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evolution
as a member of the transglutaminase family, transglutaminase 2 (TG2) can catalyze deamidation or alternatively transamidation of selected Gln residues in proteins and peptides. Redox regulation unique to TG2 and evolved relatively recently, TG2 homologues in other vertebrates appear to lack this structure feature
evolution
crayfish TGase is adapted to have significant activity at low temperatures since crayfish are living in quite cold waters
evolution
transglutaminase 2 (TG2) is a ubiquitously expressed multifunctional member of the transglutaminase enzyme family
evolution
transglutaminase is an enzyme family responsible for post-translational modification such as protein cross-linking and the attachment of primary amine and/or deamidation of glutamine-residue in proteins. The medaka orthologue of human tissue-type transglutaminase (OlTGT), identified in the established model fish, has similar functions compared to mammalian enzyme
malfunction
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transglutaminase 2 (TG2) mutations are associated with diabetes type 2. Lack of TG2 reduces glucose-stimulated insulin secretion from the pancreatic islets
malfunction
enzyme inactivation significantly reduces the virulence of Streptococcus suis serotype 2 in a pig infection model and impairs its antiphagocytosis in human blood
malfunction
double-TG1/TG2 knockout mice show epidermal features similar to TG1 knockout mice. Double-FXIII-A/TG2 knockout mice exhibit only a transient delay in bone mineral density and growth relative to wild-type mice
malfunction
effective inhibition of renal interstitial fibrosis by TG inhibitors but only partial reduction of fibrosis in TG2 knockout mice
malfunction
failure in the regulation of TG2 activities is associated with many human diseases, including inflammatory disease, celiac disease, neurodegenerative disease, diabetes, tissue fibrosis, and cancers. Comparison of wild-type with G224V mutant enzyme structrue and actives sites, overview. Since the active site cysteine (C277)-containing alpha-helix, whose location may be important for TG2 activity, is interacted with a neighboring intramolecular alpha-helix, which contains residue 224, replacement of G with V will have an effect on the transamidase activity of TG2. Decreased activity of G224 may be due to the higher chance of location shift on active site cysteine (C277) because of the loss of the hydrophobic cluster anchored by V224
malfunction
loss of TG1 and TG5 cross linking leads to defects in epidermal cornification in lamellar ichthyosis and acral peeling skin syndrome, respectively. Homozygous missense mutations in the gene encoding TG5 are found to correlate with acral peeling skin syndrome, which is characterized by continual shedding of the outer epidermis of the dorsa of the hands and feet from birth and throughout life
malfunction
loss of TG1 and TG5 cross linking leads to defects in epidermal cornification in lamellar ichthyosis and acral peeling skin syndrome, respectively. Lamellar ichthyosis is apparent at birth, with newborns encased in a shiny, waxy layer of skin (collodion babies) that sheds to reveal scaling and shedding of the outer epidermis and a severely compromised skin barrier. It is an autosomal-recessive disease, with mutations in the gene encoding TG1 accounting for about 90% of cases. Lamellar ichthyosis is an orphan disease. TG1 and TG2 are the most abundantly expressed TGs in normal kidney, and renal disease progression correlates with increases in activity of intracellular TG1 in renal tubular epithelium and of TG2 in the extracellular matrix
malfunction
loss of TG3 crosslinking in hair-cuticle formation leads to uncombable hair syndrome. A homozygous nonsense mutation of TG3 correlates with uncombable hair syndrome and the absence of TG3-mediated crosslinks between trichohyalin and keratin intermediate filaments
malfunction
loss of TG6 crosslinking leads to spinocerebellar ataxia-35
malfunction
loss of the structural erythrocyte membrane protein, protein 4.2, leads to hereditary spherocytosis type 5 associated with abnormally shaped, osmotically fragile erythrocytes
malfunction
specific tTG inhibitors, such as KCC009, can block alpha-synuclein aggregation in SH-SY5Y neuroblastoma cells
malfunction
TG1 and TG2 are the most abundantly expressed TGs in normal kidney, and renal disease progression correlates with increases in activity of intracellular TG1 in renal tubular epithelium and of TG2 in the extracellular matrix. Yet no diseases have been correlated with TG2 deficiency. TG2 deletion does not improve motor, cognitive, molecular, histologic, or lifespan phenotypes and is thus not an important factor in Huntington's disease pathology
malfunction
TG1 knockout mice show defective epidermal maturation late in embryonic development, resulting in a drastic increase in skin permeability, but unlike human patients, TG1 knockout mice die from dehydration within a few hours of birth. Double-TG1/TG2 knockout mice show epidermal features similar to TG1 knockout mice
malfunction
the removal of the pro-sequence region using proteases results in the active site of the mature enzyme to be revealed to initiate the reaction
malfunction
transglutaminase (TG) inhibitors are capable of blocking the entire osteoclastogenesis process. The most potent of the inhibitors, NC9 when added to cultures at different phases of osteoclastogenesis, inhibits differentiation, migration, and fusion of pre-osteoclasts as well as resorption activity of mature osteoclasts. NC9 increases RhoA levels and blocks podosome belt formation. The number of TRAP+ mononuclear pre-osteoclasts is significantly decreased by NC9 treatment for the first 2 days. The inhibitory effect of NC9 on osteoclastogenesis as well as podosome belt formation is completely reversed with a Rho-family inhibitor Exoenzyme C3. Microtubule architecture, acetylation, and detyrosination of alpha-tubulin are not affected
