the epithelia and endothelia but also in myelinated cells. In the central and peripheral nervous system are TJ localized between a glia and an axon and within myelin sheaths, where they facilitate the signaling. Some of TJ proteins act as a scaffolds, that connect integral proteins with the actin in a cytoskeleton. Others have an ability to crosslink junctional molecules or transport vesicles through the tight junction. Some submembrane proteins are involved in the cell signaling and gene expression due to their specific binding to the transcription factor. The most important tight junction proteins are occludin, claudin and JAM family, that establish the backbone of tight junction and allow to passing of immune cells through the tissue.^[1]

TJ proteins in epithelia and endothelia

Proteins in epithelial and endothelial cells are occludin, claudin and tetraspanin, that each has a one or two different types of the conformation. All of them are created by four transmembrane regions with two (amino-, carboxyl-) extracellular domains, that are orientated towards the cytoplasm. But occludin has a structure with two similar extracellular loops compared to claudin and tetraspanin, which have one extracellular loop significantly longer than the other one.^[1]

Occludin

Occludin (60kDa) was the first identified component of tight junction. The tetraspan membrane protein is established by two extracellular loops, two extracellular domains and one short intracellular domain. The C-terminal domain of occludin is directly bound to ZO-1, which interacts with actin filaments in cytoskeleton. It works as a transmitter from and to the tight junction, because of its association with signaling molecules (PI3-kinase, PKC, YES, protein phosphases 2A, 1).^[4] This TJ protein also participate in a selective diffusion of solutes along concentration gradient and transmigration of leukocytes across the endothelium and epithelium. Therefore the result of the overexpression of mutant occludin in epithelial cells leads to break down the barrier function of tight junction and changes in a migration of neutrophils. Occludin cooperates with members of the claudin family directly or indirectly and together they form the long strands of tight junction.^[3]

Claudin

The claudin family is composed by 24 members. Some of them haven´t been well characterized yet but all members are encoded by 20-27kDa tetraspan proteins with two extracellular domains, one short intracellular domain and two extracellular loops, where is the first one notably larger than the second one.^[1] The C-terminal domain of claudins is required for their stability and targeting. This domain contains PDZ-binding motif, that facilitate to bind them to the PDZ membrane proteins, like a ZO-1, ZO-2, ZO-3,MUPP1. Each claudin has a specific variation and amount of charged aminoacids in the first extracellular loop. So through the repolarization of aminoacids could claudins selectively regulate the molecule transfer. In contrast to occludin, which makes paracellular holes for ion-trafficking between neighbour cells.^[4] Claudins seem to be on a tissue specific manner, because some of them are expressed only in a specific cell type. Claudin 11 is expressed in oligodendrocytes and Sertoli cells or Claudin 5 is expressed in the vascular endothelial cells.^[3]

Claudin 2,3,4,7,8,12,15 are present in epithelial cells throughout the segments of intestinal tract. Claudin 7 is occurred also in epithelial cells of the lung and kidney. Claudin-18 is expressed in the alveolar epithelial cells of the lung.^[5] Most types of claudins have more than two isoforms, that have a distinguish size or function. The specific combination of these isoforms creates tight junction strands, while the occulin is not required for. Occludin play a role in selective regulation by an incorporating itself into the claudin-based strands. The different proportion of claudin species in the cell gives them specific barrier properties. Claudins also have a function in a signaling of the cell adhesion, for example Cldn 7 binds directly to adhesion molecule EpCAM on the cell membrane. And Cldn 16 is associated with reabsorption of divalent cations, because it locates in epithelial cells of thick ascending loop of Henle.^[4]

TJ proteins in myelin sheaths

OSP/Claudin 11

OSP/Claudin 11 is occurred in a myelin of nerve cells and between Sertoli cells, so it forms tight junctions in the CNS. This protein in a cooperation with the second loop of occludin maintains the blood-testis barrier and spermatogenesis.^[1]

PMP22/gas-3

PMP22/gas-3, called peripheral myelin protein, is located in the myelin sheath. The expression of this protein is associated with a differentiation of Schwann cells, an establishment of tight junction in the Schwamm cell membrane or a compact formation of myelin. It is also present in epithelial cells of lungs and intestine, where interacts with occludin and ZO-1, that together create the TJ in the epithelia. PMP22/gas-3 belongs to the epithelial membrane protein family (EMP1-3), which conducts a growth and differentiation of cells.^[1]

OAP-1/TSPAN-3

OAP-1/TSPAN-3 cooperates with β1-integrin and OSP/Claudin11 within myelin sheaths of oligodendrocytes, thereby affects the proliferation and migration.^[1]

Junctional adhesion molecules

JAM

Junctional adhesion molecules are divided in subgroups according to their composition and binding motif.

