Tissue transglutaminase

Last updated
TGM2
Tissue transglutaminase.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TGM2 , G-ALPHA-h, GNAH, HEL-S-45, TG2, TGC, TG(C), transglutaminase 2, G(h), hTG2, tTG
External IDs OMIM: 190196 MGI: 98731 HomoloGene: 3391 GeneCards: TGM2
Orthologs
SpeciesHumanMouse
Entrez

7052

21817

Ensembl

ENSG00000198959

ENSMUSG00000037820

UniProt

P21980

P21981

RefSeq (mRNA)

NM_004613
NM_198951
NM_001323316
NM_001323317
NM_001323318

Contents

NM_009373

RefSeq (protein)

NP_001310245
NP_001310246
NP_001310247
NP_004604
NP_945189

NP_033399

Location (UCSC) Chr 20: 38.13 – 38.17 Mb Chr 2: 157.96 – 157.99 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Protein-glutamine gamma-glutamyltransferase
Identifiers
EC no. 2.3.2.13
CAS no. 80146-85-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins

Tissue transglutaminase (abbreviated as tTG or TG2) is a 78-kDa, calcium-dependent enzyme (EC 2.3.2.13) of the protein-glutamine γ-glutamyltransferases family (or simply transglutaminase family). [5] [6] Like other transglutaminases, it crosslinks proteins between an ε-amino group of a lysine residue and a γ-carboxamide group of glutamine residue, creating an inter- or intramolecular bond that is highly resistant to proteolysis (protein degradation). Aside from its crosslinking function, tTG catalyzes other types of reactions including deamidation, GTP-binding/hydrolyzing, and isopeptidase activities. [7] Unlike other members of the transglutaminase family, tTG can be found both in the intracellular and the extracellular spaces of various types of tissues and is found in many different organs including the heart, the liver, and the small intestine. Intracellular tTG is abundant in the cytosol but smaller amounts can also be found in the nucleus and the mitochondria. [6] Intracellular tTG is thought to play an important role in apoptosis. [8] In the extracellular space, tTG binds to proteins of the extracellular matrix (ECM), [9] binding particularly tightly to fibronectin. [10] Extracellular tTG has been linked to cell adhesion, ECM stabilization, wound healing, receptor signaling, cellular proliferation, and cellular motility. [6]

tTG is the autoantigen in celiac disease, a lifelong illness in which the consumption of dietary gluten causes a pathological immune response resulting in the inflammation of the small intestine and subsequent villous atrophy. [11] [12] [13] It has also been implicated in the pathophysiology of many other diseases, including such as many different cancers and neurogenerative diseases. [14]

Structure

Gene

The human tTG gene is located on the 20th chromosome (20q11.2-q12).

Protein

TG2 is a multifunctional enzyme that belongs to transglutaminases which catalyze the crosslinking of proteins by epsilon-(gamma-glutamyl)lysine isopeptide bonds. [15] Similarly to other transglutaminases, tTG consists of a GTP/ GDP binding site, a catalytic domain, two beta barrel and a beta-sandwich. [16] Crystal structures of TG2 with bound GDP, GTP, or ATP have demonstrated that these forms of TG2 adopt a "closed" conformation, whereas TG2 with the active site occupied by an inhibitory gluten peptide mimic or other similar inhibitors adopts an "open" conformation. [17] [18] [19] In the open conformation the four domains of TG2 are arranged in an extended configuration, allowing for catalytic activity, whereas in the closed conformation the two C-terminal domains are folded in on the catalytic core domain which includes the residue Cys-277. [20] The N-terminal domain only shows minor structural changes between the two different conformations. [21]

Mechanism

The catalytic mechanism for crosslinking in human tTG involves the thiol group from a Cys residue in the active site of tTG. [6] The thiol group attacks the carboxamide of a glutamine residue on the surface of a protein or peptide substrate, releasing ammonia, and producing a thioester intermediate. The thioester intermediate can then be attacked by the surface amine of a second substrate (typically from a lysine residue). The end product of the reaction is a stable isopeptide bond between the two substrates (i.e. crosslinking). Alternatively, the thioester intermediate can be hydrolyzed, resulting in the net conversion of the glutamine residue to glutamic acid (i.e. deamidation). [6] The deamidation of glutamine residues catalyzed by tTG is thought to be linked to the pathological immune response to gluten in celiac disease. [12] A schematic for the crosslinking and the deamidation reactions is provided in Figure 1.

