Tissue transglutaminase

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Transglutaminase 2
Tissue transglutaminase.png
Tissue transglutaminase drawn from PDB: 1KV3​.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols TGM2 ; G-ALPHA-h; GNAH; HEL-S-45; TG2; TGC
External IDs OMIM190196 MGI98731 HomoloGene3391 ChEMBL: 2730 GeneCards: TGM2 Gene
EC number
RNA expression pattern
PBB GE TGM2 201042 at tn.png
PBB GE TGM2 211003 x at tn.png
PBB GE TGM2 211573 x at tn.png
More reference expression data
Species Human Mouse
Entrez 7052 21817
Ensembl ENSG00000198959 ENSMUSG00000037820
UniProt P21980 P21981
RefSeq (mRNA) NM_004613 NM_009373
RefSeq (protein) NP_004604 NP_033399
Location (UCSC) Chr 20:
38.13 – 38.17 Mb
Chr 2:
158.12 – 158.15 Mb
PubMed search [1] [2]
Protein-glutamine gamma-glutamyltransferase
EC number
CAS number 80146-85-6
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Tissue transglutaminase (abbreviated as tTG or TG2) is a 78-kDa, calcium dependent enzyme (EC of the protein-glutamine γ-glutamyltransferases family (or simply transglutaminase family).[1][2] 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.[3] 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.[2] Intracellular tTG is thought to play an important role in apoptosis.[4] In the extracellular space, tTG binds to proteins of the extracellular matrix (ECM),[5] binding particularly tightly to fibronectin.[6] Extracellular tTG has been linked to cell adhesion, ECM stabilization, wound healing, receptor signaling, cellular proliferation, and cellular motility.[2]

tTG is particularly notable for being the 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.[7][8][9]



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


TG2 is a multifunctional enzyme that belongs to transglutaminases which catalyze the crosslinking of proteins by epsilon-(gamma-glutamyl)lysine isopeptide bonds.[10] 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. In the open conformation the four domains of TG2 are arranged in an extended configuration, whereas in the closed conformation the two C-terminal domains are folded in on the catalytic core domain. The N-terminal domain only shows minor structural changes between the two different conformations.[11]


The catalytic mechanism for crosslinking in human tTG involves the thiol group from a Cys residue in the active site of tTG.[2] 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).[2] The deamidation of glutamine residues catalyzed by tTG is thought to be linked to the pathological immune response to gluten in celiac disease.[8] 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


Crosslinking activity by tTG requires the binding of Ca2+ ions.[12] Multiple Ca2+ can bind to a single tTG molecule.[2] In contrast, the binding of one molecule of GTP or GDP inhibits the crosslinking activity of the enzyme.[12] Therefore, intracellular tTG is mostly inactive due to the relatively high concentration of GTP/GDP and the low levels of calcium inside the cell.[2][8] 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.[2][8][12] 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 Ca2+) for the activation of tTG.[8] Thioredoxin has been shown to activate extracellular tTG by reducing the disulfide bond.[12] 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.[8] 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)[12][13][14]

X-ray crystallography images of  tissue transglutaminase in two different conformations
Figure 2: Compact (inactive) and extended (active) conformations of tTG


tTG is expressed ubiquitously. 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[7]

tTG is thought to be involved in the regulation of the cytoskeleton by crosslinking various cytoskeletal proteins including myosin, actin, and spectrin.[15] 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.[3]

tTG also has GTPase activity:[1] In the presence of GTP, it suggested to function as a G protein participating in signaling processes.[16] Besides its transglutaminase activity, tTG is proposed to also act as kinase,[17] and protein disulfide isomerase,[18] and deamidase.[19] This latter activity is important in the deamidation of gliadin peptides, thus playing important role in the pathology of coeliac disease.

Clinical significance[edit]

tTG is best known for its link with celiac disease.[9] Anti-transglutaminase antibodies (ATA) 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 ATA IgA and IgG.[20]

tTG is believed to be involved in several neurodegenerative disorders including Alzheimer, Parkinson and Huntington diseases.[21][22] 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.[23] Additionally, specific proteins associated with these disorders have been found to be in vivo and in vitro substrates of tTG.[3] 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.[24]

Recent studies suggest that tTG also plays a role in inflammation and tumor biology.[7] 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.


