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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{PBB|geneid=7052}}
{{Redirect|TGM2|the Tetris game|Tetris: The Grand Master}}
{{Infobox_gene}}
{{infobox enzyme
{{infobox enzyme
| Name = Protein-glutamine gamma-glutamyltransferase
| Name = Protein-glutamine gamma-glutamyltransferase
| EC_number = 2.3.2.13
| EC_number = 2.3.2.13
| CAS_number = 80146-85-6
| CAS_number = 80146-85-6
| IUBMB_EC_number= 2/3/2/13
| GO_code = 0003810
| GO_code = 0003810
| image =
| image =
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| caption =
| caption =
}}
}}
'''Tissue transglutaminase''' (abbreviated as '''tTG''' or '''TG2''') is a 78-kDa, calcium dependent [[enzyme]] ({{EC number|2.3.2.13}}) of the protein-glutamine γ-glutamyltransferases family (or simply [[transglutaminase]] family).<ref name=Kiraly/><ref name=Klock/> Like other transglutaminases, it crosslinks [[protein]]s 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.<ref name=Facchiano/> 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]].<ref name=Klock/> Intracellular tTG is thought to play an important role in [[apoptosis]].<ref name=McConkey/> In the extracellular space, tTG binds to proteins of the extracellular matrix (ECM),<ref name=Lortat-Jacob/> binding particularly tightly to [[fibronectin]].<ref name=Akimov/> Extracellular tTG has been linked to cell adhesion, ECM stabilization, wound healing, receptor signaling, cellular proliferation, and cellular motility.<ref name=Klock/>
'''Tissue transglutaminase''' (abbreviated as '''tTG''' or '''TG2''') is a 78-kDa, calcium-dependent [[enzyme]] ({{EC number|2.3.2.13}}) of the protein-glutamine γ-glutamyltransferases family (or simply [[transglutaminase]] family).<ref name=Kiraly/><ref name=Klock/> Like other transglutaminases, it crosslinks [[protein]]s 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.<ref name=Facchiano/> 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 [[Cell nucleus|nucleus]] and the [[mitochondria]].<ref name=Klock/> Intracellular tTG is thought to play an important role in [[apoptosis]].<ref name=McConkey/> In the extracellular space, tTG binds to proteins of the extracellular matrix (ECM),<ref name=Lortat-Jacob/> binding particularly tightly to [[fibronectin]].<ref name=Akimov/> Extracellular tTG has been linked to cell adhesion, ECM stabilization, wound healing, receptor signaling, cellular proliferation, and cellular motility.<ref name=Klock/>


tTG is particularly notable for being the [[autoimmunity|autoantigen]] in [[coeliac 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.<ref name=Griffin>{{cite journal | author = Griffin M, Casadio R, Bergamini CM | title = Transglutaminases: nature's biological glues | journal = Biochem. J. | volume = 368 | issue = Pt 2 | pages = 377–96 | year = 2002 | month = December | pmid = 12366374 | pmc = 1223021 | doi = 10.1042/BJ20021234 | url = }}</ref><ref name=DiRaimondo/><ref name=Sabatino/>
tTG is the [[autoimmunity|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 [[Intestinal villus|villous]] atrophy.<ref name=Griffin>{{cite journal | vauthors = Griffin M, Casadio R, Bergamini CM | title = Transglutaminases: nature's biological glues | journal = The Biochemical Journal | volume = 368 | issue = Pt 2 | pages = 377–96 | date = December 2002 | pmid = 12366374 | pmc = 1223021 | doi = 10.1042/BJ20021234 }}</ref><ref name=DiRaimondo/><ref name=Sabatino/> It has also been implicated in the pathophysiology of many other diseases, including such as many different cancers and neurogenerative diseases.<ref name="Király_2009">{{cite journal | vauthors = Király R, Csosz E, Kurtán T, Antus S, Szigeti K, Simon-Vecsei Z, Korponay-Szabó IR, Keresztessy Z, Fésüs L | title = Functional significance of five noncanonical Ca2+-binding sites of human transglutaminase 2 characterized by site-directed mutagenesis | journal = The FEBS Journal | volume = 276 | issue = 23 | pages = 7083–96 | date = December 2009 | pmid = 19878304 | doi = 10.1111/j.1742-4658.2009.07420.x | s2cid = 21883387 | doi-access = free }}</ref>