Figure 1: Transamidation (crosslinking) and deamidation mechanisms of tissue transglutaminase Transamidation and deamidation mechanisms of tissue transglutaminase.jpg
Figure 1: Transamidation (crosslinking) and deamidation mechanisms of tissue transglutaminase

Regulation

The expression of tTG is regulated at the transcriptional level depending on complex signal cascades. Once synthesized, most of the protein is found in the cytoplasm, plasma membrane and ECM, but a small fraction is translocated to the nucleus, where it participates in the control of its own expression through the regulation of transcription factors. [22]

Crosslinking activity by tTG requires the binding of Ca2+ ions. [23] Multiple Ca2+ can bind to a single tTG molecule. [6] Specifically, tTG binds up to 6 calcium ions at 5 different binding sites. Mutations to these binding sites causing lower calcium affinity, decrease the enzyme's transglutaminase activity. [14] In contrast, the binding of one molecule of GTP or GDP inhibits the crosslinking activity of the enzyme. [23] Therefore, intracellular tTG is mostly inactive due to the relatively high concentration of GTP/GDP and the low levels of calcium inside the cell. [6] [12] Although extracellular tTG is expected to be active due to the low concentration of guanine nucleotides and the high levels of calcium in the extracellular space, evidence has shown that extracellular tTG is mostly inactive. [6] [12] [23] Recent studies suggest that extracellular tTG is kept inactive by the formation of a disulfide bond between two vicinal cysteine residues, namely Cys 370 and Cys 371. [24] When this disulfide bond forms, the enzyme remains in an open confirmation but becomes catalytically inactive. [24] The, oxidation/reduction of the disulfide bond serves as a third allosteric regulatory mechanism (along with GTP/GDP and Ca2+) for the activation of tTG. [12] Thioredoxin-1 has been shown to activate extracellular tTG by reducing the disulfide bond. [23] Another disuplhide bond can form in tTG, between the residues Cys-230 and Cys-370. While this bond does not exist in the enzyme's native state, it appears when the enzyme is inactivated via oxidation. [20] The presence of calcium protects against the formation of both disulfide bonds, thus making the enzyme more resistant to oxidation. [20]

Figure 2: Cystein residues relevant in tTG activity. The disulfide bond between Cys 370 and Cys 371 has formed, therefore the enzyme is in an active conformation. The distance between Cys 370 and Cys 230 is 11.3 A. Cys 277 is the cystein located within the active site of the enzyme. 4cysresi.png
Figure 2: Cystein residues relevant in tTG activity. The disulfide bond between Cys 370 and Cys 371 has formed, therefore the enzyme is in an active conformation. The distance between Cys 370 and Cys 230 is 11.3 Å. Cys 277 is the cystein located within the active site of the enzyme.

Recent studies have suggested that interferon-γ may serve as an activator of extracellular tTG in the small intestine; these studies have a direct implication to the pathogenesis of celiac disease. [12] Activation of tTG has been shown to be accompanied by large conformational changes, switching from a compact (inactive) to an extended (active) conformation. (see Figure 3) [23] [25] [26]

Figure 3: Compact (inactive) and extended (active) conformations of tTG Closed and open conformations of tTG.jpg
Figure 3: Compact (inactive) and extended (active) conformations of tTG

In the extracellular matrix, TG2 is "turned off", due primarily to the oxidizing activity of endoplasmic reticulum protein 57 (ERp57). [24] Thus, tTG is allosterically regulated by two separate proteins, Erp57 and TRX-1. [24] (See Figure 4).

Figure 4: The proteins that allosterically regulate tTG. On the left Erp57 which oxidizes tTG and on the right TRX-1 which reduces tTG. Erp57 TRX1.png
Figure 4: The proteins that allosterically regulate tTG. On the left Erp57 which oxidizes tTG and on the right TRX-1 which reduces tTG.

Function

tTG is expressed ubiquitously and is present in various cellular compartments, such as the cytosol, the nucleus, and the plasma membrane. [14] It requires calcium as a cofactor for transamidation activity. Transcription is increased by retinoic acid. Among its many supposed functions, it appears to play a role in wound healing, apoptosis, and extracellular matrix development [11] as well as differentiation and cell adhesion. [14] It has been noted that tTG may have very different activity in different cell types. For example, in neurons, tTG supports the survival of cells subjected to injury whereas in astrocytes knocking out the gene expression for tTG is beneficial to cell survival. [27]

tTG is thought to be involved in the regulation of the cytoskeleton by crosslinking various cytoskeletal proteins including myosin, actin, and spectrin. [28] Evidence shows that intracellular tTG crosslinks itself to myosin. It is also believed that tTG may stabilize the structure of the dying cells during apoptosis by polymerizing the components of the cytoskeleton, therefore preventing the leakage of the cellular contents into the extracellular space. [7]

tTG also has GTPase activity: [5] In the presence of GTP, it suggested to function as a G protein participating in signaling processes. [29] Besides its transglutaminase activity, tTG is proposed to also act as kinase, [30] and protein disulfide isomerase, [31] and deamidase. [32] This latter activity is important in the deamidation of gliadin peptides, thus playing important role in the pathology of coeliac disease.