malfunction
transglutaminase (TG) inhibitors are capable of blocking the entire osteoclastogenesis process. The most potent of the inhibitors, NC9 when added to cultures at different phases of osteoclastogenesis, inhibits differentiation, migration, and fusion of pre-osteoclasts as well as resorption activity of mature osteoclasts. NC9 increases RhoA levels and blocks podosome belt formation. The number of TRAP+ mononuclear pre-osteoclasts is significantly decreased by NC9 treatment for the first 2 days. The inhibitory effect ofNC9 on osteoclastogenesis as well as podosome belt formation is completely reversed with a Rho-family inhibitor Exoenzyme C3. Microtubule architecture, acetylation, and detyrosination of alpha-tubulin are not affected
metabolism
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the enzyme activates PI3-kinase
metabolism
in general, TG-catalyzed crosslinking is the primary mechanism by which TGs promote disease progression
metabolism
regulation of human TG2, overview. Redox regulation unique to this isozyme
metabolism
transglutaminase 2 (TG2) is a ubiquitously expressed multifunctional member of the transglutaminase enzyme family. It is implicated to have roles in many physiological and pathological processes such as differentiation, apoptosis, signal transduction, adhesion and migration, wound healing and inflammation. TG2 has various intra- and extra-cellular interacting partners, which contribute to these processes. The molecular co-chaperone, DNAJA1, is an interacting partner of human isozyme TG2. DNAJA1 and TG2 are reported to regulate common pathological conditions such as neurodegenerative disorders and cancer
physiological function
complete knock-down by RNAi results in changed cell morphology, and cells start to spread intensely. After addition of astakine, a cytokine involved in hematopoiesis, cells start to spread and adopt a morphology similar to that observed after RNAi of TGase. Astakine has no effect on TGase expression, but after a prolonged incubation for one week, TGase activity inside and outside the cells is completely lost
physiological function
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hypoxia induces TG2 expression through an HIF-1 dependent pathway and concurrently activates intracellular TG2. The hypoxiccells overexpressing TG2 show resistance to apoptosis. Hypoxic cells treated with either TG2 inhibitor or small interfering RNA become sensitive to apoptosis. Activation of TG2 in response to hypoxic stress inhibits caspase-3 activity by forming crosslinked multimer, resulting in insoluble aggregates. TG2 also activates nuclear factor kappaB pathway after hypoxic stress, and thereby induces the expression of cellular inhibitor of apoptosis 2
physiological function
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inhibition of TGase activity with monodansylcadervine, or knockdown of TGase-1 with small interference RNA enhances apoptosis and decreased cell survival in hydrogen peroxide-treated renal proximal tubule cells. Overexpression of TGase-1 renders renal proximal tubule cells more resistant to hydrogen peroxide toxicity and monodansylcadaverine treatment blocks this response. Concurrent with renal proximal tubule cells apoptosis, phosphorylation of AKT, signal transducer and activator of transcription-3, and glucogen synthase kinase-3 are observed. Pretreatment of cells with monodansylcadervine or TGase-1 siRNA inhibits phosphorylation of all these molecules
physiological function
presence of bacterial lipopolysaccharide increases the level of TG2 on the surface of maturing dendritic cells
physiological function
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TG2 binds to the Rac-binding pocket in the GTPase-activating domains of regulator proteins Bcr and Abr, blocks Bcr activity and, through this mechanism, increases levels of active GTP-bound Rac and EGF-stimulated membraneruffling. Bcr exhibits preferential binding to the non-compacted conformation of TG2, in which its catalytic domain is exposed, but transamidation is not needed for the interaction
physiological function
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TG2 regulates the expression and function of matrix metalloproteinase MMP-2. TG2 knockdown down-regulates MMP-2 protein and mRNA expression in SKOV-3, IGROV-1, MDA-MB-436, and PC-3 cancer cells. TG2 knockdown or inhibition of TG2 activity using KCC009 decreases MMP-2 gelatinase activity in cancer cells. MMP-2 expression and function are regulated by TG2 at transcriptional level. Binding of CREB to the MMP-2 promoter is diminished in cells that express decreased TG2 levels. TG2 knockdown decreases CREB phosphorylation, and CREB knockdown decreases MMP-2 expression. The effect of TG2 on CREB activity and MMP-2 transcription is mediated by TG2-dependent degradation of protein phosphatase PP2A-alpha. PP2A-alpha complexes with and is targeted for degradation by TG2
physiological function
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TGase 2 has a role as a biological glue to consolidate various micro-structural components of tissues and biomaterials
physiological function
treatment of proximal renal tublule cells with inhibitor monodansylcadaverine or siRNA results in decreased proliferation accompanied by activation of signal transducer and activator of transcription, Akt and Stat-3. Treatment with monodansylcadaverine or TGase-1 siRNA decreases Stat-3 but not Akt phosphorylation. Janus-activated kinase JAK2 mediates phosphorylation of Stat-3, and knockdown of either JAK2 or Stat-3 by siRNA decreases cell proliferation. Inhibition of TGase-1 decreases phosphorylation of Stat-3 but not JAK2. JAK2 is indispensable for TGase-1 to induce Stat-3 phosphorylation and TGase-1 potentiates JAK2-induced Stat-3 phosphorylation. Inhibition of TGase-1 and the JAK2-Stat-3 signaling pathway decreases the transcriptional activity of Stat-3 and expression of the Stat-3-targeted genes, cyclin D1 and cyclin E. TGase-1 interacts with JAK2, and this interaction is inhibited by monodansylcadaverine
