Transglutaminase 2 (TG2) is the most abundant member of the transglutaminase enzyme family that is found in the intra- and extracellular spaces of various tissues. It shares a common domain structure with other TGs that includes an N-terminal β-sandwich containing integrin and fibronectin binding sites, a catalytic core for acyl transfer reactions, and two C-terminal β-barrel domains with the second containing a phospholipase C binding sequence. Unlike other TGs, TG2 has a guanidine nucleotide binding site between its catalytic core and first β-barrel. TG2 catalyzes protein crosslinking in a calcium-dependent manner, creating an inter- or intramolecular bond between the ε-amino group of a lysine residue and the γ-carboxamide group of a glutamine residue that is highly resistant to proteolysis. TG2 also exhibits calcium-independent enzyme activities, including GTPase, protein kinase, and disulfide isomerase activity in vitro and in vivo. Intracellular TG2 has important roles in protein stabilization, cytoskeletal regulation, and apoptosis. It interacts with microtubule-associated protein tau-isoform Tau-F (Tau-4) and acetylcholinesterase, implicating TG2 in the pathology of neurodegenerative diseases. Extracellular TG2 has been linked to wound healing, receptor signaling, cell motility and adhesion, as well as stabilization of the extracellular matrix (ECM).