tTG also presents PDI (Protein Disulfide Isomerase) activity. [33] [34] Based on its PDI activity, tTG plays an important role in the regulation of proteostasis, by catalyzing the trimerization of HSF1 (Heat Shock Factor 1) and thus the body's response to heat shock. In the absence of tTG, the response to heat shock is impaired since the necessary trimer is not formed. [34]

Clinical significance

tTG is the most comprehensively studied transglutaminase and has been associated with many diseases. However, none of these diseases are related to an enzyme deficiency. Indeed, thus far no disease has been attributed to the lack of tTG activity and this has been attested through the study of tTG knockout mice. [35]

Celiac Disease

tTG is best known for its link with celiac disease. [13] It was first associated with celiac disease in 1997 when the enzyme was found to be the antigen recognized by the antibodies specific to celiac. [35] Anti-transglutaminase antibodies result in a form of gluten sensitivity in which a cellular response to Triticeae glutens that are crosslinked to tTG are able to stimulate transglutaminase specific B-cell responses that eventually result in the production of anti-transglutaminase antibodies IgA and IgG. [36] [37] tTG specifically deamidates the glutamine residues creating epitopes that increase the binding affinity of the gluten peptide to the antigen presenting T cells, initiating an adaptive immune response. [35]

Cancer

Recent studies suggest that tTG also plays a role in inflammation and tumor biology. [11] tTG expression is elevated in multiple cancer cell types and is implicated in drug resistance and metastasis due to its ability to promote mesenchymal transition and stem cell like properties. In its GTP bound form, tTG contributes to cancer cell survival and appears to be a cancer driver. tTG is upregulated in cancer cells and tissues in many cancer types, including leukemia, breast cancer, prostate cancer, pancreatic cancer and cervical cancer. Higher tTG expression also correlates with higher instances of metastasis, chemotherapy resistance, lower survival rates and generally poor prognosis.  Cancer cells can be killed by increasing calcium levels through the activation of tTG transamidation activity. Preclinical trials have showed promise in using tTG inhibitors as anti-cancer therapeutic agents. [38] However, other studies [33] have noted that tTG transamidation activity could be linked to the inhibition of tumor cell invasiveness.

Other Diseases

tTG is believed to contribute to several neurodegenerative disorders including Alzheimer, Parkinson and Huntington diseases by affecting transcription, differentiation and migration and adhesion . [39] [40] Such neurological diseases are characterized in part by the abnormal aggregation of proteins due to the increased activity of protein crosslinking in the affected brain. [41] Additionally, specific proteins associated with these disorders have been found to be in vivo and in vitro substrates of tTG. [7] Although tTG is up regulated in the areas of the brain affected by Huntington's disease, a recent study showed that increasing levels of tTG do not affect the onset and/or progression of the disease in mice. [42] Recent studies show that tTG may not be involved in AD as studies show it is associated with erythrocyte lysis and is a consequence of the disease rather than a cause.

tTG has also been linked to the pathogenesis of fibrosis in various organs including the lung and the kidney. Specifically, in kidney fibrosis, tTG contributes to the stabilization and accumulation of the ECM affecting TGF beta activity. [16]

Diagnostic

Serology for anti-tTG antibodies has superseded older serological tests (anti-endomysium, anti-gliadin, and anti-reticulin) and has a strong sensitivity (99%) and specificity (>90%) for identifying celiac disease. Modern anti-tTG assays rely on a human recombinant protein as an antigen. [43]

Therapeutic

It's still experimental to use tTG as a form of surgical glue. It is also being studied as an attenuator of metastasis in certain tumors. [11] tTG shows promise as a potential therapeutic target to treat cardiac fibrosis, through the activity of a highly selective tTG inhibitor. [44] tTG inhibitors have also been shown to inhibit the formation of toxic inclusions related to neurodegenerative diseases. [45] This indicates that tTG inhibitors could also serve as a tool to mitigate the progression of tTG brain related diseases. [45]

Interactions

TG2 participates in both enzymatic and non-enzymatic interactions. Enzymatic interactions are formed between TG2 and its substrate proteins containing the glutamine donor and lysine donor groups in the presence of calcium. Substrates of TG2 are known to affect TG2 activity, which enables it to subsequently execute diverse biological functions in the cell. However, the importance of non-enzymatic interactions in regulating TG2 activities is yet to be revealed. Recent studies indicate that non-enzymatic interactions play physiological roles and enable diverse TG2 functions in a context-specific manner. [46]