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 coeliac disease. Modern anti-tTG assays rely on a human recombinant protein as an antigen.[25]


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.[7]


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.[26]

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


  1. ^ a b Király R, Demény M, Fésüs L (Dec 2011). "Protein transamidation by transglutaminase 2 in cells: a disputed Ca2+-dependent action of a multifunctional protein". The FEBS Journal 278 (24): 4717–39. doi:10.1111/j.1742-4658.2011.08345.x. PMID 21902809. 
  2. ^ a b c d e f g h Klöck C, Diraimondo TR, Khosla C (Jul 2012). "Role of transglutaminase 2 in celiac disease pathogenesis". Seminars in Immunopathology 34 (4): 513–22. doi:10.1007/s00281-012-0305-0. PMID 22437759. 
  3. ^ a b c Facchiano F, Facchiano A, Facchiano AM (2006). "The role of transglutaminase-2 and its substrates in human diseases". Frontiers in Bioscience 11: 1758–73. doi:10.2741/1921. PMID 16368554. 
  4. ^ McConkey DJ, Orrenius S (Oct 1997). "The role of calcium in the regulation of apoptosis". Biochemical and Biophysical Research Communications 239 (2): 357–66. doi:10.1006/bbrc.1997.7409. PMID 9344835. 
  5. ^ Lortat-Jacob H, Burhan I, Scarpellini A, Thomas A, Imberty A, Vivès RR, Johnson T, Gutierrez A, Verderio EA (May 2012). "Transglutaminase-2 interaction with heparin: identification of a heparin binding site that regulates cell adhesion to fibronectin-transglutaminase-2 matrix". The Journal of Biological Chemistry 287 (22): 18005–17. doi:10.1074/jbc.M111.337089. PMC 3365763. PMID 22442151. 
  6. ^ Akimov SS, Krylov D, Fleischman LF, Belkin AM (Feb 2000). "Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin". The Journal of Cell Biology 148 (4): 825–38. doi:10.1083/jcb.148.4.825. PMC 2169362. PMID 10684262. 
  7. ^ a b c d Griffin M, Casadio R, Bergamini CM (Dec 2002). "Transglutaminases: nature's biological glues". The Biochemical Journal 368 (Pt 2): 377–96. doi:10.1042/BJ20021234. PMC 1223021. PMID 12366374. 
  8. ^ a b c d e f Diraimondo TR, Klöck C, Khosla C (Apr 2012). "Interferon-γ activates transglutaminase 2 via a phosphatidylinositol-3-kinase-dependent pathway: implications for celiac sprue therapy". The Journal of Pharmacology and Experimental Therapeutics 341 (1): 104–14. doi:10.1124/jpet.111.187385. PMC 3310700. PMID 22228808. 
  9. ^ a b Di Sabatino A, Vanoli A, Giuffrida P, Luinetti O, Solcia E, Corazza GR (Aug 2012). "The function of tissue transglutaminase in celiac disease". Autoimmunity Reviews 11 (10): 746–53. doi:10.1016/j.autrev.2012.01.007. PMID 22326684. 
  10. ^ "Entrez Gene: TGM2 transglutaminase 2". 
  11. ^ Chen X, Hnida K, Graewert MA, Andersen JT, Iversen R, Tuukkanen A, Svergun D, Sollid LM (Aug 2015). "Structural Basis for Antigen Recognition by Transglutaminase 2-specific Autoantibodies in Celiac Disease". The Journal of Biological Chemistry 290 (35): 21365–75. doi:10.1074/jbc.M115.669895. PMID 26160175. 
  12. ^ a b c d e Jin X, Stamnaes J, Klöck C, DiRaimondo TR, Sollid LM, Khosla C (Oct 2011). "Activation of extracellular transglutaminase 2 by thioredoxin". The Journal of Biological Chemistry 286 (43): 37866–73. doi:10.1074/jbc.M111.287490. PMC 3199528. PMID 21908620. 
  13. ^ Pinkas DM, Strop P, Brunger AT, Khosla C (Dec 2007). "Transglutaminase 2 undergoes a large conformational change upon activation". PLoS Biology 5 (12): e327. doi:10.1371/journal.pbio.0050327. PMC 2140088. PMID 18092889. 