== Structure ==

===Gene===
⚫
The human tTG gene is located on the [[chromosome 20|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.<ref name="entrez">{{cite web | title = Entrez Gene: TGM2 transglutaminase 2 | url = https://www.ncbi.nlm.nih.gov/gene/7052 }}</ref> Similarly to other transglutaminases, tTG consists of a GTP/ GDP binding site, a [[Active site|catalytic domain]], two [[beta barrel]] and a [[beta-sandwich]].<ref name="Hitomi_2015">{{cite book | first1 = Kiyotaka | last1 = Hitomi | first2 = Soichi | last2 = Kojima | first3 = Laszlo | last3 = Fesus | name-list-style = vanc |title=Transglutaminases : multiple functional modifiers and targets for new drug discovery|isbn=9784431558255|location=Tokyo|oclc=937392418 | date = 2015 }}</ref> [[Crystal structures]] of TG2 with bound [[Guanosine diphosphate|GDP]], [[Guanosine triphosphate|GTP]], or [[Adenosine triphosphate|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.<ref name="pmid18092889">{{cite journal | vauthors = Pinkas DM, Strop P, Brunger AT, Khosla C | title = Transglutaminase 2 undergoes a large conformational change upon activation | journal = PLOS Biology | volume = 5 | issue = 12 | pages = e327 | date = December 2007 | pmid = 18092889 | pmc = 2140088 | doi = 10.1371/journal.pbio.0050327 | doi-access = free }}</ref><ref name="pmid11867708">{{cite journal | vauthors = Liu S, Cerione RA, Clardy J | title = Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 5 | pages = 2743–7 | date = March 2002 | pmid = 11867708 | pmc = 122418 | doi = 10.1073/pnas.042454899 | bibcode = 2002PNAS...99.2743L | doi-access = free }}</ref><ref name="pmid20450932">{{cite journal | vauthors = Han BG, Cho JW, Cho YD, Jeong KC, Kim SY, Lee BI | title = Crystal structure of human transglutaminase 2 in complex with adenosine triphosphate | journal = International Journal of Biological Macromolecules | volume = 47 | issue = 2 | pages = 190–5 | date = August 2010 | pmid = 20450932 | doi = 10.1016/j.ijbiomac.2010.04.023 }}</ref> 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-terminus|C-terminal domains]] are folded in on the catalytic core domain which includes the residue Cys-277.<ref name="Stamnaes_2010">{{cite journal | vauthors = Stamnaes J, Pinkas DM, Fleckenstein B, Khosla C, Sollid LM | title = Redox regulation of transglutaminase 2 activity | journal = The Journal of Biological Chemistry | volume = 285 | issue = 33 | pages = 25402–9 | date = August 2010 | pmid = 20547769 | pmc = 2919103 | doi = 10.1074/jbc.M109.097162 | doi-access = free }}</ref> The [[N-terminus|N-terminal domain]] only shows minor structural changes between the two different conformations.<ref name="pmid=26160175">{{cite journal | vauthors = Chen X, Hnida K, Graewert MA, Andersen JT, Iversen R, Tuukkanen A, Svergun D, Sollid LM | title = Structural Basis for Antigen Recognition by Transglutaminase 2-specific Autoantibodies in Celiac Disease | journal = The Journal of Biological Chemistry | volume = 290 | issue = 35 | pages = 21365–75 | date = August 2015 | pmid = 26160175 | pmc = 4571865 | doi = 10.1074/jbc.M115.669895 | doi-access = free }}</ref>


==Mechanism==
==Mechanism==
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==Regulation==
==Regulation==


The expression of tTG is regulated at the transcriptional level depending on complex [[Signal transduction|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 [[Cell nucleus|nucleus]], where it participates in the control of its own expression through the regulation of [[transcription factor]]s.<ref>{{cite journal | vauthors = Bianchi N, Beninati S, Bergamini CM | title = Spotlight on the transglutaminase 2 gene: a focus on genomic and transcriptional aspects | journal = The Biochemical Journal | volume = 475 | issue = 9 | pages = 1643–1667 | date = May 2018 | pmid = 29764956 | doi = 10.1042/BCJ20170601 | hdl = 11392/2388638 | url = http://www.biochemj.org/content/475/9/1643.full-text.pdf }}</ref>
⚫
Crosslinking activity by tTG requires the binding of Ca<sup>2+</sup> ions.<ref name=Jin/> Multiple Ca<sup>2+</sup> can bind to a single tTG molecule.<ref name=Klock/> In contrast, the binding of one molecule of [[GTP]] or [[GDP]] inhibits the crosslinking activity of the enzyme.<ref name=Jin/> Therefore, intracellular tTG is mostly inactive due to the relatively high concentration of GTP/GDP and the low levels of calcium inside the cell.<ref name=Klock/><ref name=DiRaimondo/> 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.<ref name=Klock/><ref name=DiRaimondo/><ref name=Jin/> Recent studies suggest that extracellular tTG is kept inactive by the formation of a [[disulfide]] bond between two vicinal Cys residues. Therefore, oxidation/reduction of the disulfide bond serves as a third allosteric regulatory mechanism (along with GTP/GDP and Ca<sup><sup>2+</sup></sup>) for the activation of tTG.<ref name=DiRaimondo/> Thioredoxin has been shown to activate extracellular tTG by reducing the disulfide bond.<ref name=Jin/> 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.<ref name=DiRaimondo/> 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 2)<ref name=Jin/><ref name=Pinkas/><ref name=Colak/>


⚫
Crosslinking activity by tTG requires the binding of Ca<sup>2+</sup> ions.<ref name="Jin" /> Multiple Ca<sup>2+</sup> can bind to a single tTG molecule.<ref name="Klock" /> 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.<ref name="Király_2009"/> In contrast, the binding of one molecule of [[Guanosine triphosphate|GTP]] or [[Guanosine diphosphate|GDP]] inhibits the crosslinking activity of the enzyme.<ref name="Jin" /> Therefore, intracellular tTG is mostly inactive due to the relatively high concentration of GTP/GDP and the low levels of calcium inside the cell.<ref name="Klock" /><ref name="DiRaimondo" /> 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.<ref name="Klock" /><ref name="DiRaimondo" /><ref name="Jin" /> 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.<ref name="Yi_2018">{{cite journal | vauthors = Yi MC, Melkonian AV, Ousey JA, Khosla C | title = Endoplasmic reticulum-resident protein 57 (ERp57) oxidatively inactivates human transglutaminase 2 | journal = The Journal of Biological Chemistry | volume = 293 | issue = 8 | pages = 2640–2649 | date = February 2018 | pmid = 29305423 | pmc = 5827427 | doi = 10.1074/jbc.RA117.001382 | doi-access = free }}</ref> When this disulfide bond forms, the enzyme remains in an open confirmation but becomes catalytically inactive.<ref name="Yi_2018" /> The, oxidation/reduction of the disulfide bond serves as a third allosteric regulatory mechanism (along with GTP/GDP and Ca<sup><sup>2+</sup></sup>) for the activation of tTG.<ref name="DiRaimondo" /> [[Thioredoxin]]-1 has been shown to activate extracellular tTG by reducing the disulfide bond.<ref name="Jin" /> 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.<ref name="Stamnaes_2010" /> The presence of calcium protects against the formation of both disulfide bonds, thus making the enzyme more resistant to oxidation.<ref name="Stamnaes_2010" />
⚫
[[File:Closed and open conformations of tTG.jpg|thumb|center|300px|alt=X-ray crystallography images of tissue transglutaminase in two different conformations|Figure 2: Compact (inactive) and extended (active) conformations of tTG]]
[[File:4cysresi.png|alt=|center|thumb|358x358px|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.<ref name="DiRaimondo" /> 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)<ref name="Jin" /><ref name="Pinkas" /><ref name="Colak" />