Mouse Mutant Alleles for Tgm2
Marker Symbol for Mouse Gene. This symbol is assigned to the genomic locus by the MGI Tgm2
Mutant Mouse Embryonic Stem Cell Clones. These are the known targeted mutations for this gene in a mouse. Tgm2tm1a(KOMP)Wtsi
Example structure of targeted conditional mutant allele for this gene
Tgm2 tm1a(KOMP)Wtsi.jpg
These Mutant ES Cells can be studied directly or used to generate mice with this gene knocked out. Study of these mice can shed light on the function of Tgm2: see Knockout mouse

Erp57

Endoplasmic reticulum protein 57 (Erp57), is a chaperone molecule involved in loading peptide onto MHC class I molecules in the endoplasmic reticulum.

Transglutaminase 2 (TG2) is a ubiquitously expressed (intracellular as well as extracellular) protein, with multiple modes of Post-translational regulation, including an allosteric disulfide bond between Cys-370-Cys-371 that renders the enzyme inactive in the extracellular matrix. [24]

Endoplasmic reticulum (ER)-resident protein 57 (ERp57), a protein in the ER that promotes folding of nascent proteins and is also present in the extracellular environment, has the cellular and biochemical characteristics for inactivating TG2. We found that ERp57 colocalizes with extracellular TG2 in cultured human umbilical vein endothelial cells (HUVECs). ERp57 oxidized TG2 with a rate constant that was 400-2000-fold higher than those of the aforementioned small molecule oxidants. Moreover, its specificity for TG2 was also markedly higher than those of other secreted redox proteins, including protein disulfide isomerase (PDI), ERp72, TRX, and quiescin sulfhydryl oxidase 1 (QSOX1).

Related Research Articles

<span class="mw-page-title-main">G protein-coupled receptor</span> Class of cell surface receptors coupled to G-protein-associated intracellular signaling

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in form of six loops of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.

<span class="mw-page-title-main">Signal transduction</span> Cascade of intracellular and molecular events for transmission/amplification of signals

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Most commonly, protein phosphorylation is catalyzed by protein kinases, ultimately resulting in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.

<span class="mw-page-title-main">Allosteric regulation</span> Regulation of enzyme activity

In biochemistry, allosteric regulation is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.

<span class="mw-page-title-main">Proteoglycan</span> Class of compounds

Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge. The Ser residue is generally in the sequence -Ser-Gly-X-Gly-, although not every protein with this sequence has an attached glycosaminoglycan. The chains are long, linear carbohydrate polymers that are negatively charged under physiological conditions due to the occurrence of sulfate and uronic acid groups. Proteoglycans occur in connective tissue.

<span class="mw-page-title-main">Transglutaminase</span> Class of enzymes capable of forming isopeptide bonds in certain regions of proteins

Transglutaminases are enzymes that in nature primarily catalyze the formation of an isopeptide bond between γ-carboxamide groups ( -(C=O)NH2 ) of glutamine residue side chains and the ε-amino groups ( -NH2 ) of lysine residue side chains with subsequent release of ammonia ( NH3 ). Lysine and glutamine residues must be bound to a peptide or a protein so that this cross-linking (between separate molecules) or intramolecular (within the same molecule) reaction can happen. Bonds formed by transglutaminase exhibit high resistance to proteolytic degradation (proteolysis). The reaction is

<span class="mw-page-title-main">Epidermal growth factor</span> Protein that stimulates cell division and differentiation

Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-kDa and has 53 amino acid residues and three intramolecular disulfide bonds.

<span class="mw-page-title-main">Urokinase</span> Human protein

Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.

Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. Second messengers trigger physiological changes at cellular level such as proliferation, differentiation, migration, survival, apoptosis and depolarization.

<span class="mw-page-title-main">Hemagglutinin esterase</span> Glycoprotein present in some enveloped viruses

Hemagglutinin esterase (HEs) is a glycoprotein that certain enveloped viruses possess and use as an invading mechanism. HEs helps in the attachment and destruction of certain sialic acid receptors that are found on the host cell surface. Viruses that possess HEs include influenza C virus, toroviruses, and coronaviruses of the subgenus Embecovirus. HEs is a dimer transmembrane protein consisting of two monomers, each monomer is made of three domains. The three domains are: membrane fusion, esterase, and receptor binding domains.