Glycosylated transmembrane proteins JAMs are classified in the immunoglobulin superfamily, that are formed by two extracellular Ig-like domains: the transmembrane region and the C-terminal cytoplasmatic domain. Members of this JAM family could express two distinguish binding motifs. First subgroup composed by JAM-A, JAM-B, JAM-C has a PDZ-domain binding motif type II at their C-termini, which interacts with the PDZ domain of ZO-1, AF-6, PAR-3 and MUPP1.^[3]^[4] JAM proteins are not a part of tight junction strands but they participate in a signalization that leads to an adhesion of monocytes and neutrophils and their transmigration through the epithelium. JAMs in epithelial cells can aggregate with TJ strands, that are made of polymers of claudin and occludin. JAM-A maintains barrier properties in the endothelium and the epithelium as well as JAM-B and -C in Sertoli cells and spermatids.^[1]

The second subgroup of CAR, ESAM, CLMP and JAM4 proteins contains a PDZ-domain binding motif type I at their C-termini.

CAR (coxsackie and adenovirus receptor) also belongs to the immunoglobulin superfamily, same like JAM proteins. CAR is expressed in the epithelia of trachea, bronchi, kidney, liver and intestine, where positively contributes to the barrier function of the tight junction. This protein mediates a neutrophil migration, cells contacts and an aggregation. It´s necessary for the embryonal heart development, especially for the organization of myofibrils in cardiomyocytes. CAR is associated with PDZ-scaffolding proteins MAGI-1b, PICK, PSD-95, MUPP1 and LNX.^[6]

ESAM (endothelial cell selective adhesion molecule) is an immunoglobulin-transmembrane protein, which influences properties of the endothelial TJ. ESAM is present in endothelial cells and platelets but not in the epithelium and leukocytes. There, it directly binds to the MAGI-1 molecules through the ligation of C-terminal domain and PDZ-domain. This cooperation provides the formation of large molecular complex at tight junctions in the endothelium.^[7]

JAM4 is a component of immunoglobulin superfamily JAM but it expresses a PDZ-domain binding motif class I (doesn´t express a class II like members JAM-A,-B,-C). The JAM4 is situated in a kidney glomeruli and an intestine epithelium, where cooperates with MAGI-1, ZO-1, occludin and effectively regulates the permeability of these cells. JAM4 has a cell adhesion activity, which is conducted by MAGI-1.^[8]

Myelin Protein 0

Protein 0 is a major myelin protein of the peripheral nervous system, which integrates with PMP22. Together they form and compact myelin sheaths of nerve cells.^[1]

Plaque proteins in the tight junction

Plaque proteins are molecules, that are required for the coordination of signals coming from the plasma membrane. In recent years exist about 30 different proteins associated with cytoplasmatic properties of the tight junction.

One group of these proteins are attended in the organization of transmembrane proteins and the interaction with actin filaments. This PDZ-containing group is composed by ZO-1, ZO-2, ZO-3, AF-6, MAGI, MUPP1, PAR, PATJ, and the PDZ domain gives them a scaffolding function. PDZ domains are important for a clustering and an anchoring of transmembrane proteins. With the first group interacts one plaque protein without PDZ domain, called cingulin, which plays a key role in the cell adhesion.

The second group of plague proteins are used for a vesicular trafficking, barrier regulation and gene transcription, because certain of them are transcription factors or proteins with nuclear functions. Members of this second group are ZONAB, Ral-A, Raf-1, PKC, symplekin, cingulin and some more. They are characterized by lacking of the PDZ domain.^[1]

Related Research Articles

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.

Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca²⁺) ions to function, hence their name. Cell-cell adhesion is mediated by extracellular cadherin domains, whereas the intracellular cytoplasmic tail associates with numerous adaptors and signaling proteins, collectively referred to as the cadherin adhesome.

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.

<span class="mw-page-title-main">ICAM-1</span> Mammalian protein found in Homo sapiens

ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.

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.

<span class="mw-page-title-main">Occludin</span> Mammalian protein found in Homo sapiens

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.

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.

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.

Multiple PDZ domain protein is a protein that in humans is encoded by the MPDZ gene.

Cingulin is a cytosolic protein encoded by the CGN gene in humans localized at tight junctions (TJs) of vertebrate epithelial and endothelial cells.

<span class="mw-page-title-main">Intestinal epithelium</span> Single-cell layer lining the intestines

The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorption, and secretion. Useful substances are absorbed into the body, and the entry of harmful substances is restricted. Secretions include mucins, and peptides.

Cell–cell interaction refers to the direct interactions between cell surfaces that play a crucial role in the development and function of multicellular organisms. These interactions allow cells to communicate with each other in response to changes in their microenvironment. This ability to send and receive signals is essential for the survival of the cell. Interactions between cells can be stable such as those made through cell junctions. These junctions are involved in the communication and organization of cells within a particular tissue. Others are transient or temporary such as those between cells of the immune system or the interactions involved in tissue inflammation. These types of intercellular interactions are distinguished from other types such as those between cells and the extracellular matrix. The loss of communication between cells can result in uncontrollable cell growth and cancer.

IgSF CAMs are cell adhesion molecules that belong to Immunoglobulin superfamily. It is regarded as the most diverse superfamily of CAMs. This family is characterized by their extracellular domains containing Ig-like domains. The Ig domains are then followed by Fibronectin type III domain repeats and IgSFs are anchored to the membrane by a GPI moiety. This family is involved in both homophilic or heterophilic binding and has the ability to bind integrins or different IgSF CAMs.

The internal surface of the uterus is lined by uterine epithelial cells which undergo dramatic changes during pregnancy. The role of the uterine epithelial cells is to selectively allow the blastocyst to implant at a specific time. All other times of the cycle, these uterine epithelial cells are refractory to blastocyst implantation. Uterine epithelial cells have a similar structure in most species and the changes which occur in the uterine epithelial cells at the time of blastocyst implantation are also conserved among most species.

A junctional adhesion molecule (JAM) is a protein that is a member of the immunoglobulin superfamily, and is expressed in a variety of different tissues, such as leukocytes, platelets, and epithelial and endothelial cells. They have been shown to regulate signal complex assembly on both their cytoplasmic and extracellular domains through interaction with scaffolding that contains a PDZ domain and adjacent cell's receptors, respectively. JAMs adhere to adjacent cells through interactions with integrins LFA-1 and Mac-1, which are contained in leukocyte β2 and α4β1, which is contained in β1. JAMs have many influences on leukocyte-endothelial cell interactions, which are primarily moderated by the integrins discussed above. They interact in their cytoplasmic domain with scaffold proteins that contain a PDZ domain, which are common protein interaction modules that target short amino acid sequences at the C-terminus of proteins, to form tight junctions in both epithelial and endothelial cells as polarity is gained in the cell.