⚫
[[File:Closed and open conformations of tTG.jpg|thumb|center|300px|alt=X-ray crystallography images of tissue transglutaminase in two different conformations|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).<ref name="Yi_2018" /> Thus, tTG is allosterically regulated by two separate proteins, Erp57 and TRX-1.<ref name="Yi_2018" /> (See Figure 4).
==Genetics==
[[File:Erp57_TRX1.png|alt=|center|thumb|327x327px|Figure 4: The proteins that allosterically regulate tTG. On the left Erp57 which oxidizes tTG and on the right TRX-1 which reduces tTG.]]
⚫
The human tTG gene is located on the [[chromosome 20|20th chromosome]] (20q11.2-q12).


==Physiology==
== Function ==
tTG is expressed ubiquitously. It requires [[calcium in biology|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<ref name=Griffin/>
tTG is expressed ubiquitously and is present in various cellular compartments, such as the cytosol, the nucleus, and the plasma membrane.<ref name="Király_2009" /> It requires [[calcium in biology|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<ref name=Griffin/> as well as [[Cellular differentiation|differentiation]] and [[cell adhesion]].<ref name="Király_2009" /> It has been noted that tTG may have very different activity in different cell types. For example, in [[neuron]]s, tTG supports the survival of cells subjected to injury whereas in [[astrocyte]]s knocking out the gene expression for tTG is beneficial to cell survival.<ref>{{cite journal | vauthors = Quinn BR, Yunes-Medina L, Johnson GV | title = Transglutaminase 2: Friend or foe? The discordant role in neurons and astrocytes | journal = Journal of Neuroscience Research | volume = 96 | issue = 7 | pages = 1150–1158 | date = July 2018 | pmid = 29570839 | pmc = 5980740 | doi = 10.1002/jnr.24239 }}</ref>
tTG is thought to be involved in the regulation of the cytoskeleton by crosslinking various cytoskeletal proteins including myosin, actin, and spectrin.<ref name=Nurminskaya/> 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.<ref name=Facchiano/>
tTG is thought to be involved in the regulation of the cytoskeleton by crosslinking various cytoskeletal proteins including myosin, actin, and [[spectrin]].<ref name=Nurminskaya/> 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.<ref name=Facchiano/>


