Protein transamidation by transglutaminase 2 in cells: a disputed Ca2+‐dependent action of a multifunctional protein

Transglutaminase 2 (TG2) is the first described cellular member of an enzyme family catalyzing Ca2+‐dependent transamidation of proteins. During the last two decades its additional enzymatic (GTP binding and hydrolysis, protein disulfide isomerase, protein kinase) and non‐enzymatic (multiple interactions in protein scaffolds) activities, which do not require Ca2+, have been recognized. It became a prevailing view that TG2 is silent as a transamidase, except in extreme stress conditions, in the intracellular environment characterized by low Ca2+ and high GTP concentrations. To counter this presumption a critical review of the experimental evidence supporting the role of this enzymatic activity in cellular processes is provided. It includes the structural basis of TG2 regulation through non‐canonical Ca2+ binding sites, mechanisms making it sensitive to low Ca2+ concentrations, techniques developed for the detection of protein transamidation in cells and examples of basic cellular phenomena as well as pathological conditions influenced by this irreversible post‐translational protein modification.