Tight junction proteins (TJ proteins) are molecules situated at the

tight junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...

s of

epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...

endothelial The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...

and

myelinated Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

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 The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

. 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 Osmoregulation is the active regulation of the osmotic pressure of an organism's body fluids, detected by osmoreceptors, to maintain the homeostasis of the organism's water content; that is, it maintains the fluid balance and the concentration of ...

and trans-cellular transport of tissue specific molecules. Nowadays is known more than 40 different proteins, that are involved in these selective TJ channels.

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 A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

, that interact with the

actin Actin is a protein family, family of Globular protein, globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in myofibril, muscle fibrils. It is found in essentially all Eukaryote, eukaryotic cel ...

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is comp ...

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 An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a ...

, which shows the individual strands of the tight junction.

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 The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain a ...

are TJ localized between a

glia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...

and an

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action ...

and within

myelin sheaths Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

, 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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

. The most important tight junction proteins are

occludin Occludin is an enzyme ( EC 1.6) that oxidizes NADH. 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 be ...

claudin Claudins are a family of proteins which, along with occludin, are the most important components of the tight junctions ( zonulae occludentes). Tight junctions establish the paracellular barrier that controls the flow of molecules in the intercel ...

and JAM family, that establish the backbone of tight junction and allow to passing of

immune cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

through the tissue.

TJ proteins in epithelia and endothelia

Proteins in epithelial and endothelial cells are occludin, claudin and

tetraspanin Tetraspanins are a family of membrane proteins found in all multicellular eukaryotes. Tetraspanins, also referred to as the transmembrane 4 superfamily (TM4SF) proteins, have four transmembrane alpha-helices and two extracellular domains, one ...

, 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 In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

. 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.

Occludin

Occludin Occludin is an enzyme ( EC 1.6) that oxidizes NADH. 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 be ...

(60kDa) was the first identified component of tight junction. The tetraspan membrane protein is established by two extracellular loops, two

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

domains and one short

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

domain. The C-terminal domain of occludin is directly bound to

ZO-1 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'' (ZO-1, ZO-2, and ZO-3), which are ti ...

, which interacts with actin filaments in cytoskeleton. It works as a

transmitter In electronics and telecommunications, a radio transmitter or just transmitter is an electronic device which produces radio waves with an antenna. The transmitter itself generates a radio frequency alternating current, which is applied to ...

from and to the tight junction, because of its association with signaling molecules ( PI3-kinase, PKC, YES, protein phosphases 2A, 1). This TJ protein also participate in a selective

diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...

of solutes along

concentration gradient Molecular diffusion, often simply called diffusion, is the thermal motion of all (liquid or gas) particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size (mass) o ...

and transmigration of

leukocytes White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mul ...

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 Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying i ...

. Occludin cooperates with members of the claudin family directly or indirectly and together they form the long strands of tight junction.

Claudin

The

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. 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-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. 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 Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

and

Sertoli cells Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-stimu ...

or Claudin 5 is expressed in the

vascular endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the v ...

. 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. Most types of claudins have more than two

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

, 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 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 indir ...

, 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 In the kidney, the loop of Henle () (or Henle's loop, Henle loop, nephron loop or its Latin counterpart ''ansa nephroni'') is the portion of a nephron that leads from the proximal convoluted tubule to the distal convoluted tubule. Named after i ...

TJ proteins in myelin sheaths

OSP/Claudin 11

OSP/ Claudin 11 is occurred in a myelin of

nerve cells A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

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 Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the t ...

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 Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory en ...

, 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.

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.

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. JAM proteins are not a part of tight junction strands but they participate in a signalization that leads to an adhesion of

monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...

and

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

and

spermatids The spermatid is the haploid male gametid that results from division of secondary spermatocytes. As a result of meiosis, each spermatid contains only half of the genetic material present in the original primary spermatocyte. Spermatids are co ...

. The second subgroup of

CAR A car or automobile is a motor vehicle with wheels. Most definitions of ''cars'' say that they run primarily on roads, seat one to eight people, have four wheels, and mainly transport people instead of goods. The year 1886 is regarded as t ...

, ESAM, CLMP and JAM4 proteins contains a PDZ-domain binding motif type I at their C-termini. CAR ( coxsackie and

adenovirus Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...

receptor) also belongs to the

immunoglobulin superfamily The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ...

, same like JAM proteins. CAR is expressed in the epithelia of

trachea The trachea, also known as the windpipe, is a cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air-breathing animals with lungs. The trachea extends from th ...

bronchi A bronchus is a passage or airway in the lower respiratory tract that conducts air into the lungs. The first or primary bronchi pronounced (BRAN-KAI) to branch from the trachea at the carina are the right main bronchus and the left main bronch ...

, 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 A myofibril (also known as a muscle fibril or sarcostyle) is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myof ...

cardiomyocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

. CAR is associated with PDZ-scaffolding proteins MAGI-1b, PICK, PSD-95, MUPP1 and LNX. 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 Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...

but not in the epithelium and

. 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. 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 ''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn". ''Glomerulus'' may refer to: * the filter ...

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.{{cite journal , last1=Hirabayashi , first1=S. , last2=Tajima , first2=M. , last3=Yao , first3=I. , last4=Nishimura , first4=W. , last5=Mori , first5=H. , last6=Hata , first6=Y. , title=JAM4, a Junctional Cell Adhesion Molecule Interacting with a Tight Junction Protein, MAGI-1 , journal=Molecular and Cellular Biology , date=15 June 2003 , volume=23 , issue=12 , pages=4267–4282 , doi=10.1128/MCB.23.12.4267-4282.2003, pmid=12773569 , pmc=156145

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.

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-2, ZO-3, AF-6,

MAGI Magi (; singular magus ; from Latin '' magus'', cf. fa, مغ ) were priests in Zoroastrianism and the earlier religions of the western Iranians. The earliest known use of the word ''magi'' is in the trilingual inscription written by Darius t ...

, 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 The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane t ...

, called cingulin, which plays a key role in the cell adhesion. The second group of plague proteins are used for a

vesicular trafficking Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory c ...

, barrier regulation and

gene transcription Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...

, 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.

References

Proteins Cell biology