tTG also has [[GTPase]] activity:<ref name=Kiraly/> In the presence of GTP, it suggested to function as a G protein participating in signaling processes.<ref name=Fesus>{{cite journal | author = Fesus L, Piacentini M | title = Transglutaminase 2: an enigmatic enzyme with diverse functions | journal = Trends Biochem. Sci. | volume = 27 | issue = 10 | pages = 534–9 | year = 2002 | month = October | pmid = 12368090 | doi = 10.1016/S0968-0004(02)02182-5| url = }}</ref> Besides its transglutaminase activity, tTG is proposed to also act as kinase,<ref name=Mishra>{{cite journal | author = Mishra S, Murphy LJ | title = Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase | journal = J. Biol. Chem. | volume = 279 | issue = 23 | pages = 23863–8 | year = 2004 | month = June | pmid = 15069073 | doi = 10.1074/jbc.M311919200 | url = }}</ref> and protein disulfide isomerase,<ref name=Hasegawa>{{cite journal | author = Hasegawa G, Suwa M, Ichikawa Y, Ohtsuka T, Kumagai S, Kikuchi M, Sato Y, Saito Y | title = A novel function of tissue-type transglutaminase: protein disulphide isomerase | journal = Biochem. J. | volume = 373 | issue = Pt 3 | pages = 793–803 | year = 2003 | month = August | pmid = 12737632 | pmc = 1223550 | doi = 10.1042/BJ20021084 | url = }}</ref> and deamidase.<ref name=Sakly>{{cite journal | author = Sakly W, Thomas V, Quash G, El Alaoui S | title = A role for tissue transglutaminase in alpha-gliadin peptide cytotoxicity | journal = Clin. Exp. Immunol. | volume = 146 | issue = 3 | pages = 550–8 | year = 2006 | month = December | pmid = 17100777 | pmc = 1810403 | doi = 10.1111/j.1365-2249.2006.03236.x | url = }}</ref> This latter activity is important in the deamidation of gliadin peptides, thus playing important role in the pathology of [[coeliac disease]].
tTG also has [[GTPase]] activity:<ref name=Kiraly/> In the presence of GTP, it suggested to function as a G protein participating in signaling processes.<ref name=Fesus>{{cite journal | vauthors = Fesus L, Piacentini M | title = Transglutaminase 2: an enigmatic enzyme with diverse functions | journal = Trends in Biochemical Sciences | volume = 27 | issue = 10 | pages = 534–9 | date = October 2002 | pmid = 12368090 | doi = 10.1016/S0968-0004(02)02182-5 }}</ref> Besides its transglutaminase activity, tTG is proposed to also act as kinase,<ref name=Mishra>{{cite journal | vauthors = Mishra S, Murphy LJ | title = Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase | journal = The Journal of Biological Chemistry | volume = 279 | issue = 23 | pages = 23863–8 | date = June 2004 | pmid = 15069073 | doi = 10.1074/jbc.M311919200 | doi-access = free }}</ref> and protein disulfide isomerase,<ref name=Hasegawa>{{cite journal | vauthors = Hasegawa G, Suwa M, Ichikawa Y, Ohtsuka T, Kumagai S, Kikuchi M, Sato Y, Saito Y | title = A novel function of tissue-type transglutaminase: protein disulphide isomerase | journal = The Biochemical Journal | volume = 373 | issue = Pt 3 | pages = 793–803 | date = August 2003 | pmid = 12737632 | pmc = 1223550 | doi = 10.1042/BJ20021084 }}</ref> and deamidase.<ref name=Sakly>{{cite journal | vauthors = Sakly W, Thomas V, Quash G, El Alaoui S | title = A role for tissue transglutaminase in alpha-gliadin peptide cytotoxicity | journal = Clinical and Experimental Immunology | volume = 146 | issue = 3 | pages = 550–8 | date = December 2006 | pmid = 17100777 | pmc = 1810403 | doi = 10.1111/j.1365-2249.2006.03236.x }}</ref> 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.<ref name="Tabolacci_2019">{{cite journal | vauthors = Tabolacci C, De Martino A, Mischiati C, Feriotto G, Beninati S | title = The Role of Tissue Transglutaminase in Cancer Cell Initiation, Survival and Progression | journal = Medical Sciences | volume = 7 | issue = 2 | pages = 19 | date = January 2019 | pmid = 30691081 | doi = 10.3390/medsci7020019 | pmc = 6409630 | doi-access = free }}</ref><ref name="Rossin_2018">{{cite journal | vauthors = 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 | title = TG2 regulates the heat-shock response by the post-translational modification of HSF1 | journal = EMBO Reports | volume = 19 | issue = 7 | pages = e45067 | date = July 2018 | pmid = 29752334 | pmc = 6030705 | doi = 10.15252/embr.201745067 }}</ref> 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.<ref name="Rossin_2018" />
==Role in disease==
⚫
tTG is best known for its link with [[celiac disease]].<ref name=Sabatino/> [[Anti-transglutaminase antibodies]] (ATA) result in a form of [[gluten sensitivity]] in which a cellular response to [[Triticeae glutens|''Triticeae'' glutens]] that are crosslinked to tTG are able to stimulate transglutaminase specific [[B-cell]] responses that eventually result in the production of ATA IgA and IgG.<ref name="pmid9212111">{{cite journal | author = Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D | title = Identification of tissue transglutaminase as the autoantigen of celiac disease | journal = Nat. Med. | volume = 3 | issue = 7 | pages = 797–801 | year = 1997 | month = July | pmid = 9212111 | doi = 10.1038/nm0797-797 }}</ref>


== Clinical significance ==
⚫
tTG is believed to be involved in several neurodegenerative disorders including [[Alzheimer]], [[Parkinson]] and [[Huntington]] diseases.<ref name=Wilhelmus/><ref name=Ricotta/> 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.<ref name =Martin/> Additionally, specific proteins associated with these disorders have been found to be in vivo and in vitro substrates of tTG.<ref name=Facchiano/>
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.<ref name="Lorand_2019">{{cite journal | vauthors = Lorand L, Iismaa SE | title = Transglutaminase diseases: from biochemistry to the bedside | journal = FASEB Journal | volume = 33 | issue = 1 | pages = 3–12 | date = January 2019 | pmid = 30593123 | doi = 10.1096/fj.201801544R | s2cid = 58551851 | doi-access = free }}</ref>
⚫
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.<ref name=Kumar/>


=== Celiac Disease ===
Recent studies suggest that tTG also plays a role in [[inflammation]], and tumor biology.<ref name=Griffin/> 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.


⚫
tTG is best known for its link with [[celiac disease]].<ref name="Sabatino" /> 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.<ref name="Lorand_2019" /> [[Anti-transglutaminase antibodies]] result in a form of [[gluten sensitivity]] in which a cellular response to [[Triticeae glutens|''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.<ref name="pmid9212111">{{cite journal | vauthors = Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D | s2cid = 20033968 | title = Identification of tissue transglutaminase as the autoantigen of celiac disease | journal = Nature Medicine | volume = 3 | issue = 7 | pages = 797–801 | date = July 1997 | pmid = 9212111 | doi = 10.1038/nm0797-797 }}</ref><ref>{{cite journal | vauthors = Murray JA, Frey MR, Oliva-Hemker M | title = Celiac Disease | journal = Gastroenterology | volume = 154 | issue = 8 | pages = 2005–2008 | date = June 2018 | pmid = 29550590 | pmc = 6203336 | doi = 10.1053/j.gastro.2017.12.026 }}</ref> 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.<ref name="Lorand_2019" />
⚫
==Diagnostic use==
⚫
[[Serology]] for anti-tTG [[antibody|antibodies]] has superseded older serological tests (anti-endomysium, anti-gliadin, and anti-reticulin) and has a strong [[sensitivity (tests)|sensitivity]] (99%) and [[Specificity (tests)|specificity]] (>90%) for identifying coeliac disease. Modern anti-tTG assays rely on a human recombinant protein as an antigen.<ref name="pmid10811336">{{cite journal | author = Sblattero D, Berti I, Trevisiol C, Marzari R, Tommasini A, Bradbury A, Fasano A, Ventura A, Not T | title = Human recombinant tissue transglutaminase ELISA: an innovative diagnostic assay for celiac disease | journal = Am. J. Gastroenterol. | volume = 95 | issue = 5 | pages = 1253–7 | year = 2000 | month = May | pmid = 10811336 | doi = 10.1111/j.1572-0241.2000.02018.x }}</ref>