References

1 2 3 4 5 6 7 8 9 10 González-Mariscal, L; Betanzos, A; Nava, P; Jaramillo, B.E (January 2003). "Tight junction proteins". Progress in Biophysics and Molecular Biology. 81 (1): 1–44. doi:10.1016/S0079-6107(02)00037-8.
↑ Balda, Maria S; Matter, Karl (August 2000). "Transmembrane proteins of tight junctions". Seminars in Cell & Developmental Biology. 11 (4): 281–289. doi:10.1006/scdb.2000.0177. PMID 10966862.
1 2 3 4 Förster, Carola (16 April 2008). "Tight junctions and the modulation of barrier function in disease". Histochemistry and Cell Biology. 130 (1): 55–70. doi:10.1007/s00418-008-0424-9. PMC 2413111 . PMID 18415116.
1 2 3 4 Chiba, Hideki; Osanai, Makoto; Murata, Masaki; Kojima, Takashi; Sawada, Norimasa (March 2008). "Transmembrane proteins of tight junctions". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1778 (3): 588–600. doi: 10.1016/j.bbamem.2007.08.017 . PMID 17916321.
↑ Schlingmann, Barbara (June 2015). "Claudins: Gatekeepers of lung epithelial function". Seminars in Cell & Developmental Biology. 42: 47–57. doi:10.1016/j.semcdb.2015.04.009. PMC 4562902 . PMID 25951797.
↑ Dorner, A. A. (1 August 2005). "Coxsackievirus-adenovirus receptor (CAR) is essential for early embryonic cardiac development". Journal of Cell Science. 118 (15): 3509–3521. doi: 10.1242/jcs.02476 . PMID 16079292.
↑ Wegmann, Frank; Ebnet, Klaus; Du Pasquier, Louis; Vestweber, Dietmar; Butz, Stefan (October 2004). "Endothelial adhesion molecule ESAM binds directly to the multidomain adaptor MAGI-1 and recruits it to cell contacts". Experimental Cell Research. 300 (1): 121–133. doi:10.1016/j.yexcr.2004.07.010. PMID 15383320.
↑ Hirabayashi, S.; Tajima, M.; Yao, I.; Nishimura, W.; Mori, H.; Hata, Y. (15 June 2003). "JAM4, a Junctional Cell Adhesion Molecule Interacting with a Tight Junction Protein, MAGI-1". Molecular and Cellular Biology. 23 (12): 4267–4282. doi:10.1128/MCB.23.12.4267-4282.2003. PMC 156145 . PMID 12773569.

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[:0-1] 1 2 3 4 5 6 7 8 9 10 González-Mariscal, L; Betanzos, A; Nava, P; Jaramillo, B.E (January 2003). "Tight junction proteins". Progress in Biophysics and Molecular Biology. 81 (1): 1–44. doi:10.1016/S0079-6107(02)00037-8.

[2] Balda, Maria S; Matter, Karl (August 2000). "Transmembrane proteins of tight junctions". Seminars in Cell & Developmental Biology. 11 (4): 281–289. doi:10.1006/scdb.2000.0177. PMID 10966862.

[:1-3] 1 2 3 4 Förster, Carola (16 April 2008). "Tight junctions and the modulation of barrier function in disease". Histochemistry and Cell Biology. 130 (1): 55–70. doi:10.1007/s00418-008-0424-9. PMC 2413111 . PMID 18415116.

[:2-4] 1 2 3 4 Chiba, Hideki; Osanai, Makoto; Murata, Masaki; Kojima, Takashi; Sawada, Norimasa (March 2008). "Transmembrane proteins of tight junctions". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1778 (3): 588–600. doi: 10.1016/j.bbamem.2007.08.017 . PMID 17916321.

[5] Schlingmann, Barbara (June 2015). "Claudins: Gatekeepers of lung epithelial function". Seminars in Cell & Developmental Biology. 42: 47–57. doi:10.1016/j.semcdb.2015.04.009. PMC 4562902 . PMID 25951797.

[6] Dorner, A. A. (1 August 2005). "Coxsackievirus-adenovirus receptor (CAR) is essential for early embryonic cardiac development". Journal of Cell Science. 118 (15): 3509–3521. doi: 10.1242/jcs.02476 . PMID 16079292.

[7] Wegmann, Frank; Ebnet, Klaus; Du Pasquier, Louis; Vestweber, Dietmar; Butz, Stefan (October 2004). "Endothelial adhesion molecule ESAM binds directly to the multidomain adaptor MAGI-1 and recruits it to cell contacts". Experimental Cell Research. 300 (1): 121–133. doi:10.1016/j.yexcr.2004.07.010. PMID 15383320.

[8] Hirabayashi, S.; Tajima, M.; Yao, I.; Nishimura, W.; Mori, H.; Hata, Y. (15 June 2003). "JAM4, a Junctional Cell Adhesion Molecule Interacting with a Tight Junction Protein, MAGI-1". Molecular and Cellular Biology. 23 (12): 4267–4282. doi:10.1128/MCB.23.12.4267-4282.2003. PMC 156145 . PMID 12773569.

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