The formyl peptide receptors (FPR) belong to a class of G protein-coupled receptors involved in chemotaxis. In humans, there are three formyl peptide receptor isoforms, each encoded by a separate gene that are named FPR1, FPR2, and FPR3. These receptors were originally identified by their ability to bind N-formyl peptides such as N-formylmethionine produced by the degradation of either bacterial or host cells. Hence formyl peptide receptors are involved in mediating immune cell response to infection. These receptors may also act to suppress the immune system under certain conditions. The close phylogenetic relation of signaling in chemotaxis and olfaction was recently proved by detection formyl peptide receptor like proteins as a distinct family of vomeronasal organ chemosensors in mice.

<span class="mw-page-title-main">PDIA3</span> Protein-coding gene in the species Homo sapiens

Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) to modulate folding of newly synthesized glycoproteins. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates.

Anti-transglutaminase antibodies (ATA) are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substances can be foreign and also can be produced by the body. Antibodies against the body's own products are called autoantibodies. Autoantibodies can sometimes errantly be directed against healthy portions of the organism, causing autoimmune diseases.

<span class="mw-page-title-main">MMP7</span> Protein-coding gene in humans

Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene. The enzyme has also been known as matrin, putative metalloproteinase-1, matrix metalloproteinase pump 1, PUMP-1 proteinase, PUMP, metalloproteinase pump-1, putative metalloproteinase, MMP). Human MMP-7 has a molecular weight around 30 kDa.

<span class="mw-page-title-main">EGF-like domain</span> Protein domain named after the epidermal growth factor protein

The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostly animal proteins. Most occurrences of the EGF-like domain are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. An exception to this is the prostaglandin-endoperoxide synthase. The EGF-like domain includes 6 cysteine residues which in the epidermal growth factor have been shown to form 3 disulfide bonds. The structures of 4-disulfide EGF-domains have been solved from the laminin and integrin proteins. The main structure of EGF-like domains is a two-stranded β-sheet followed by a loop to a short C-terminal, two-stranded β-sheet. These two β-sheets are usually denoted as the major (N-terminal) and minor (C-terminal) sheets. EGF-like domains frequently occur in numerous tandem copies in proteins: these repeats typically fold together to form a single, linear solenoid domain block as a functional unit.

<span class="mw-page-title-main">Cathepsin D</span> Protein-coding gene in the species Homo sapiens

Cathepsin D is a protein that in humans is encoded by the CTSD gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathepsin D is an aspartic endo-protease that is ubiquitously distributed in lysosomes. The main function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre-lysosomal compartments. This proteinase, which is a member of the peptidase A1 family, has a specificity similar to but narrower than that of pepsin A. Transcription of the CTSD gene is initiated from several sites, including one that is a start site for an estrogen-regulated transcript. Mutations in this gene are involved in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer disease. Homozygous deletion of the CTSD gene leads to early lethality in the postnatal phase. Deficiency of CTSD gene has been reported an underlying cause of neuronal ceroid lipofuscinosis (NCL).

<span class="mw-page-title-main">PRKCH</span> Protein-coding gene in the species Homo sapiens

Protein kinase C eta type is an enzyme that in humans is encoded by the PRKCH gene.

<span class="mw-page-title-main">Involucrin</span> Protein-coding gene in the species Homo sapiens

Involucrin is a protein component of human skin and in humans is encoded by the IVL gene. In binding the protein loricrin, involucrin contributes to the formation of a cell envelope that protects corneocytes in the skin.

The immunochemistry of Triticeae glutens is important in several inflammatory diseases. It can be subdivided into innate responses, class II mediated presentation, class I mediated stimulation of killer cells, and antibody recognition. The responses to gluten proteins and polypeptide regions differs according to the type of gluten sensitivity. The response is also dependent on the genetic makeup of the human leukocyte antigen genes. In gluten sensitive enteropathy, there are four types of recognition, innate immunity, HLA-DQ, and antibody recognition of gliadin and transglutaminase. With idiopathic gluten sensitivity only antibody recognition to gliadin has been resolved. In wheat allergy, the response pathways are mediated through IgE against other wheat proteins and other forms of gliadin.

<span class="mw-page-title-main">Cell surface receptor</span> Class of ligand activated receptors localized in surface of plama cell membrane

Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.