physiological function
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phosphorylation of transglutaminase 2 at Ser216 plays a role in transglutaminase 2-mediated activation of nuclear factor-kappaB, Akt and in the downregulation of phosphatase and tensin homologue deleted on chromosome 10
physiological function
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phosphorylation of transglutaminase 2 at Ser216 plays a role in transglutaminase 2-mediated activation of nuclear factor-kappaB, Akt and in the downregulation of phosphatase and tensin homologue deleted on chromosome 10
physiological function
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the enzyme is involved in the apical growth of apple pollen tube
physiological function
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the enzyme reduces the pore diameter and inhibits the activity of transient receptor potential vanilloid 5 in an N-glycosylation-dependent manner
physiological function
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tissue transglutaminase activity protects from cutaneous melanoma metastatic dissemination. The number of melanoma lung foci is more markedly reduced by enzyme overexpression than the metastatic size
physiological function
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tissue transglutaminase activity protects from cutaneous melanoma metastatic dissemination. The number of melanoma lung foci is more markedly reduced by enzyme overexpression than the metastatic size
physiological function
major and functional transglutaminas of Macrobrachium rosenbergii for haemolymph coagulation and also in spread of infection
physiological function
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the enzyme has an intrinsic capability to promote cell survival and contributes to oncogenesis
physiological function
the enzyme is a virulence factor in Streptococcus suis serotype 2 with antiphagocytic activity
physiological function
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the enzyme is associated with amyloid-beta deposits and lesion-associated astrocytes in Alzheimer's disease
physiological function
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transglutaminase 2 is involved in homocysteine-induced activation of human THP-1 monocytes
physiological function
DNAJA1 interacts with the open form of TG2 and regulates its transamidation activity under both in vitro and in situ conditions. DNAJA1 and TG2 are reported to regulate common pathological conditions such as neurodegenerative disorders and cancer, molecular mechanisms, overview
physiological function
enzyme transglutaminase 2 (TG2) catalyzes deamidation or alternatively transamidation of selected Gln residues in proteins and peptides. As TG2 is natively inactive, TRX is able to reduce the vicinal disulfide bond between C370-C371 to activate TG2, and ERp57 can oxidize the disulfide between C230 and C370 to catalytically inactivate the enzyme. Redox regulation of human TG2, overview. The 220 kDa fibronectin monomer harbors multiple Gln residues susceptible to TG2 modification, including sites within its N-terminal collagen/fibrinbinding domain, its central (RGD-containing) integrin-binding domain, and its C-terminal glycosaminoglycan-binding domain. In addition, its N-terminal domain also harbors a high-affinity non-covalent docking site for TG2. Remarkably, the biogenic amine serotonin can serve as an effective nucleophile in TG2-catalyzed modification of fibronectin; this post-translational modification of fibronectin appears to be a biomarker of pulmonary hypertension in humans as well as cellular and animal models of the disease. Like fibronectin, a number of other proteins comprising the extracellular matrix have been shown to harbor TG2-reactive sites. Amongst these, TG2-catalyzed crosslinking of the amino-propeptide of type III collagen onto the mature collagen fibril and the oligomerization of osteonectin in the matrix of differentiating cartilage represent especially intriguing examples, notwithstanding very limited insight into their biological relevance. TG2 catalyzes an early step in the activation of transforming growth factor-beta (TGF-beta) by crosslinking latent TGF-beta binding protein (LTBP) to the extracellular matrix. Two classes of non-physiological substrates of TG2 warrant attention. The first includes peptides derived from dietary gluten
physiological function
essential role for membrane-bound TG1 in cornified envelope assembly
physiological function
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human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. hTG2 function is tightly regulated by the presence of specific allosteric and redox regulators. Enzyme hTG2 is allosterically modulated by calcium ions and redox proteins to primarily exist in an open or extended conformation that is catalytically active when specific disulfide bonds are reduced. Intracellularly, hTG2 is regulated by guanidine-containing nucleotides, such as GTP that bind hTG2 at a site remote from the catalytic active site. The enzyme is implicated in several disease processes
physiological function