==Therapeutic use==
=== Cancer ===
Recent studies suggest that tTG also plays a role in [[inflammation]] and tumor biology.<ref name="Griffin" /> 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 trial]]s have showed promise in using tTG inhibitors as anti-cancer therapeutic agents.<ref>{{Cite journal|last=Eckert|first=Richard L.|date=2019-01-29|title=Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target: Transglutaminase in cancer|journal=Molecular Carcinogenesis|volume=58|issue=6|pages=837–853|language=en|doi=10.1002/mc.22986|pmid=30693974|s2cid=59341070|pmc=7754084}}</ref> However, other studies <ref name="Tabolacci_2019" /> have noted that tTG transamidation activity could be linked to the inhibition of tumor cell invasiveness.
Use of tTG as a form of surgical glue is still experimental. It is also being studied as an attenuator of [[metastasis]] in certain tumors.<ref name=Griffin/>

=== Other Diseases ===
⚫
tTG is believed to contribute to several neurodegenerative disorders including [[Alzheimer]], [[Parkinson's disease|Parkinson]] and [[Huntington's disease|Huntington]] diseases by affecting transcription, differentiation and migration and adhesion .<ref name=Wilhelmus/><ref name=Ricotta/> 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.<ref name =Martin/> Additionally, specific proteins associated with these disorders have been found to be in vivo and in vitro substrates of tTG.<ref name=Facchiano/>
⚫
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.<ref name=Kumar/>
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 1|TGF beta]] activity.<ref name="Hitomi_2015" />

⚫
=== Diagnostic ===

⚫
[[Serology]] for anti-tTG [[antibody|antibodies]] has superseded older serological tests (anti-endomysium, anti-gliadin, and anti-reticulin) and has a strong [[sensitivity (tests)|sensitivity]] (99%) and [[Specificity (tests)|specificity]] (>90%) for identifying celiac disease. Modern anti-tTG assays rely on a human recombinant protein as an antigen.<ref name="pmid10811336">{{cite journal | vauthors = Sblattero D, Berti I, Trevisiol C, Marzari R, Tommasini A, Bradbury A, Fasano A, Ventura A, Not T | title = Human recombinant tissue transglutaminase ELISA: an innovative diagnostic assay for celiac disease | journal = The American Journal of Gastroenterology | volume = 95 | issue = 5 | pages = 1253–7 | date = May 2000 | doi = 10.1111/j.1572-0241.2000.02018.x | pmid = 10811336 | s2cid = 11018740 }}</ref>

=== 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.<ref name=Griffin/> tTG shows promise as a potential therapeutic target to treat [[cardiac fibrosis]], through the activity of a highly selective tTG [[Enzyme inhibitor|inhibitor]].<ref>{{cite journal | vauthors = Wang Z, Stuckey DJ, Murdoch CE, Camelliti P, Lip GY, Griffin M | title = Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor | journal = Cell Death & Disease | volume = 9 | issue = 6 | pages = 613 | date = April 2018 | pmid = 29795262 | pmc = 5966415 | doi = 10.1038/s41419-018-0573-2 }}</ref> tTG inhibitors have also been shown to inhibit the formation of toxic inclusions related to [[Neurodegeneration|neurodegenerative]] diseases.<ref name="Min_2018">{{cite journal | vauthors = Min B, Chung KC | title = New insight into transglutaminase 2 and link to neurodegenerative diseases | journal = BMB Reports | volume = 51 | issue = 1 | pages = 5–13 | date = January 2018 | pmid = 29187283 | pmc = 5796628 | doi = 10.5483/BMBRep.2018.51.1.227 }}</ref> This indicates that tTG inhibitors could also serve as a tool to mitigate the progression of tTG brain related diseases.<ref name="Min_2018" />

== Interactions ==

TG2 participates in both enzymatic and non-enzymatic [[Protein-protein interaction|interactions]]. Enzymatic interactions are formed between TG2 and its substrate proteins containing the [[glutamine]] donor and [[lysine]] donor groups in the presence of [[calcium]]. [[Substrate (chemistry)|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.<ref name=Travis>{{cite journal | vauthors = Kanchan K, Fuxreiter M, Fésüs L | s2cid = 14849506 | title = Physiological, pathological, and structural implications of non-enzymatic protein-protein interactions of the multifunctional human transglutaminase 2 | journal = Cellular and Molecular Life Sciences | volume = 72 | issue = 16 | pages = 3009–35 | date = August 2015 | pmid = 25943306 | doi = 10.1007/s00018-015-1909-z | pmc = 11113818 }}</ref>


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==References==
==Erp57==
Endoplasmic reticulum protein 57 (Erp57), is a [[Chaperone (protein)|chaperone]] molecule involved in loading [[peptide]] onto [[MHC class I molecule]]s in the [[endoplasmic reticulum]].
⚫
{{Reflist|35em|

Transglutaminase 2 (TG2) is a ubiquitously expressed (intracellular as well as extracellular) protein, with multiple modes of [[Post-translational regulation]], including an [[Allosteric regulation|allosteric]] [[disulfide]] bond between Cys-370-Cys-371 that renders the [[enzyme]] inactive in the extracellular matrix.<ref name="Yi_2018" />

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).

