About TGM2 / Transglutaminase:
TGM2, also called tissue transglutaminase, is an enzyme involved in crosslinking.
TGM2 is found in a variety of cellular compartments, including the plasma membrane, nucleus, and cytosol. Its primary role appears to be the construction of the extracellular matrix, especially in response to an injury, but its precise activity is cell-type dependent. In neurons, for example, TGM2 supports the survival of injured cells (perhaps from a head injury). In astrocytes, by contrast, knocking out the enzyme assists with their survival.
TGM2 is also thought to play a role in a variety of other structures in the body that depend on cellular crosslinking. The most obvious example is bone. Here, TGM2 regulates the activity of cytoskeleton, allowing structures such as spectrin, actin, and myosin to cross-link more effective with one another.
TGM2 may play a role in cellular apoptosis or programmed cell death. Its purpose is to stabilize the structure of the cell as it dies, helping to polymerize the cell, preventing the leakage of cellular contents into the extracellular space. It may, therefore, be an essential adjunct to fasting and other longevity interventions.
Researchers are also increasingly coming to believe that TGM2 plays a vital role in the regulation of proteostasis by catalyzing the trimerization of heat shock factor 1. When the body experiences extremes of hot or cold, TGM2 upregulates to form the necessary trimer to buffer against excessive heat. Model organisms that do not have the ability to create the TGM2 enzyme do not react as well to heat insult.
TGM2 is an enzyme that is a part of the transglutaminase family, which catalyzes the crosslinking of proteins using lysine isopeptide bonds. Just lie other transglutaminases, it has a GDP/GTP binding site, a beta-sandwich, two beta-barrel, and a catalytic domain. When in crystal structures, TGM2 adopts a closed conformation. However, when it is on the active site and accompanied by an inhibitor, it assumes the “open position.”
TGM2 is responsible for catalyzing the reaction that crosslinks human and animal cells. In humans, this crosslinking relies on the thiol group from a Cys residue on the active TGM2 site. The thiol group reacts with the carboxamide of glutamine residue on the surface of the protein or peptide substrate, leading to the formation of ammonia and the production of a thioester intermediate. This intermediate then reacts with the surface amine of a second substrate (such as a lysine residue), leading to a stable isopeptide bond between the two substances - hence the completion of the crosslinking process.
TGM2 is most famous for its link to celiac disease. Researchers found that TGM2 was the enzyme recognized by the antibodies specific to celiac. These antibodies result in a form of gluten hypersensitivity, which results in an immune response whenever an affected person eats gluten-containing foods.
TGM2 is also linked with cancer. Researchers have found that TGM2 expression is elevated in many forms of cancer, leading to higher levels of inflammation and biochemistry that promotes tumor growth. Higher expression appears to lead to a greater number of metastases.