Ludvig M. Sollid is a Norwegian physician-scientist whose laboratory has made discoveries in the pathogenesis of HLA associated human disorders, most notably celiac disease. He is currently a Professor of Medicine (immunology) at the University of Oslo and a Senior Consultant at Oslo University Hospital.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000198959 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000037820 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Király R, Demény M, Fésüs L (December 2011). "Protein transamidation by transglutaminase 2 in cells: a disputed Ca2+-dependent action of a multifunctional protein". The FEBS Journal. 278 (24): 4717–39. doi: 10.1111/j.1742-4658.2011.08345.x . PMID   21902809. S2CID   19217277.
  6. 1 2 3 4 5 6 7 8 Klöck C, Diraimondo TR, Khosla C (July 2012). "Role of transglutaminase 2 in celiac disease pathogenesis". Seminars in Immunopathology. 34 (4): 513–22. doi:10.1007/s00281-012-0305-0. PMC   3712867 . PMID   22437759.
  7. 1 2 3 Facchiano F, Facchiano A, Facchiano AM (May 2006). "The role of transglutaminase-2 and its substrates in human diseases". Frontiers in Bioscience. 11: 1758–73. doi: 10.2741/1921 . PMID   16368554.
  8. ↑ McConkey DJ, Orrenius S (October 1997). "The role of calcium in the regulation of apoptosis". Biochemical and Biophysical Research Communications. 239 (2): 357–66. CiteSeerX   10.1.1.483.2738 . doi:10.1006/bbrc.1997.7409. PMID   9344835. S2CID   11242870.
  9. ↑ Lortat-Jacob H, Burhan I, Scarpellini A, Thomas A, Imberty A, Vivès RR, Johnson T, Gutierrez A, Verderio EA (May 2012). "Transglutaminase-2 interaction with heparin: identification of a heparin binding site that regulates cell adhesion to fibronectin-transglutaminase-2 matrix". The Journal of Biological Chemistry. 287 (22): 18005–17. doi: 10.1074/jbc.M111.337089 . PMC   3365763 . PMID   22442151.
  10. ↑ Akimov SS, Krylov D, Fleischman LF, Belkin AM (February 2000). "Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin". The Journal of Cell Biology. 148 (4): 825–38. doi:10.1083/jcb.148.4.825. PMC   2169362 . PMID   10684262.
  11. 1 2 3 4 Griffin M, Casadio R, Bergamini CM (December 2002). "Transglutaminases: nature's biological glues". The Biochemical Journal. 368 (Pt 2): 377–96. doi:10.1042/BJ20021234. PMC   1223021 . PMID   12366374.
  12. 1 2 3 4 5 6 Diraimondo TR, Klöck C, Khosla C (April 2012). "Interferon-γ activates transglutaminase 2 via a phosphatidylinositol-3-kinase-dependent pathway: implications for celiac sprue therapy". The Journal of Pharmacology and Experimental Therapeutics. 341 (1): 104–14. doi:10.1124/jpet.111.187385. PMC   3310700 . PMID   22228808.
  13. 1 2 Di Sabatino A, Vanoli A, Giuffrida P, Luinetti O, Solcia E, Corazza GR (August 2012). "The function of tissue transglutaminase in celiac disease". Autoimmunity Reviews. 11 (10): 746–53. doi:10.1016/j.autrev.2012.01.007. PMID   22326684.
  14. 1 2 3 4 Király R, Csosz E, Kurtán T, Antus S, Szigeti K, Simon-Vecsei Z, Korponay-Szabó IR, Keresztessy Z, Fésüs L (December 2009). "Functional significance of five noncanonical Ca2+-binding sites of human transglutaminase 2 characterized by site-directed mutagenesis". The FEBS Journal. 276 (23): 7083–96. doi: 10.1111/j.1742-4658.2009.07420.x . PMID   19878304. S2CID   21883387.
  15. ↑ "Entrez Gene: TGM2 transglutaminase 2".
  16. 1 2 Hitomi K, Kojima S, Fesus L (2015). Transglutaminases : multiple functional modifiers and targets for new drug discovery. Tokyo. ISBN   9784431558255. OCLC   937392418.
  17. ↑ Pinkas DM, Strop P, Brunger AT, Khosla C (December 2007). "Transglutaminase 2 undergoes a large conformational change upon activation". PLOS Biology. 5 (12): e327. doi:10.1371/journal.pbio.0050327. PMC   2140088 . PMID   18092889.
  18. ↑ Liu S, Cerione RA, Clardy J (March 2002). "Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity". Proceedings of the National Academy of Sciences of the United States of America. 99 (5): 2743–7. Bibcode:2002PNAS...99.2743L. doi: 10.1073/pnas.042454899 . PMC   122418 . PMID   11867708.
