| IED ID | IndEnz0002009454 |
| Enzyme Type ID | protease009454 |
| Protein Name |
Protein-glutamine gamma-glutamyltransferase 2 EC 2.3.2.13 Guinea pig liver transglutaminase Isopeptidase TGM2 EC 3.4.-.- Protein-glutamine deamidase TGM2 EC 3.5.1.44 Protein-glutamine dopaminyltransferase TGM2 EC 2.3.1.- Protein-glutamine histaminyltransferase TGM2 EC 2.3.1.- Protein-glutamine noradrenalinyltransferase TGM2 EC 2.3.1.- Protein-glutamine serotonyltransferase TGM2 EC 2.3.1.- Tissue transglutaminase tTG tTgase Transglutaminase-2 TGase-2 |
| Gene Name | TGM2 |
| Organism | Cavia cutleri (Guinea pig) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Hystricomorpha Caviidae (cavies) Cavia (guinea pigs) Cavia cutleri (Guinea pig) |
| Enzyme Sequence | MAEDLILERCDLQLEVNGRDHRTADLCRERLVLRRGQPFWLTLHFEGRGYEAGVDTLTFNAVTGPDPSEEAGTMARFSLSSAVEGGTWSASAVDQQDSTVSLLLSTPADAPIGLYRLSLEASTGYQGSSFVLGHFILLYNPRCPADAVYMDSDQERQEYVLTQQGFIYQGSAKFINGIPWNFGQFEDGILDICLMLLDTNPKFLKNAGQDCSRRSRPVYVGRVVSAMVNCNDDQGVLQGRWDNNYSDGVSPMSWIGSVDILRRWKDYGCQRVKYGQCWVFAAVACTVLRCLGIPTRVVTNFNSAHDQNSNLLIEYFRNESGEIEGNKSEMIWNFHCWVESWMTRPDLEPGYEGWQALDPTPQEKSEGTYCCGPVPVRAIKEGHLNVKYDAPFVFAEVNADVVNWIRQKDGSLRKSINHLVVGLKISTKSVGRDEREDITHTYKYPEGSEEEREAFVRANHLNKLATKEEAQEETGVAMRIRVGQNMTMGSDFDIFAYITNGTAESHECQLLLCARIVSYNGVLGPVCSTNDLLNLTLDPFSENSIPLHILYEKYGDYLTESNLIKVRGLLIEPAANSYVLAERDIYLENPEIKIRVLGEPKQNRKLIAEVSLKNPLPVPLLGCIFTVEGAGLTKDQKSVEVPDPVEAGEQAKVRVDLLPTEVGLHKLVVNFECDKLKAVKGYRNVIIGPA |
| Enzyme Length | 690 |
| Uniprot Accession Number | P08587 |
| Absorption | |
| Active Site | ACT_SITE 277; /evidence=ECO:0000255|PROSITE-ProRule:PRU10024; ACT_SITE 335; /evidence=ECO:0000255|PROSITE-ProRule:PRU10024; ACT_SITE 358; /evidence=ECO:0000255|PROSITE-ProRule:PRU10024 |
| 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:2879844). In contrast, Ca(2+) acts as a cofactor by inducing conformational change to the active open form (PubMed:2879844). In absence of Ca(2+), Mg(2+) may bind Ca(2+)-binding sites, promoting GTP-binding and subsequent inhibition of the acyltransferase activity (By similarity). {ECO:0000250|UniProtKB:P21980, ECO:0000269|PubMed:2879844}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=L-glutaminyl-[protein] + L-lysyl-[protein] = [protein]-L-lysyl-N(6)-5-L-glutamyl-[protein] + NH4(+); Xref=Rhea:RHEA:54816, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10207, Rhea:RHEA-COMP:14005, ChEBI:CHEBI:28938, ChEBI:CHEBI:29969, ChEBI:CHEBI:30011, ChEBI:CHEBI:138370; EC=2.3.2.13; Evidence={ECO:0000255|PROSITE-ProRule:PRU10024, ECO:0000269|PubMed:16385579, ECO:0000269|PubMed:29618516};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54817; Evidence={ECO:0000269|PubMed:16385579, ECO:0000269|PubMed:29618516}; CATALYTIC ACTIVITY: Reaction=L-glutaminyl-[protein] + serotonin = 5-serotonyl-L-glutamyl-[protein] + NH4(+); Xref=Rhea:RHEA:66552, Rhea:RHEA-COMP:10207, Rhea:RHEA-COMP:17052, ChEBI:CHEBI:28938, ChEBI:CHEBI:30011, ChEBI:CHEBI:167174, ChEBI:CHEBI:350546; Evidence={ECO:0000269|PubMed:14697203, ECO:0000269|PubMed:22858378};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66553; Evidence={ECO:0000269|PubMed:14697203, ECO:0000269|PubMed:22858378}; CATALYTIC ACTIVITY: Reaction=dopamine + L-glutaminyl-[protein] = 