in humans, 9 members of the transglutaminase (TG) family have been identified, of which eight (factor XIII (FXIII) A and TG1-TG7) catalyze posttranslational protein-modifying reactions, and one (protein 4.2) does not. The TG enzymatic activities considered for human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. Essential role for membrane-bound TG1 in cornified envelope assembly. TG1 may contribute to intracellular crosslinking processes. Intracellular TG1 activity is unlikely to contribute extracellularly to extracellular matrix crosslinking
physiological function
in humans, 9 members of the transglutaminase (TG) family have been identified, of which eight (factor XIII (FXIII) A and TG1-TG7) catalyze posttranslational protein-modifying reactions, and one (protein 4.2) does not. The TG enzymatic activities considered for human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. TG3 is an autoantigen, causing autoantibody production, in dermatitis herpetiformis
physiological function
in humans, 9 members of the transglutaminase (TG) family have been identified, of which eight (factor XIII (FXIII) A and TG1-TG7) catalyze posttranslational protein-modifying reactions, and one (protein 4.2) does not. The TG enzymatic activities considered for human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. TG4 is an autoantigen, causing autoantibody production, in autoimmume polyglandular syndrome type 1. Role of TG4 in cancer
physiological function
in humans, 9 members of the transglutaminase (TG) family have been identified, of which eight (factor XIII (FXIII) A and TG1-TG7) catalyze posttranslational protein-modifying reactions, and one (protein 4.2) does not. The TG enzymatic activities considered for human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. TG5 is not an autoantigen and does not cause autoantibody production. Role for the cytoplasmic TG5 in epidermal cornification
physiological function
in humans, 9 members of the transglutaminase (TG) family have been identified, of which eight (factor XIII (FXIII) A and TG1-TG7) catalyze posttranslational protein-modifying reactions, and one (protein 4.2) does not. The TG enzymatic activities considered for human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. TG6 is an autoantigen, causing autoantibody production, in gluten axonal neuropathy and gluten ataxia
physiological function
in humans, 9 members of the transglutaminase (TG) family have been identified, of which eight (factor XIII (FXIII) A and TG1-TG7) catalyze posttranslational protein-modifying reactions, and one (protein 4.2) does not. The TG enzymatic activities considered for human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. TG7 is not an autoantigen and does not cause autoantibody production
physiological function
in humans, 9 members of the transglutaminase (TG) family have been identified, of which eight (factor XIII (FXIII) A and TG1-TG7) catalyze posttranslational protein-modifying reactions, and one (protein 4.2) does not. The TG enzymatic activities considered for human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. The enzymatic activity of TG2 is involved in the exacerbation of celiac disease. TG2 has been identified as the principal autoantigen recognized by disease-specific autoantibodies in the serum of patientswith active celiac disease. And TGS is involved in at least one case of hemoglobinopathy, characterized by shortened erythrocyte lifespan. TG2-mediated formation of crosslinked supramolecular membrane proteins and the resultant stiffening of the erythrocyte membrane by these polymers contribute to the extra-rapid clearing of erythrocytes from the circulation and hence, the shortened lifespan of Hb-Koeln erythrocytes, from 120 to 31 days. TG2 might contribute to neurologic diseases by affecting transcription, cellular differentiation, or cell migration and adhesion. TG2 is implicated in Huntington's disease pathogenesis. TG2 is implicated in extracellular collagen crosslinking. TG2 has been reported to enhance cancer cellmotility through induction of epithelial-to-mesenchymal transition, and TG2 enzymatic activity has been reported to be required for the development and survival of cancer stem cells. TG2 is an autoantigen, causing autoantibody production, in celiac disease
physiological function
in humans, 9 members of the transglutaminase (TG) family have been identified, of which eight (factor XIII (FXIII) A and TG1-TG7) catalyze posttranslational protein-modifying reactions, and one (protein 4.2) does not. The TG enzymatic activities considered for human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. The noncatalytic structural role of protein 4.2 is clearly important for erythrocyte membrane integrity
physiological function
mammalian transglutaminases (TGs) catalyze irreversible posttranslational modifications of proteins, the most prominent of which is the calcium-dependent formation of covalent acyl transfers between the gamma-carboxamide group of glutamine and the epsilon-amino-group of lysine (GGEL-linkage)
physiological function
mammalian transglutaminases (TGs) catalyze irreversible posttranslational modifications of proteins, the most prominent of which is the calcium-dependent formation of covalent acyl transfers between the gamma-carboxamide group of glutamine and the epsilon-amino-group of lysine (GGEL-linkage)
physiological function
microbial transglutaminase (mTG) is a robust enzyme catalyzing the formation of an isopeptide bond between glutamine and lysine residues. Transglutaminase catalyzes the acyl transfer reaction between gamma-carboxyamide groups (acyl donor) and primary amines (acyl acceptor). In proteins, it is able to crosslink the gamma-carboxyamide of glutamine and the primary epsilon-amine in lysine
physiological function
microbial transglutaminase alters the immunogenic potential and cross-reactivity of horse and cow milk proteins. The effect of TG on immunoreactivity depends on enzyme quantity and milk protein type. Determination of immunoreactivity of milk proteins by competitive ELISA
physiological function
