Calcium-dependent acyltransferase that catalyzes the formation of covalent bonds between peptide-bound glutamine and various primary amines, such as gamma-amino group of peptide-bound lysine, or mono- and polyamines, thereby producing cross-linked or aminated proteins, respectively (PubMed:9252372, PubMed:23941696, PubMed:31991788). Involved in many biological processes, such as bone development, angiogenesis, wound healing, cellular differentiation, chromatin modification and apoptosis (PubMed:1683874, PubMed:7935379, PubMed:9252372, PubMed:27270573). Acts as a protein-glutamine gamma-glutamyltransferase by mediating the cross-linking of proteins, such as ACO2, HSPB6, FN1, HMGB1, RAP1GDS1, SLC25A4/ANT1, SPP1 and WDR54 (PubMed:23941696, PubMed:24349085, PubMed:29618516, PubMed:30458214). Under physiological conditions, the protein cross-linking activity is inhibited by GTP; inhibition is relieved by Ca(2+) in response to various stresses (PubMed:7649299, PubMed:7592956, PubMed:18092889). When secreted, catalyzes cross-linking of proteins of the extracellular matrix, such as FN1 and SPP1 resulting in the formation of scaffolds (PubMed:12506096). Plays a key role during apoptosis, both by (1) promoting the cross-linking of cytoskeletal proteins resulting in condensation of the cytoplasm, and by (2) mediating cross-linking proteins of the extracellular matrix, resulting in the irreversible formation of scaffolds that stabilize the integrity of the dying cells before their clearance by phagocytosis, thereby preventing the leakage of harmful intracellular components (PubMed:7935379, PubMed:9252372). In addition to protein cross-linking, can use different monoamine substrates to catalyze a vast array of protein post-translational modifications: mediates aminylation of serotonin, dopamine, noradrenaline or histamine into glutamine residues of target proteins to generate protein serotonylation, dopaminylation, noradrenalinylation or histaminylation, respectively (PubMed:23797785, PubMed:30867594). Mediates protein serotonylation of small GTPases during activation and aggregation of platelets, leading to constitutive activation of these GTPases (By similarity). Plays a key role in chromatin organization by mediating serotonylation and dopaminylation of histone H3 (PubMed:30867594, PubMed:32273471). Catalyzes serotonylation of 'Gln-5' of histone H3 (H3Q5ser) during serotonergic neuron differentiation, thereby facilitating transcription (PubMed:30867594). Acts as a mediator of neurotransmission-independent role of nuclear dopamine in ventral tegmental area (VTA) neurons: catalyzes dopaminylation of 'Gln-5' of histone H3 (H3Q5dop), thereby regulating relapse-related transcriptional plasticity in the reward system (PubMed:32273471). Regulates vein remodeling by mediating serotonylation and subsequent inactivation of ATP2A2/SERCA2 (By similarity). Also acts as a protein deamidase by mediating the side chain deamidation of specific glutamine residues of proteins to glutamate (PubMed:9623982, PubMed:20547769). Catalyzes specific deamidation of protein gliadin, a component of wheat gluten in the diet (PubMed:9623982). May also act as an isopeptidase cleaving the previously formed cross-links (PubMed:26250429, PubMed:27131890). Also able to participate in signaling pathways independently of its acyltransferase activity: acts as a signal transducer in alpha-1 adrenergic receptor-mediated stimulation of phospholipase C-delta (PLCD) activity and is required for coupling alpha-1 adrenergic agonists to the stimulation of phosphoinositide lipid metabolism (PubMed:8943303). Has cytotoxic activity: is able to induce apoptosis independently of its acyltransferase activity. L-glutaminyl-[protein] + L-lysyl-[protein] = [protein]-L-lysyl-N(6)-5-L-glutamyl-[protein] + NH4(+) L-glutaminyl-[protein] + serotonin = 5-serotonyl-L-glutamyl-[protein] + NH4(+) dopamine + L-glutaminyl-[protein] = 5-dopaminyl-L-glutamyl-[protein] + NH4(+) histamine + L-glutaminyl-[protein] = 5-histaminyl-L-glutamyl-[protein] + NH4(+) (R)-noradrenaline + L-glutaminyl-[protein] = 5-(R)-noradrenalinyl-L-glutamyl-[protein] + NH4(+) H2O + L-glutaminyl-[protein] = L-glutamyl-[protein] + NH4(+) Acyltransferase activity is regulated by the binding of GTP and Ca(2+): inactivated by GTP, which stabilizes its closed structure, thereby obstructing the accessibility of substrates to the active sites (PubMed:2903073, PubMed:7592956, PubMed:18092889, PubMed:31991788). In contrast, Ca(2+) acts as a cofactor by inducing conformational change to the active open form (PubMed:2903073, PubMed:18092889, PubMed:31991788). In absence of Ca(2+), Mg(2+) may bind Ca(2+)-binding sites, promoting GTP-binding and subsequent inhibition of the acyltransferase activity (PubMed:31991788). Specifically inhibited by compound VA4 ((S)-Benzyl (6-Acrylamido-1-(4-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)piperazin-1-yl)-1-oxohexan-2-yl)carbamate), which specifically abolishes both the transamidation and GTP-binding activities (PubMed:28858494). kcat is 11.2 min(-1) with benzyloxycarbonyl-Gln-Gly substrate for protein-glutamine deamidase activity. Monomer (PubMed:25192068). Interacts with phospholipase C; promoting alpha-1 adrenergic receptor signaling (PubMed:7592956). Interacts with PLCD1 (By similarity). Homooligomer. Mainly localizes to the cytosol (PubMed:9575137). Present at much lower level in the nucleus and chromatin (PubMed:9575137). Also secreted via a non-classical secretion pathway to the extracellular matrix (PubMed:27270573). By retinoic acid. Disulfide bond formation inactivates the calcium-dependent acyltransferase activity (PubMed:20547769). Cys-370 can form disulfide bonds with both Cys-230 and Cys-371: formation of a disulfide bond between Cys-230 and Cys-370 facilitates formation of the disulfide between Cys-370 and Cys-371, which promotes inactivation of the acyltransferase activity (PubMed:20547769). May also form interchain disulfids between Cys-230 and Cys-370 (PubMed:25192068). Ca(2+) protects against disulfide bond formation and inactivation (PubMed:20547769). Auto-transglutaminated: Forms covalent cross-links mediated by transglutaminase between Gln-633 and the epsilon-amino group of a lysine residue of itself or HMGB1, forming homopolymers and heteropolymers, respectively. S-nitrosylated, leading to inactivation of the acyltransferase activity. TGM2 constitutes the major autoantigen in celiac disease, a multifactorial chronic disorder of the small intestine caused by intolerance to gluten (PubMed:9212111, PubMed:9623982). Celiac disease is characterized by immune-mediated enteropathy associated with failed intestinal absorption and malnutrition: intestinal inflammation is precipitated by ingestion of the protein gliadin, a component of wheat gluten in the diet (PubMed:9212111, PubMed:9623982). TGM2 is the main target for celiac disease-associated anti-endomysium autoantibodies (PubMed:9212111). It mediates its effect by catalyzing specific deamidation of gliadin; this deamidation creates an epitope that binds efficiently to HLA-DQ2 and is recognized by gut-derived T-cells (PubMed:9623982). Belongs to the transglutaminase superfamily. Transglutaminase family. Initial enzymatic assays were performed with a protein sequence containing a Gly residue instead of a Val at position 224: such protein displays lower Ca(2+)-binding affinity and reduced transglutaminase activity. Tissue transglutaminase entry Versatile - Issue 236 of May 2021