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

Abstract

Transglutaminase 2 (TG2) is the first described cellular member of an enzyme family catalyzing Ca 2+ -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 Ca 2+ , 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 Ca 2+ 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 noncanonical Ca 2+ binding sites, mechanisms making it sensitive to low Ca

Role of transglutaminase 2 in PAC1 receptor mediated protection against hypoxia-induced cell death and neurite outgrowth in differentiating N2a neuroblastoma cells

“…form of TG2 and negates the inhibitory actions of the nucleotides GTP, GDP and ATP (Király et al, 2011). Previous studies have shown that release of Ca 2+ from intracellular Ca 2+ stores or influx of extracellular Ca 2+ is linked to TG activation in response to GPCR stimulation (Zhang et al, 1998;Walther et al, 2003;Vyas et al, 2016 et al, 2011).…”

Transglutaminase activity is decreased in large arteries from hypertensive rats compared with normotensive controls

“…While it has become a general view in the field that intracellular TG2 is not active, there is evidence that suggests the reducing milieu in cells, increases in intracellular Ca 2ϩ levels, and decreases in intracellular GTP levels can lead to sensitization and activation of TG2, as outlined in Ref. 11. The inhibitor cystamine was used because it is not isoform specific and therefore was ideal for our research, as opposed to other inhibitors, such as TG2-specific L682.777.…”

Regulation of the activities of the mammalian transglutaminase family of enzymes

“…43,44 These mutations map to the vicinity of the putative calcium-binding site S3. 45 The vicinal disulfide bond between Cys370 and Cys371 is depicted in the inset.…”