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serotonin (5-hydroxytryptamine, 5-HT) is a key player in many physiological processes in both the adult organism and developing embryo. One of the mechanisms for 5-HT-mediated effects is covalent binding of 5-HT to the target proteins catalyzed by transglutaminases (serotonylation). In some cases, protein serotonylation (or generally monoaminylation) may lead to the formation of an active or inactive molecule that remains stable until its proteolytic degradation
physiological function
serotonin (5-hydroxytryptamine, 5-HT) is a key player in many physiological processes in both the adult organism and developing embryo. One of the mechanisms for 5-HT-mediated effects is covalent binding of 5-HT to the target proteins catalyzed by transglutaminases (serotonylation). In some cases, protein serotonylation (or generally monoaminylation) may lead to the formation of an active or inactive molecule that remains stable until its proteolytic degradation
physiological function
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serotonin (5-hydroxytryptamine, 5-HT) is a key player in many physiological processes in both the adult organism and developing embryo. One of the mechanisms for 5-HT-mediated effects is covalent binding of 5-HT to the target proteins catalyzed by transglutaminases (serotonylation). In some cases, protein serotonylation (or generally monoaminylation) may lead to the formation of an active or inactive molecule that remains stable until its proteolytic degradation
physiological function
TG2 is involved in extracellular collagen crosslinking
physiological function
the Ca2+-dependent deamidation and transamidation activities of transglutaminase 2 are important to numerous physiological and pathological processes
physiological function
tissue transglutaminase (t-TG) is a multifunctional protein involved in the healing of gastric erosions and ulcers in animal models. Determination of increased gastric t-TG activity in patients with dyspepsia according to Helicobacter pylori infection and cytotoxin-associated gene A (cagA) and vacuolating cytotoxin (vacA) subtype status. t-TG activity is significantly greater in gastritis associated with Helicobacter pylori infection, suggesting that this enzyme is induced by inflammation and may have an important role in the natural history of human gastritis. Tissue-TG is expressed at sites of inflammation, and can act as a modulator of inflammation, exerting both pro- and anti-inflammatory effects. The enzyme covalently cross-links a variety of proteins in the extracellular matrix, increasing fibrosis in order to favor wound healing by increasing resistance to chemical, enzymatic, and physical disruption
physiological function
tissue transglutaminase (TG2) catalyzes the Ca2+-dependent cross-linking of peptides and proteins via the formation of gamma-glutamyl-epsilon-lysyl isopeptide bonds
physiological function
transglutaminase (TG) activity regulates differentiation, migration, and fusion of osteoclasts via affecting actin dynamics. TG activity regulates actin dynamics in pre-osteoclasts. Increased osteoclast activity is responsible for bone destruction in diseases such as osteoporosis, periodontitis and rheumatoid arthritis. Analysis of the role of TG activity in osteoclastogenesis in vitro, overview. TG activity is required for pre-osteoclast migration
physiological function
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transglutaminase (TGase) catalyzes post-translational modification of proteins by gamma-glutamyl-epsilon-lysine chain links, covalent conjugation of polyamines, and deamidation. Analysis of cross-linking effect of recombinant TGZ on the properties of acid-induced milk protein concentrate (MPC) gel
physiological function
transglutaminase (TGase) catalyzes protein cross-linking reactions essential for several biological processes. In differentiating keratinocytes, TG1 (keratinocyte-type) is crucial for the cross-linking of substrate proteins required for the complete formation of the cornified envelope, a proteinaceous supermolecule located in the outermost layer of the epidermis
physiological function
transglutaminase 2 (TG2) is a multi-functional protein that possesses various biological activities, including protein cross-linking activity, GTPase activity, protein disulfide isomerase activity, kinase activity, and scaffold activity. Because of its various functions, TG2 is involved in many important cellular processes, including apoptosis, angiogenesis, wound healing, neuronal regeneration, and bone development. Isozyme TG2 function differs according to its location in the cell. In the cytosol, TG2 acts as a signal transfer molecule that transmits a receptor signal to an intracellular effector through GTP hydrolysis. When it is secreted into the extracellular environment, TG2 functions as a cross-linking enzyme in the matrix. This protein transamidase activity of TG2 is positively regulated by calcium and negatively regulated by GTP
physiological function
transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes
physiological function
transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes
physiological function
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transglutaminase is a transferase that catalyzes the acyl transfer reaction between the gamma-carboxamide group in glutamine residues and various primary amines in polyamine
physiological function
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transglutaminases (TGase) catalyze the acyl transfer reaction between a free amine group (e.g. in a protein or peptide-bound lysine or an amine) and the gamma-carboxy amide group of proteins or peptide bound glutamine thus leading to the modification of proteins. When an epsilon-amino group of a peptide bound lysine acts as a acyl acceptor, isopeptide bond is formed between the glutamine and lysine residues in them, introducing both inter- and intramolecular covalent cross-links, resulting in the polymerization of the proteins