  19. ↑ Han BG, Cho JW, Cho YD, Jeong KC, Kim SY, Lee BI (August 2010). "Crystal structure of human transglutaminase 2 in complex with adenosine triphosphate". International Journal of Biological Macromolecules. 47 (2): 190–5. doi:10.1016/j.ijbiomac.2010.04.023. PMID   20450932.
  20. 1 2 3 Stamnaes J, Pinkas DM, Fleckenstein B, Khosla C, Sollid LM (August 2010). "Redox regulation of transglutaminase 2 activity". The Journal of Biological Chemistry. 285 (33): 25402–9. doi: 10.1074/jbc.M109.097162 . PMC   2919103 . PMID   20547769.
  21. ↑ Chen X, Hnida K, Graewert MA, Andersen JT, Iversen R, Tuukkanen A, Svergun D, Sollid LM (August 2015). "Structural Basis for Antigen Recognition by Transglutaminase 2-specific Autoantibodies in Celiac Disease". The Journal of Biological Chemistry. 290 (35): 21365–75. doi: 10.1074/jbc.M115.669895 . PMC   4571865 . PMID   26160175.
  22. ↑ Bianchi N, Beninati S, Bergamini CM (May 2018). "Spotlight on the transglutaminase 2 gene: a focus on genomic and transcriptional aspects" (PDF). The Biochemical Journal. 475 (9): 1643–1667. doi:10.1042/BCJ20170601. hdl:11392/2388638. PMID   29764956.
  23. 1 2 3 4 5 Jin X, Stamnaes J, Klöck C, DiRaimondo TR, Sollid LM, Khosla C (October 2011). "Activation of extracellular transglutaminase 2 by thioredoxin". The Journal of Biological Chemistry. 286 (43): 37866–73. doi: 10.1074/jbc.M111.287490 . PMC   3199528 . PMID   21908620.
  24. 1 2 3 4 5 Yi MC, Melkonian AV, Ousey JA, Khosla C (February 2018). "Endoplasmic reticulum-resident protein 57 (ERp57) oxidatively inactivates human transglutaminase 2". The Journal of Biological Chemistry. 293 (8): 2640–2649. doi: 10.1074/jbc.RA117.001382 . PMC   5827427 . PMID   29305423.
  25. ↑ Pinkas DM, Strop P, Brunger AT, Khosla C (December 2007). "Transglutaminase 2 undergoes a large conformational change upon activation". PLOS Biology. 5 (12): e327. doi:10.1371/journal.pbio.0050327. PMC   2140088 . PMID   18092889.
  26. ↑ Colak G, Keillor JW, Johnson GV (January 2011). Polymenis M (ed.). "Cytosolic guanine nucledotide binding deficient form of transglutaminase 2 (R580a) potentiates cell death in oxygen glucose deprivation". PLOS ONE. 6 (1): e16665. Bibcode:2011PLoSO...616665C. doi: 10.1371/journal.pone.0016665 . PMC   3031627 . PMID   21304968.
  27. ↑ Quinn BR, Yunes-Medina L, Johnson GV (July 2018). "Transglutaminase 2: Friend or foe? The discordant role in neurons and astrocytes". Journal of Neuroscience Research. 96 (7): 1150–1158. doi:10.1002/jnr.24239. PMC   5980740 . PMID   29570839.
  28. ↑ Nurminskaya MV, Belkin AM (2012). Cellular functions of tissue transglutaminase. International Review of Cell and Molecular Biology. Vol. 294. pp. 1–97. doi:10.1016/B978-0-12-394305-7.00001-X. ISBN   9780123943057. PMC   3746560 . PMID   22364871.
  29. ↑ Fesus L, Piacentini M (October 2002). "Transglutaminase 2: an enigmatic enzyme with diverse functions". Trends in Biochemical Sciences. 27 (10): 534–9. doi:10.1016/S0968-0004(02)02182-5. PMID   12368090.
  30. ↑ Mishra S, Murphy LJ (June 2004). "Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase". The Journal of Biological Chemistry. 279 (23): 23863–8. doi: 10.1074/jbc.M311919200 . PMID   15069073.
  31. ↑ Hasegawa G, Suwa M, Ichikawa Y, Ohtsuka T, Kumagai S, Kikuchi M, Sato Y, Saito Y (August 2003). "A novel function of tissue-type transglutaminase: protein disulphide isomerase". The Biochemical Journal. 373 (Pt 3): 793–803. doi:10.1042/BJ20021084. PMC   1223550 . PMID   12737632.
  32. ↑ Sakly W, Thomas V, Quash G, El Alaoui S (December 2006). "A role for tissue transglutaminase in alpha-gliadin peptide cytotoxicity". Clinical and Experimental Immunology. 146 (3): 550–8. doi:10.1111/j.1365-2249.2006.03236.x. PMC   1810403 . PMID   17100777.