== References ==
⚫
{{Reflist|30em|
refs =
refs =
<ref name="Kiraly">{{cite journal | author = Király R, Demény M, Fésüs L | title = Protein transamidation by transglutaminase 2 in cells: a disputed Ca2+-dependent action of a multifunctional protein | journal = FEBS J. | volume = 278 | issue = 24 | pages = 4717–39 | year = 2011 | month = December | pmid = 21902809 | doi = 10.1111/j.1742-4658.2011.08345.x }}</ref>
<ref name="Kiraly">{{cite journal | vauthors = Király R, Demény M, Fésüs L | title = Protein transamidation by transglutaminase 2 in cells: a disputed Ca2+-dependent action of a multifunctional protein | journal = The FEBS Journal | volume = 278 | issue = 24 | pages = 4717–39 | date = December 2011 | pmid = 21902809 | doi = 10.1111/j.1742-4658.2011.08345.x | s2cid = 19217277 | doi-access = free }}</ref>
<ref name="Klock">{{cite journal | author = Klöck C, Diraimondo TR, Khosla C | title = Role of transglutaminase 2 in celiac disease pathogenesis | journal = Semin Immunopathol | volume = 34 | issue = 4 | pages = 513–22 | year = 2012 | month = July | pmid = 22437759 | doi = 10.1007/s00281-012-0305-0 }}</ref>
<ref name="Klock">{{cite journal | vauthors = Klöck C, Diraimondo TR, Khosla C | title = Role of transglutaminase 2 in celiac disease pathogenesis | journal = Seminars in Immunopathology | volume = 34 | issue = 4 | pages = 513–22 | date = July 2012 | pmid = 22437759 | pmc = 3712867 | doi = 10.1007/s00281-012-0305-0 }}</ref>


<ref name="Facchiano">{{cite journal | author = Facchiano F, Facchiano A, Facchiano AM | title = The role of transglutaminase-2 and its substrates in human diseases | journal = Front. Biosci. | volume = 11 | issue = | pages = 1758–73 | year = 2006 | pmid = 16368554 | doi =10.2741/1921 }}</ref>
<ref name="Facchiano">{{cite journal | vauthors = Facchiano F, Facchiano A, Facchiano AM | title = The role of transglutaminase-2 and its substrates in human diseases | journal = Frontiers in Bioscience | volume = 11 | pages = 1758–73 | date = May 2006 | pmid = 16368554 | doi = 10.2741/1921 | doi-access = free }}</ref>


<ref name="McConkey">{{cite journal | author = McConkey DJ, Orrenius S | title = The role of calcium in the regulation of apoptosis | journal = Biochem. Biophys. Res. Commun. | volume = 239 | issue = 2 | pages = 357–66 | year = 1997 | month = October | pmid = 9344835 | doi = 10.1006/bbrc.1997.7409 }}</ref>
<ref name="McConkey">{{cite journal | vauthors = McConkey DJ, Orrenius S | title = The role of calcium in the regulation of apoptosis | journal = Biochemical and Biophysical Research Communications | volume = 239 | issue = 2 | pages = 357–66 | date = October 1997 | pmid = 9344835 | doi = 10.1006/bbrc.1997.7409 | citeseerx = 10.1.1.483.2738 | s2cid = 11242870 }}</ref>


<ref name="Akimov">{{cite journal | author = Akimov SS, Krylov D, Fleischman LF, Belkin AM | title = Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin | journal = J. Cell Biol. | volume = 148 | issue = 4 | pages = 825–38 | year = 2000 | month = February | pmid = 10684262 | pmc = 2169362 | doi =10.1083/jcb.148.4.825 }}</ref>
<ref name="Akimov">{{cite journal | vauthors = Akimov SS, Krylov D, Fleischman LF, Belkin AM | title = Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin | journal = The Journal of Cell Biology | volume = 148 | issue = 4 | pages = 825–38 | date = February 2000 | pmid = 10684262 | pmc = 2169362 | doi = 10.1083/jcb.148.4.825 }}</ref>


<ref name="Jin">{{cite journal | author = Jin X, Stamnaes J, Klöck C, DiRaimondo TR, Sollid LM, Khosla C | title = Activation of extracellular transglutaminase 2 by thioredoxin | journal = J. Biol. Chem. | volume = 286 | issue = 43 | pages = 37866–73 | year = 2011 | month = October | pmid = 21908620 | pmc = 3199528 | doi = 10.1074/jbc.M111.287490 }}</ref>
<ref name="Jin">{{cite journal | vauthors = Jin X, Stamnaes J, Klöck C, DiRaimondo TR, Sollid LM, Khosla C | title = Activation of extracellular transglutaminase 2 by thioredoxin | journal = The Journal of Biological Chemistry | volume = 286 | issue = 43 | pages = 37866–73 | date = October 2011 | pmid = 21908620 | pmc = 3199528 | doi = 10.1074/jbc.M111.287490 | doi-access = free }}</ref>


<ref name="DiRaimondo">{{cite journal | author = Diraimondo TR, Klöck C, Khosla C | title = Interferon-γ activates transglutaminase 2 via a phosphatidylinositol-3-kinase-dependent pathway: implications for celiac sprue therapy | journal = J. Pharmacol. Exp. Ther. | volume = 341 | issue = 1 | pages = 104–14 | year = 2012 | month = April | pmid = 22228808 | doi = 10.1124/jpet.111.187385 | pmc = 3310700 }}</ref>
<ref name="DiRaimondo">{{cite journal | vauthors = Diraimondo TR, Klöck C, Khosla C | title = Interferon-γ activates transglutaminase 2 via a phosphatidylinositol-3-kinase-dependent pathway: implications for celiac sprue therapy | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 341 | issue = 1 | pages = 104–14 | date = April 2012 | pmid = 22228808 | pmc = 3310700 | doi = 10.1124/jpet.111.187385 }}</ref>