physiological function
transglutaminases (TGases) catalyze a Ca2+-dependent acyl transfer reaction between the epsilon-amino group of lysine (acyl acceptors) and gamma-carboxamide groups of glutamine residues (acyl donors) and forms cross-links by catalyzing the isopeptide bond formation between Lys and Gln residues to form epsilon-(gamma-glutamyl) lysine bonds between appropriate substrates. This reaction is essential for physiological cell functions, such as in blood coagulation, during cell differentiation and survival, skin formation, and signal transduction
physiological function
transglutaminases (TGases) catalyze a Ca2+-dependent acyl transfer reaction between the epsilon-amino group of lysine (acyl acceptors) and gamma-carboxamide groups of glutamine residues (acyl donors) and forms cross-links by catalyzing the isopeptide bond formation between Lys and Gln residues to form epsilon-(gamma-glutamyl) lysine bonds between appropriate substrates. This reaction is essential for physiological cell functions, such as in blood coagulation, during cell differentiation and survival, skin formation, and signal transduction
physiological function
transglutaminases form extensively crosslinked, generally insoluble protein polymers. These structures are important for organisms in the formation of skin barrier, hair growth, wound healing and blood clotting. Transglutaminases are a family of enzymes that catalyse the cross-linking of proteins by forming covalent bonds between glutamine (Q) and lysine (K) residues in different polypeptides. Such isopeptide bonds created by TG are highly resistant to proteolysis and increase the mechanical stability of the modified proteins
physiological function
type 2 transglutaminase, tTG, is an important player in numerous diseases, including celiac disease, neuronal degenerative diseases, and cancer, and its roles in these diseases often depend as much upon its conformation as its catalytic activity. Several roles of tTG in diseases, detailed overview. ApoE is able to protect against Abeta plaque formation by transporting Abeta out of the brain. Crosslinking by tTG inactivates the protein, rendering it unable to clear Abeta. Parkinson's disease is a related disorder, and tTG plays similar, but unique, roles in this disease as well. Where Alzheimer's disease is driven in part by a buildup of Abeta aggregates, Parkinson's disease is caused by the aggregation of alpha-synuclein. In Parkinson's disease, alpha-synuclein is incorrectly processed into beta-pleated fibrils, which in turn aggregate to form cytoplasmic inclusions called Lewy Bodies. tTG catalyzes the crosslinking of alpha-synuclein, both in vitro and in cell models, tTG and alpha-synuclein both localize to the endoplasmic reticulum in disease brain samples. tTG is the major autoantigen in celiac disease. Celiac disease is an auto-immune disorder in which T-cells attack and damage the small intestine. This process is driven by gliadin, a protein in most grains, which precipitates an immune response. Crosslinking of gliadin formed antigenic complexes. And thioredoxin-1 is released by macrophages exposed to inflammatory stimuli in sufficient quantity to reduce the tTG C370-C371 disulfide bond, activating the enzyme. Since inflammatory conditions are present in celiac disease gut, this effect essentially creates a self-stimulating loop in which activated tTG leads to inflammation, which then activates more tTG. tTG has been shown to play roles in cancer cell adhesion, migration, and invasion via its interactions with fibronectin. tTG binds to fibronectin, and crosslinks it to various surfaces, allowing cells to adhere. Matrix metalloproteinase can then break these crosslinks, and in combination with tTG crosslinking this allows for cell motility. Similarly, tTG is thought to play a role in vesicle trafficking by helping to dock extracellular vesicles (microvesicles) generated by aggressive cancer cells to fibroblasts, through its ability to bind and crosslink fibronectin on the vesicle surface. This docking event can then be blocked by inhibiting its crosslinking activity. tTG can promote either cell survival or apoptosis, depending upon the physiological context. As a pro-survival protein, the crosslinking-competent, open-state form of tTG has been shown to crosslink pRB (a pro-apoptotic protein), causing it to oligomerize and thus lose its activity. This is analogous to its role in Alzheimer's disease, crosslinking ApoE. Closed-state tTG is able to sequester c-Cbl, and block ubiquitinylation and subsequent degradation of the EGF receptor, thereby also promoting cell growth and survival. Thus, both open- and closed-state can tTG promote survival depending upon the specific conditions. The same is true of its pro-apoptotic functions. In pancreatic cancer cells treated with the calcium ionophore A23187, tTG adopts the crosslinking-active open-state to facilitate release of the apoptosis-inducing factor from mitochondria, promoting cell death. In contrast, ectopically expressed tTG in SH-SY5Y cells, which presumably exists in the closed-state, is found to promote apoptosis following osmotic shock or staurosporine treatment. Cytotoxicity of the open-state of tTG
physiological function
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mammalian transglutaminases (TGs) catalyze irreversible posttranslational modifications of proteins, the most prominent of which is the calcium-dependent formation of covalent acyl transfers between the gamma-carboxamide group of glutamine and the epsilon-amino-group of lysine (GGEL-linkage)
