TGM2
entrez
7052
canonical
uniprot
P21980
canonical
ensembl
ENSG00000198959
resolver
ensp
ENSP00000355330
resolver
ensp
ENSP00000549230
resolver
ensp
ENSP00000549231
resolver
ensp
ENSP00000711866
resolver
genesymbol
TGM2
resolver
hgnc
HGNC:11778
resolver
uniprot
B4DIT7
resolver
uniprot
B4DTN7
resolver
uniprot
E1P5V9
resolver
uniprot
Q16436
resolver
uniprot
Q6B838
resolver
uniprot
Q9BTN7
resolver
uniprot
Q9H035
resolver
uniprot
Q9UH35
resolver
uniprot_entry
B4DIT7_HUMAN
resolver
uniprot_entry
B4DTN7_HUMAN
resolver
uniprot_entry
TGM2_HUMAN
resolver
uniprot_sec
E1P5V9
resolver
uniprot_sec
Q16436
resolver
uniprot_sec
Q6B838
resolver
uniprot_sec
Q9BTN7
resolver
uniprot_sec
Q9H035
resolver
uniprot_sec
Q9UH35
resolver
activity_regulation
ACTIVITY REGULATION: 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:18092889, PubMed:2903073, PubMed:31991788, PubMed:7592956). In contrast, Ca(2+) acts as a cofactor by inducing conformational change to the active open form (PubMed:18092889, PubMed:2903073, 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). Extracellularly reduced and activated by CLIC3 (PubMed:28198360). 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). {ECO:0000269|PubMed:18092889, ECO:0000269|PubMed:28198360, ECO:0000269|PubMed:28858494, ECO:0000269|PubMed:2903073, ECO:0000269|PubMed:31991788, ECO:0000269|PubMed:7592956}.
uniprot
proteins
amino_acid_sequence
MAEELVLERCDLELETNGRDHHTADLCREKLVVRRGQPFWLTLHFEGRNYEASVDSLTFSVVTGPAPSQEAGTKARFPLRDAVEEGDWTATVVDQQDCTLSLQLTTPANAPIGLYRLSLEASTGYQGSSFVLGHFILLFNAWCPADAVYLDSEEERQEYVLTQQGFIYQGSAKFIKNIPWNFGQFEDGILDICLILLDVNPKFLKNAGRDCSRRSSPVYVGRVVSGMVNCNDDQGVLLGRWDNNYGDGVSPMSWIGSVDILRRWKNHGCQRVKYGQCWVFAAVACTVLRCLGIPTRVVTNYNSAHDQNSNLLIEYFRNEFGEIQGDKSEMIWNFHCWVESWMTRPDLQPGYEGWQALDPTPQEKSEGTYCCGPVPVRAIKEGDLSTKYDAPFVFAEVNADVVDWIQQDDGSVHKSINRSLIVGLKISTKSVGRDEREDITHTYKYPEGSSEEREAFTRANHLNKLAEKEETGMAMRIRVGQSMNMGSDFDVFAHITNNTAEEYVCRLLLCARTVSYNGILGPECGTKYLLNLNLEPFSEKSVPLCILYEKYRDCLTESNLIKVRALLVEPVINSYLLAERDLYLENPEIKIRILGEPKQKRKLVAEVSLQNPLPVALEGCTFTVEGAGLTEEQKTVEIPDPVEAGEEVKVRMDLLPLHMGLHKLVVNFESDKLKAVKGFRNVIIGPA
uniprot
proteins
disease_involvement
DISEASE: Note=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). {ECO:0000269|PubMed:9212111, ECO:0000269|PubMed:9623982}.