<ref name="Pinkas">{{cite journal | author = Pinkas DM, Strop P, Brunger AT, Khosla C | title = Transglutaminase 2 undergoes a large conformational change upon activation | journal = PLoS Biol. | volume = 5 | issue = 12 | pages = e327 | year = 2007 | month = December | pmid = 18092889 | pmc = 2140088 | doi = 10.1371/journal.pbio.0050327 }}</ref>
<ref name="Pinkas">{{cite journal | vauthors = Pinkas DM, Strop P, Brunger AT, Khosla C | title = Transglutaminase 2 undergoes a large conformational change upon activation | journal = PLOS Biology | volume = 5 | issue = 12 | pages = e327 | date = December 2007 | pmid = 18092889 | pmc = 2140088 | doi = 10.1371/journal.pbio.0050327 | doi-access = free }}</ref>


<ref name="Colak">{{cite journal | author = Colak G, Keillor JW, Johnson GV | title = Cytosolic guanine nucledotide binding deficient form of transglutaminase 2 (R580a) potentiates cell death in oxygen glucose deprivation | journal = PLoS ONE | volume = 6 | issue = 1 | pages = e16665 | year = 2011 | pmid = 21304968 | pmc = 3031627 | doi = 10.1371/journal.pone.0016665 | editor1-last = Polymenis | editor1-first = Michael }}</ref>
<ref name="Colak">{{cite journal | vauthors = Colak G, Keillor JW, Johnson GV | title = Cytosolic guanine nucledotide binding deficient form of transglutaminase 2 (R580a) potentiates cell death in oxygen glucose deprivation | journal = PLOS ONE | volume = 6 | issue = 1 | pages = e16665 | date = January 2011 | pmid = 21304968 | pmc = 3031627 | doi = 10.1371/journal.pone.0016665 | bibcode = 2011PLoSO...616665C | editor1-last = Polymenis | editor1-first = Michael | doi-access = free }}</ref>


<ref name="Lortat-Jacob">{{cite journal | author = Lortat-Jacob H, Burhan I, Scarpellini A, Thomas A, Imberty A, Vivès RR, Johnson T, Gutierrez A, Verderio EA | title = Transglutaminase-2 interaction with heparin: identification of a heparin binding site that regulates cell adhesion to fibronectin-transglutaminase-2 matrix | journal = J. Biol. Chem. | volume = 287 | issue = 22 | pages = 18005–17 | year = 2012 | month = May | pmid = 22442151 | pmc = 3365763 | doi = 10.1074/jbc.M111.337089 }}</ref>
<ref name="Lortat-Jacob">{{cite journal | vauthors = Lortat-Jacob H, Burhan I, Scarpellini A, Thomas A, Imberty A, Vivès RR, Johnson T, Gutierrez A, Verderio EA | title = Transglutaminase-2 interaction with heparin: identification of a heparin binding site that regulates cell adhesion to fibronectin-transglutaminase-2 matrix | journal = The Journal of Biological Chemistry | volume = 287 | issue = 22 | pages = 18005–17 | date = May 2012 | pmid = 22442151 | pmc = 3365763 | doi = 10.1074/jbc.M111.337089 | doi-access = free }}</ref>


<ref name="Wilhelmus">{{cite journal | author = Wilhelmus MM, Verhaar R, Andringa G, Bol JG, Cras P, Shan L, Hoozemans JJ, Drukarch B | title = Presence of tissue transglutaminase in granular endoplasmic reticulum is characteristic of melanized neurons in Parkinson's disease brain | journal = Brain Pathol. | volume = 21 | issue = 2 | pages = 130–9 | year = 2011 | month = March | pmid = 20731657 | doi = 10.1111/j.1750-3639.2010.00429.x }}</ref>
<ref name="Wilhelmus">{{cite journal | vauthors = Wilhelmus MM, Verhaar R, Andringa G, Bol JG, Cras P, Shan L, Hoozemans JJ, Drukarch B | title = Presence of tissue transglutaminase in granular endoplasmic reticulum is characteristic of melanized neurons in Parkinson's disease brain | journal = Brain Pathology | volume = 21 | issue = 2 | pages = 130–9 | date = March 2011 | pmid = 20731657 | doi = 10.1111/j.1750-3639.2010.00429.x | s2cid = 586174 | pmc = 8094245 }}</ref>


<ref name="Martin">{{cite journal | author = Martin A, Giuliano A, Collaro D, De Vivo G, Sedia C, Serretiello E, Gentile V | title = Possible involvement of transglutaminase-catalyzed reactions in the physiopathology of neurodegenerative diseases | journal = Amino Acids | volume = 44 | issue = 1 | pages = 111–8 | year = 2013 | month = January | pmid = 21938398 | doi = 10.1007/s00726-011-1081-1 }}</ref>
<ref name="Martin">{{cite journal | vauthors = Martin A, Giuliano A, Collaro D, De Vivo G, Sedia C, Serretiello E, Gentile V | s2cid = 16143202 | title = Possible involvement of transglutaminase-catalyzed reactions in the physiopathology of neurodegenerative diseases | journal = Amino Acids | volume = 44 | issue = 1 | pages = 111–8 | date = January 2013 | pmid = 21938398 | doi = 10.1007/s00726-011-1081-1 }}</ref>