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physiological function
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mammalian transglutaminases (TGs) catalyze irreversible posttranslational modifications of proteins, the most prominent of which is the calcium-dependent formation of covalent acyl transfers between the gamma-carboxamide group of glutamine and the epsilon-amino-group of lysine (GGEL-linkage)
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additional information
active-site titration using N-[(5S)-6-[4-(6-nitropyridin-3-yl)piperazin-1-yl]-6-oxo-5-(2-phenylacetamido)hexyl]prop-2-enamide and Z-Glu(HMC)-Gly-OH
additional information
active-site titration using N-[(5S)-6-[4-(6-nitropyridin-3-yl)piperazin-1-yl]-6-oxo-5-(2-phenylacetamido)hexyl]prop-2-enamide and Z-Glu(HMC)-Gly-OH
additional information
active-site titration using N-[(5S)-6-[4-(6-nitropyridin-3-yl)piperazin-1-yl]-6-oxo-5-(2-phenylacetamido)hexyl]prop-2-enamide and Z-Glu(HMC)-Gly-OH
additional information
active-site titration using N-[(5S)-6-[4-(6-nitropyridin-3-yl)piperazin-1-yl]-6-oxo-5-(2-phenylacetamido)hexyl]prop-2-enamide and Z-Glu(HMC)-Gly-OH
additional information
active-site titration using N-[(5S)-6-[4-(6-nitropyridin-3-yl)piperazin-1-yl]-6-oxo-5-(2-phenylacetamido)hexyl]prop-2-enamide and Z-Glu(HMC)-Gly-OH
additional information
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addition of TGase at 0.1 U/mg increases the gel strength, setting temperature, setting time, and melting temperature of cold-set gelatin gel
additional information
comparison of the crayfish enzyme to the commercial enzyme from guinea pig liver, which is highly active at 37°C
additional information
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comparison of the crayfish enzyme to the commercial enzyme from guinea pig liver, which is highly active at 37°C
additional information
comparison of the crayfish enzyme, which is highly active at 4°C, to the commercial enzyme from guinea pig liver
additional information
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comparison of the crayfish enzyme, which is highly active at 4°C, to the commercial enzyme from guinea pig liver
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comparison of the different TGases from Streptomyces mobaranensis and Streptomyces cinnamoneus, and of a chimeric mutant constructed from both, overview
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comparison of the different TGases from Streptomyces mobaranensis and Streptomyces cinnamoneus, and of a chimeric mutant constructed from both, overview
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comparison of the different TGases from Streptomyces mobaranensis and Streptomyces cinnamoneus, and of a chimeric mutant constructed from both, overview
additional information
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comparison of the different TGases from Streptomyces mobaranensis and Streptomyces cinnamoneus, and of a chimeric mutant constructed from both, overview
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comparison of the recombinantly expressed enzyme TGZo from Zea mays with the microbial transglutaminase(MTG) enzymes from Streptomyces mobaraensis and Streptomyces hygroscopicus. TGZo has higher thermostability and wider range of pH than the MTGs from the Streptomyces strains. Texture analysis of cow milk yogurts cross-linked by different concentrations of TGZo and MTG
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docking study and homology structure molecular modeling using the crystal structure of homologous hTGase 2 (PDB ID 2Q3Z) as template
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effect of microbial transglutaminase on the mechanical properties and microstructure of acid-induced gels and emulsion gels produced from thermal denatured egg white proteins (TD-EWPs), overview. Impact of TGase on mechanical, rheological, and microstructural properties of cold-set EWP gels and emulsion gels produced from the TD-EWP. EWP is sufficiently cross-linked by MTGase
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in the open active conformation, the catalytic core, which contains the catalytic triad Cys277, His335, and Asp358, is accessible and capable of catalyzing the formation of isopeptide bonds (cross-links) between peptide bound Gln and Lys residues. The cross-linking activity is also referred to as transamidation and occurs via a ping-pong mechanism. First, the nucleophilic active site thiolate (Cys277) attacks an acyl donor substrate (i.e. a peptide-bound Gln residue) resulting in the release of one equivalent of ammonia and the formation of the intermediate thioester. Subsequently, the thiolate is regenerated by nucleophilic attack of an acyl acceptor substrate (i.e. a peptide-bound Lys residue) to afford the isopeptide product, or the thioester is cleaved by water to afford the deamidated (or hydrolysis) product. Upon GTP binding, hTG2 primarily adopts a closed or compact conformation where the catalytic Cys277 becomes inaccessible
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intracellular tTG is predominantly in the closed-state, with a small portion being in the crosslinking-competent open-state, while extracellular tTG would adopt the open-state, and be crosslinking-competent. This view is somewhat complicated by the mildly oxidative conditions in the extracellular space. A triad of cysteine residues (Cys 230, Cys 370, and Cys 371) are able to make one of two disulfide bonds (C370-C230, or C370-C371) in oxidative conditions. Either disulfide bond reduces crosslinking catalytic activity, but oxidized tTG maintains a conformation similar to the open-state. Cp4d is a reversible small molecule which has little effect on tTG conformation, while NC9 is a bulkier, irreversible peptidomimetic compound presumed to stabilize tTG in the open-state. Cp4d treatment has little effect on the sensitivity of the assorted cells to glucose-oxygen deprivation-induced cell death. NC9 causes the tTG wild-type and tTG C277S mutant expressing cells to undergo a greater degree of cell death under the same conditions. The conformation of tTG is responsible for the cell death enhancement. Binding partners of tTG depend upon its conformation, confromation-independent binding modes of tTG, structure-function analysis, detailed overview
