Tissue transglutaminase

Protein coding gene in the species Homo sapiens

Tissue transglutaminase (abbreviated as tTG or TG2) is a 78 kDa, calcium dependent enzyme of the protein glutamine γ glutamyltransferases family (or simply transglutaminase family).

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. Similarly to other transglutaminases, tTG consists of a GTP/ GDP binding site, a catalytic domain, two beta barrel and a beta sandwich. 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, 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. The N terminal domain only shows minor structural changes between the two different conformations.

The catalytic mechanism for crosslinking in human tTG involves the thiol group from a Cys residue in the active site of tTG. Crosslinking activity by tTG requires the binding of Ca2+ ions. When this disulfide bond forms, the enzyme remains in an open confirmation but becomes catalytically inactive. tTG is thought to be involved in the regulation of the cytoskeleton by crosslinking various cytoskeletal proteins including myosin, actin, and spectrin. Besides its transglutaminase activity, tTG is proposed to also act as kinase, and protein disulfide isomerase, and deamidase. 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. 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.

tTG is best known for its link with celiac disease. 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. However, other studies

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. tTG inhibitors have also been shown to inhibit the formation of toxic inclusions related to neurodegenerative diseases. This indicates that tTG inhibitors could also serve as a tool to mitigate the progression of tTG brain related diseases. Mouse Mutant Alleles for Tgm2 Marker Symbol for Mouse Gene. This symbol is assigned to the genomic locus by the MGITgm2Mutant 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 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

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.