<ref name="Kumar">{{cite journal | author = Kumar A, Kneynsberg A, Tucholski J, Perry G, van Groen T, Detloff PJ, Lesort M | title = Tissue transglutaminase overexpression does not modify the disease phenotype of the R6/2 mouse model of Huntington's disease | journal = Exp. Neurol. | volume = 237 | issue = 1 | pages = 78–89 | year = 2012 | month = September | pmid = 22698685 | doi = 10.1016/j.expneurol.2012.05.015 | pmc = 3418489 }}</ref>
<ref name="Kumar">{{cite journal | vauthors = Kumar A, Kneynsberg A, Tucholski J, Perry G, van Groen T, Detloff PJ, Lesort M | title = Tissue transglutaminase overexpression does not modify the disease phenotype of the R6/2 mouse model of Huntington's disease | journal = Experimental Neurology | volume = 237 | issue = 1 | pages = 78–89 | date = September 2012 | pmid = 22698685 | pmc = 3418489 | doi = 10.1016/j.expneurol.2012.05.015 }}</ref>


<ref name="Sabatino">{{cite journal | author = Di Sabatino A, Vanoli A, Giuffrida P, Luinetti O, Solcia E, Corazza GR | title = The function of tissue transglutaminase in celiac disease | journal = Autoimmun Rev | volume = 11 | issue = 10 | pages = 746–53 | year = 2012 | month = August | pmid = 22326684 | doi = 10.1016/j.autrev.2012.01.007 }}</ref>
<ref name="Sabatino">{{cite journal | vauthors = Di Sabatino A, Vanoli A, Giuffrida P, Luinetti O, Solcia E, Corazza GR | title = The function of tissue transglutaminase in celiac disease | journal = Autoimmunity Reviews | volume = 11 | issue = 10 | pages = 746–53 | date = August 2012 | pmid = 22326684 | doi = 10.1016/j.autrev.2012.01.007 }}</ref>


<ref name="Ricotta">{{cite journal | author = Ricotta M, Iannuzzi M, Vivo GD, Gentile V | title = Physio-pathological roles of transglutaminase-catalyzed reactions | journal = World J Biol Chem | volume = 1 | issue = 5 | pages = 181–7 | year = 2010 | month = May | pmid = 21541002 | pmc = 3083958 | doi = 10.4331/wjbc.v1.i5.181 }}</ref>
<ref name="Ricotta">{{cite journal | vauthors = Ricotta M, Iannuzzi M, Vivo GD, Gentile V | title = Physio-pathological roles of transglutaminase-catalyzed reactions | journal = World Journal of Biological Chemistry | volume = 1 | issue = 5 | pages = 181–7 | date = May 2010 | pmid = 21541002 | pmc = 3083958 | doi = 10.4331/wjbc.v1.i5.181 | doi-access = free }}</ref>


<ref name="Nurminskaya">{{cite journal | author = Nurminskaya MV, Belkin AM | title = Cellular functions of tissue transglutaminase | journal = Int Rev Cell Mol Biol | volume = 294 | issue = | pages = 1–97 | year = 2012 | pmid = 22364871 | doi = 10.1016/B978-0-12-394305-7.00001-X | series = International Review of Cell and Molecular Biology | isbn = 9780123943057 }}</ref>
<ref name="Nurminskaya">{{cite book | vauthors = Nurminskaya MV, Belkin AM | title = Cellular functions of tissue transglutaminase | volume = 294 | pages = 1–97 | year = 2012 | pmid = 22364871 | doi = 10.1016/B978-0-12-394305-7.00001-X | isbn = 9780123943057 | series = International Review of Cell and Molecular Biology | pmc=3746560}}</ref>
}}
}}


==External links==
== External links ==
*[http://www.antibodypatterns.com/endomysial.php Endomysial antibodies]
*[http://www.antibodypatterns.com/endomysial.php Endomysial antibodies] {{Webarchive|url=https://web.archive.org/web/20210512150317/http://www.antibodypatterns.com/endomysial.php |date=2021-05-12 }}
* A collection of substrates and interaction partners of TG2 is accessible in the [http://genomics.dote.hu/wiki/index.php/Main_Page TRANSDAB], an interactive transglutaminase substrate database.
* A collection of substrates and interaction partners of TG2 is accessible in the [http://genomics.dote.hu/wiki/index.php/Main_Page TRANSDAB], an interactive transglutaminase substrate database.


{{PDB_Gallery|geneid=7052}}
{{PDB_Gallery|geneid=7052}}
{{Acyltransferases}}
{{Acyltransferases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}
{{Autoantigens}}
{{Autoantigens}}


Latest revision as of 23:30, 30 May 2024

"TGM2" redirects here. For the Tetris game, see Tetris: The Grand Master.
TGM2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTGM2, G-ALPHA-h, GNAH, HEL-S-45, TG2, TGC, TG(C), transglutaminase 2, G(h), hTG2, tTG
External IDsOMIM: 190196; MGI: 98731; HomoloGene: 3391; GeneCards: TGM2; OMA:TGM2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7052

21817

Ensembl

ENSG00000198959

ENSMUSG00000037820

UniProt

P21980

P21981

RefSeq (mRNA)

NM_004613
NM_198951
NM_001323316
NM_001323317
NM_001323318

NM_009373

RefSeq (protein)

NP_001310245
NP_001310246
NP_001310247
NP_004604
NP_945189

NP_033399

Location (UCSC)Chr 20: 38.13 – 38.17 MbChr 2: 157.96 – 157.99 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Protein-glutamine gamma-glutamyltransferase
Identifiers
EC no.2.3.2.13
CAS no.80146-85-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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

[edit]

Gene

[edit]

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

Protein

[edit]

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

[edit]

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.

reaction mechanism of tTG
Figure 1: Transamidation (crosslinking) and deamidation mechanisms of tissue transglutaminase

Regulation

[edit]

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 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]

X-ray crystallography images of tissue transglutaminase in two different conformations
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.

Function

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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

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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

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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

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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

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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

[edit]

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

[edit]

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

[edit]

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
Molecular structure of Tgm2 region with inserted mutation sequence
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

[edit]

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).

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