  33. 1 2 Tabolacci C, De Martino A, Mischiati C, Feriotto G, Beninati S (January 2019). "The Role of Tissue Transglutaminase in Cancer Cell Initiation, Survival and Progression". Medical Sciences. 7 (2): 19. doi: 10.3390/medsci7020019 . PMC   6409630 . PMID   30691081.
  34. 1 2 Rossin F, Villella VR, D'Eletto M, Farrace MG, Esposito S, Ferrari E, Monzani R, Occhigrossi L, Pagliarini V, Sette C, Cozza G, Barlev NA, Falasca L, Fimia GM, Kroemer G, Raia V, Maiuri L, Piacentini M (July 2018). "TG2 regulates the heat-shock response by the post-translational modification of HSF1". EMBO Reports. 19 (7): e45067. doi:10.15252/embr.201745067. PMC   6030705 . PMID   29752334.
  35. 1 2 3 Lorand L, Iismaa SE (January 2019). "Transglutaminase diseases: from biochemistry to the bedside". FASEB Journal. 33 (1): 3–12. doi: 10.1096/fj.201801544R . PMID   30593123. S2CID   58551851.
  36. ↑ Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D (July 1997). "Identification of tissue transglutaminase as the autoantigen of celiac disease". Nature Medicine. 3 (7): 797–801. doi:10.1038/nm0797-797. PMID   9212111. S2CID   20033968.
  37. ↑ Murray JA, Frey MR, Oliva-Hemker M (June 2018). "Celiac Disease". Gastroenterology. 154 (8): 2005–2008. doi:10.1053/j.gastro.2017.12.026. PMC   6203336 . PMID   29550590.
  38. ↑ Eckert, Richard L. (2019-01-29). "Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target: Transglutaminase in cancer". Molecular Carcinogenesis. 58 (6): 837–853. doi:10.1002/mc.22986. PMC   7754084 . PMID   30693974. S2CID   59341070.
  39. ↑ Wilhelmus MM, Verhaar R, Andringa G, Bol JG, Cras P, Shan L, Hoozemans JJ, Drukarch B (March 2011). "Presence of tissue transglutaminase in granular endoplasmic reticulum is characteristic of melanized neurons in Parkinson's disease brain". Brain Pathology. 21 (2): 130–9. doi:10.1111/j.1750-3639.2010.00429.x. PMC   8094245 . PMID   20731657. S2CID   586174.
  40. ↑ Ricotta M, Iannuzzi M, Vivo GD, Gentile V (May 2010). "Physio-pathological roles of transglutaminase-catalyzed reactions". World Journal of Biological Chemistry. 1 (5): 181–7. doi:10.4331/wjbc.v1.i5.181. PMC   3083958 . PMID   21541002.
  41. ↑ Martin A, Giuliano A, Collaro D, De Vivo G, Sedia C, Serretiello E, Gentile V (January 2013). "Possible involvement of transglutaminase-catalyzed reactions in the physiopathology of neurodegenerative diseases". Amino Acids. 44 (1): 111–8. doi:10.1007/s00726-011-1081-1. PMID   21938398. S2CID   16143202.
  42. ↑ Kumar A, Kneynsberg A, Tucholski J, Perry G, van Groen T, Detloff PJ, Lesort M (September 2012). "Tissue transglutaminase overexpression does not modify the disease phenotype of the R6/2 mouse model of Huntington's disease". Experimental Neurology. 237 (1): 78–89. doi:10.1016/j.expneurol.2012.05.015. PMC   3418489 . PMID   22698685.
  43. ↑ Sblattero D, Berti I, Trevisiol C, Marzari R, Tommasini A, Bradbury A, Fasano A, Ventura A, Not T (May 2000). "Human recombinant tissue transglutaminase ELISA: an innovative diagnostic assay for celiac disease". The American Journal of Gastroenterology. 95 (5): 1253–7. doi:10.1111/j.1572-0241.2000.02018.x. PMID   10811336. S2CID   11018740.
  44. ↑ Wang Z, Stuckey DJ, Murdoch CE, Camelliti P, Lip GY, Griffin M (April 2018). "Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor". Cell Death & Disease. 9 (6): 613. doi:10.1038/s41419-018-0573-2. PMC   5966415 . PMID   29795262.
  45. 1 2 Min B, Chung KC (January 2018). "New insight into transglutaminase 2 and link to neurodegenerative diseases". BMB Reports. 51 (1): 5–13. doi:10.5483/BMBRep.2018.51.1.227. PMC   5796628 . PMID   29187283.
  46. ↑ Kanchan K, Fuxreiter M, Fésüs L (August 2015). "Physiological, pathological, and structural implications of non-enzymatic protein-protein interactions of the multifunctional human transglutaminase 2". Cellular and Molecular Life Sciences. 72 (16): 3009–35. doi:10.1007/s00018-015-1909-z. PMID   25943306. S2CID   14849506.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.