  14. ^ Colak G, Keillor JW, Johnson GV (2011). Polymenis M, ed. "Cytosolic guanine nucledotide binding deficient form of transglutaminase 2 (R580a) potentiates cell death in oxygen glucose deprivation". PloS One 6 (1): e16665. doi:10.1371/journal.pone.0016665. PMC 3031627. PMID 21304968. 
  15. ^ Nurminskaya MV, Belkin AM (2012). "Cellular functions of tissue transglutaminase". International Review of Cell and Molecular Biology. International Review of Cell and Molecular Biology 294: 1–97. doi:10.1016/B978-0-12-394305-7.00001-X. ISBN 9780123943057. PMID 22364871. 
  16. ^ Fesus L, Piacentini M (Oct 2002). "Transglutaminase 2: an enigmatic enzyme with diverse functions". Trends in Biochemical Sciences 27 (10): 534–9. doi:10.1016/S0968-0004(02)02182-5. PMID 12368090. 
  17. ^ Mishra S, Murphy LJ (Jun 2004). "Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase". The Journal of Biological Chemistry 279 (23): 23863–8. doi:10.1074/jbc.M311919200. PMID 15069073. 
  18. ^ Hasegawa G, Suwa M, Ichikawa Y, Ohtsuka T, Kumagai S, Kikuchi M, Sato Y, Saito Y (Aug 2003). "A novel function of tissue-type transglutaminase: protein disulphide isomerase". The Biochemical Journal 373 (Pt 3): 793–803. doi:10.1042/BJ20021084. PMC 1223550. PMID 12737632. 
  19. ^ Sakly W, Thomas V, Quash G, El Alaoui S (Dec 2006). "A role for tissue transglutaminase in alpha-gliadin peptide cytotoxicity". Clinical and Experimental Immunology 146 (3): 550–8. doi:10.1111/j.1365-2249.2006.03236.x. PMC 1810403. PMID 17100777. 
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  21. ^ Wilhelmus MM, Verhaar R, Andringa G, Bol JG, Cras P, Shan L, Hoozemans JJ, Drukarch B (Mar 2011). "Presence of tissue transglutaminase in granular endoplasmic reticulum is characteristic of melanized neurons in Parkinson's disease brain". Brain Pathology 21 (2): 130–9. doi:10.1111/j.1750-3639.2010.00429.x. PMID 20731657. 
  22. ^ Ricotta M, Iannuzzi M, Vivo GD, Gentile V (May 2010). "Physio-pathological roles of transglutaminase-catalyzed reactions". World Journal of Biological Chemistry 1 (5): 181–7. doi:10.4331/wjbc.v1.i5.181. PMC 3083958. PMID 21541002. 
  23. ^ Martin A, Giuliano A, Collaro D, De Vivo G, Sedia C, Serretiello E, Gentile V (Jan 2013). "Possible involvement of transglutaminase-catalyzed reactions in the physiopathology of neurodegenerative diseases". Amino Acids 44 (1): 111–8. doi:10.1007/s00726-011-1081-1. PMID 21938398. 
  24. ^ Kumar A, Kneynsberg A, Tucholski J, Perry G, van Groen T, Detloff PJ, Lesort M (Sep 2012). "Tissue transglutaminase overexpression does not modify the disease phenotype of the R6/2 mouse model of Huntington's disease". Experimental Neurology 237 (1): 78–89. doi:10.1016/j.expneurol.2012.05.015. PMC 3418489. PMID 22698685. 
  25. ^ Sblattero D, Berti I, Trevisiol C, Marzari R, Tommasini A, Bradbury A, Fasano A, Ventura A, Not T (May 2000). "Human recombinant tissue transglutaminase ELISA: an innovative diagnostic assay for celiac disease". The American Journal of Gastroenterology 95 (5): 1253–7. doi:10.1111/j.1572-0241.2000.02018.x. PMID 10811336. 
  26. ^ Kanchan K, Fuxreiter M, Fésüs L (Aug 2015). "Physiological, pathological, and structural implications of non-enzymatic protein-protein interactions of the multifunctional human transglutaminase 2". Cellular and Molecular Life Sciences 72 (16): 3009–35. doi:10.1007/s00018-015-1909-z. PMID 25943306. 

External links[edit]

  • Endomysial antibodies
  • A collection of substrates and interaction partners of TG2 is accessible in the TRANSDAB, an interactive transglutaminase substrate database.