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mechanism of mTG-catalyzed isopeptide bond formation between protein-bound glutamine and lysine residues. Structure-function analysis, substrate specificity, overview
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mechanism of mTG-catalyzed isopeptide bond formation between protein-bound glutamine and lysine residues. Structure-function analysis, substrate specificity, overview
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mechanism of mTG-catalyzed isopeptide bond formation between protein-bound glutamine and lysine residues. Structure-function analysis, substrate specificity, overview
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mechanism of mTG-catalyzed isopeptide bond formation between protein-bound glutamine and lysine residues. Structure-function analysis, substrate specificity, overview
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molecular dynamics simulations
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molecular dynamics simulations are developed to model the binding modes of donor substrates in the gTG2 active site. The inability of gTG2 to efficiently catalyze peptide synthesis from donors containing alanine results from the narrow substrate binding tunnel, which prevents bulkier donors from adopting a catalytically productive binding mode. Molecular homology modeling of TG2 using the structure of inhibitor-complexed human enzyme as template (PDB ID: 2Q3Z). Donor substrate specificity of gTG2-catalyzed peptide synthesis, overview
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mTGase structure-function relationship, overview. The active site is a single cysteine (C64) residing at the bottom cleft of the crystal structure (PDB ID 3IU0) where it forms a catalytic triad with the aspartic acid (D255) and histidine (H274) residues. The pro-sequence region is vital for enzyme folding and inhibition of enzyme activation within the cells to avoid detrimental cross-linking of cytosolic proteins. The enzyme structure has a wide active site cleft position that accommodates the alpha-helix pro-sequence. This unique attribute explains the broad substrate specificity for acyl donors which allows for additional flexibility in the active site to accommodate a less specific substrate, overview
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the catalytic core domain of TG2 is essential for the TG2-DNAJA1 interaction, mass spectrometry analysis. In contrast, the cross-linking activity of TG2 is not essential for the interaction since DNAJA1 also interacts with the catalytically inactive form of TG2. DNAJA1 interacts with the open form of TG2 and regulates its transamidation activity under both in vitro and in situ conditions
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the catalytic core domain of TG2 is essential for the TG2-DNAJA1 interaction, mass spectrometry analysis. In contrast, the cross-linking activity of TG2 is not essential for the interaction since DNAJA1 also interacts with the catalytically inactive form of TG2. DNAJA1 interacts with the open form of TG2 and regulates its transamidation activity under both in vitro and in situ conditions
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the enzyme shows a ping-pong mechanism
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the MTG has a triplet active center Cys151-Asp342-His361
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the N-terminal amino acid sequence of MsTGase is GKIEEG-LVI
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transglutaminase 2 (TG2) is the only mammalian transglutaminase to harbor the conserved Cys-triad
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transglutaminase 2 (TG2) is the only mammalian transglutaminase to harbor the conserved Cys-triad
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comparison of the different TGases from Streptomyces mobaranensis and Streptomyces cinnamoneus, and of a chimeric mutant constructed from both, overview
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additional information
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mechanism of mTG-catalyzed isopeptide bond formation between protein-bound glutamine and lysine residues. Structure-function analysis, substrate specificity, overview
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additional information
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the MTG has a triplet active center Cys151-Asp342-His361
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additional information
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comparison of the different TGases from Streptomyces mobaranensis and Streptomyces cinnamoneus, and of a chimeric mutant constructed from both, overview
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additional information
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the enzyme shows a ping-pong mechanism
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additional information
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mechanism of mTG-catalyzed isopeptide bond formation between protein-bound glutamine and lysine residues. Structure-function analysis, substrate specificity, overview
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