uniprot
proteins
ec_number
2.3.1.-
uniprot
proteins
ec_number
2.3.2.13
uniprot
proteins
ec_number
3.4.-.-
uniprot
proteins
ec_number
3.5.1.44
uniprot
proteins
function
FUNCTION: 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:23941696, PubMed:31991788, PubMed:9252372). Involved in many biological processes, such as bone development, angiogenesis, wound healing, cellular differentiation, chromatin modification and apoptosis (PubMed:1683874, PubMed:27270573, PubMed:28198360, PubMed:7935379, PubMed:9252372). 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:18092889, PubMed:7592956, PubMed:7649299). 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:20547769, PubMed:9623982). 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). {ECO:0000250|UniProtKB:P08587, ECO:0000250|UniProtKB:P21981, ECO:0000269|PubMed:12506096, ECO:0000269|PubMed:1683874, ECO:0000269|PubMed:18092889, ECO:0000269|PubMed:20547769, ECO:0000269|PubMed:23797785, ECO:0000269|PubMed:23941696, ECO:0000269|PubMed:24349085, ECO:0000269|PubMed:26250429, ECO:0000269|PubMed:27131890, ECO:0000269|PubMed:28198360, ECO:0000269|PubMed:29618516, ECO:0000269|PubMed:30458214, ECO:0000269|PubMed:30867594, ECO:0000269|PubMed:31991788, ECO:0000269|PubMed:32273471, ECO:0000269|PubMed:7592956, ECO:0000269|PubMed:7649299, ECO:0000269|PubMed:7935379, ECO:0000269|PubMed:8943303, ECO:0000269|PubMed:9252372, ECO:0000269|PubMed:9623982, ECO:0000303|PubMed:27270573}.; FUNCTION: [Isoform 2]: Has cytotoxic activity: is able to induce apoptosis independently of its acyltransferase activity. {ECO:0000269|PubMed:17116873}.
uniprot
proteins
mass_dalton
77329
uniprot
proteins
mutagenesis
MUTAGEN 171; /note="S->E: Abolishes GTP-binding and transglutaminase activities. Does not have cytotoxic activity when overexpressed."; /evidence="ECO:0000269|PubMed:17116873"; MUTAGEN 180; /note="W->F: Abolished isopeptidase activity and reduced transamidase activity."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 180; /note="W->L: Abolished isopeptidase and transamidase activities."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 224; /note="V->G: Displays lower Ca(2+)-binding affinity and reduced transglutaminase activity."; /evidence="ECO:0000269|PubMed:23941696"; MUTAGEN 230; /note="C->A: Does not affect the protein-glutamine deamidase activity."; /evidence="ECO:0000269|PubMed:20547769"; MUTAGEN 241; /note="W->F,L: Abolished isopeptidase and transamidase activities."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 277; /note="C->S: Abolished protein-glutamine gamma-glutamyltransferase activity without affecting alpha-1 adrenergic receptor signaling. Abolished isopeptidase activity."; /evidence="ECO:0000269|PubMed:24349085, ECO:0000269|PubMed:26250429, ECO:0000269|PubMed:7649299, ECO:0000269|PubMed:8943303"; MUTAGEN 277; /note="C->V: Dominant negative mutant. Abolishes WDR54 cross-linking."; /evidence="ECO:0000269|PubMed:30458214"; MUTAGEN 278; /note="W->F: In TG2-T; strongly reduced isopeptidase activity without affecting the transamidase activity."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 278; /note="W->L: Abolished isopeptidase and transamidase activities."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 332; /note="W->F: In TG2-I; strongly reduced transamidase activity without affecting the isopeptidase activity."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 332; /note="W->L: Abolished isopeptidase and transamidase activities."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 334; /note="F->L: Abolished isopeptidase and transamidase activities."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 337; /note="W->F: Reduced isopeptidase and transamidase activities."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 337; /note="W->L: Abolished isopeptidase and transamidase activities."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 370; /note="C->A: Impaired substrate recognition for the protein-glutamine deamidase activity."; /evidence="ECO:0000269|PubMed:20547769"; MUTAGEN 371; /note="C->A: Impaired substrate recognition for the protein-glutamine deamidase activity."; /evidence="ECO:0000269|PubMed:20547769"; MUTAGEN 437; /note="E->R: Impaired Ca(2+)-binding leading to reduced transglutaminase activity."; /evidence="ECO:0000269|PubMed:31991788"; MUTAGEN 516; /note="Y->L: No effect on isopeptidase and transamidase activities."; /evidence="ECO:0000269|PubMed:26250429"; MUTAGEN 539; /note="E->R: Impaired Ca(2+)-binding leading to reduced transglutaminase activity."; /evidence="ECO:0000269|PubMed:31991788"; MUTAGEN 665..672; /note="VVNFESDK->IASMSSDS: Substitution with F13A1 sequence. Abolished interaction with phospholipase C and ability to promote alpha-1 adrenergic receptor signaling."; /evidence="ECO:0000269|PubMed:7592956"; MUTAGEN P21980-2:277; /note="C->V: Abolished protein-glutamine gamma-glutamyltransferase activity without affecting cytotoxic activity."; /evidence="ECO:0000269|PubMed:17116873
uniprot
proteins
post_translational_modification
PTM: 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). {ECO:0000269|PubMed:20547769, ECO:0000269|PubMed:25192068}.; PTM: 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. {ECO:0000250|UniProtKB:P08587}.; PTM: S-nitrosylated, leading to inactivation of the acyltransferase activity. {ECO:0000250|UniProtKB:P21981}.
uniprot
proteins
protein_family
Transglutaminase family
uniprot
proteins
protein_family
Transglutaminase superfamily
uniprot
proteins
pubmed
11230166
uniprot
proteins
pubmed
11390390
uniprot
proteins
pubmed
11780052
uniprot
proteins
pubmed
11867708
uniprot
proteins
pubmed
12506096
uniprot
proteins
pubmed
1358880
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
1670766
uniprot
proteins
pubmed
1683874
uniprot
proteins
pubmed
16959974
uniprot
proteins
pubmed
17116873
uniprot
proteins
pubmed
17939176
uniprot
proteins
pubmed
18092889
uniprot
proteins
pubmed
20450932
uniprot
proteins
pubmed
20547769
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
22814378
uniprot
proteins
pubmed
23797785
uniprot
proteins
pubmed
23941696
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24349085
uniprot
proteins
pubmed
25192068
uniprot
proteins
pubmed
26250429
uniprot
proteins
pubmed
27131890
uniprot
proteins
pubmed
27270573
uniprot
proteins
pubmed
28198360
uniprot
proteins
pubmed
28858494
uniprot
proteins
pubmed
2903073
uniprot
proteins
pubmed
29618516
uniprot
proteins
pubmed
30321187
uniprot
proteins
pubmed
30458214
uniprot
proteins
pubmed
30867594
uniprot
proteins
pubmed
31991788
uniprot
proteins
pubmed
32273471
uniprot
proteins
pubmed
7592956
uniprot
proteins
pubmed
7649299
uniprot
proteins
pubmed
7935379
uniprot
proteins
pubmed
8611626
uniprot
proteins
pubmed
8943303
uniprot
proteins
pubmed
9212111
uniprot
proteins
pubmed
9252372
uniprot
proteins
pubmed
9575137
uniprot
proteins
pubmed
9623982
uniprot
proteins
sequence_length
687
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:24349085, ECO:0000269|PubMed:29618516, ECO:0000269|PubMed:9575137}. Nucleus {ECO:0000269|PubMed:29618516, ECO:0000269|PubMed:9575137}. Chromosome {ECO:0000269|PubMed:9575137}. Secreted, extracellular space, extracellular matrix {ECO:0000269|PubMed:12506096, ECO:0000269|PubMed:1683874, ECO:0000269|PubMed:28198360}. Cell membrane {ECO:0000250|UniProtKB:Q9WVJ6}. Mitochondrion {ECO:0000269|PubMed:24349085}. Note=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). {ECO:0000269|PubMed:9575137, ECO:0000303|PubMed:27270573}.; SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm, perinuclear region {ECO:0000269|PubMed:17116873}.
uniprot
proteins