5-dopaminyl-L-glutamyl-[protein] + NH4(+); Xref=Rhea:RHEA:66556, Rhea:RHEA-COMP:10207, Rhea:RHEA-COMP:17053, ChEBI:CHEBI:28938, ChEBI:CHEBI:30011, ChEBI:CHEBI:59905, ChEBI:CHEBI:167175; Evidence={ECO:0000269|PubMed:22858378};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66557; Evidence={ECO:0000269|PubMed:22858378}; CATALYTIC ACTIVITY: Reaction=histamine + L-glutaminyl-[protein] = 5-histaminyl-L-glutamyl-[protein] + NH4(+); Xref=Rhea:RHEA:66564, Rhea:RHEA-COMP:10207, Rhea:RHEA-COMP:17056, ChEBI:CHEBI:28938, ChEBI:CHEBI:30011, ChEBI:CHEBI:58432, ChEBI:CHEBI:167179; Evidence={ECO:0000269|PubMed:23022564};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66565; Evidence={ECO:0000269|PubMed:23022564}; CATALYTIC ACTIVITY: Reaction=(R)-noradrenaline + L-glutaminyl-[protein] = 5-(R)-noradrenalinyl-L-glutamyl-[protein] + NH4(+); Xref=Rhea:RHEA:66560, Rhea:RHEA-COMP:10207, Rhea:RHEA-COMP:17054, ChEBI:CHEBI:28938, ChEBI:CHEBI:30011, ChEBI:CHEBI:72587, ChEBI:CHEBI:167178; Evidence={ECO:0000269|PubMed:22858378};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66561; Evidence={ECO:0000269|PubMed:22858378}; CATALYTIC ACTIVITY: Reaction=H2O + L-glutaminyl-[protein] = L-glutamyl-[protein] + NH4(+); Xref=Rhea:RHEA:16441, Rhea:RHEA-COMP:10207, Rhea:RHEA-COMP:10208, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938, ChEBI:CHEBI:29973, ChEBI:CHEBI:30011; EC=3.5.1.44; Evidence={ECO:0000269|PubMed:16385579};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16442; Evidence={ECO:0000269|PubMed:16385579}; |
| DNA Binding | |
| EC Number | 2.3.2.13; 3.4.-.-; 3.5.1.44; 2.3.1.- |
| Enzyme 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:16385579, PubMed:14697203, PubMed:22858378, PubMed:23022564). Involved in many biological processes, such as bone development, angiogenesis, wound healing, cellular differentiation, chromatin modification and apoptosis (By similarity). 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:16385579, PubMed:29618516). Under physiological conditions, the protein cross-linking activity is inhibited by GTP; inhibition is relieved by Ca(2+) in response to various stresses (By similarity). When secreted, catalyzes cross-linking of proteins of the extracellular matrix, such as FN1 and SPP1 resulting in the formation of scaffolds (By similarity). 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 (By similarity). 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:14697203, PubMed:22858378, PubMed:23022564). Mediates protein serotonylation of small GTPases during activation and aggregation of platelets, leading to constitutive activation of these GTPases (PubMed:14697203). Plays a key role in chromatin organization by mediating serotonylation and dopaminylation of histone H3 (By similarity). Catalyzes serotonylation of 'Gln-5' of histone H3 (H3Q5ser) during serotonergic neuron differentiation, thereby facilitating transcription (By similarity). 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 (By similarity). 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:16385579). Catalyzes specific deamidation of protein gliadin, a component of wheat gluten in the diet (Ref.6). May also act as an isopeptidase cleaving the previously formed cross-links (By similarity). 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 (By similarity). {ECO:0000250|UniProtKB:P21980, ECO:0000250|UniProtKB:P21981, ECO:0000269|PubMed:14697203, ECO:0000269|PubMed:16385579, ECO:0000269|PubMed:22858378, ECO:0000269|PubMed:23022564, ECO:0000269|PubMed:29618516, ECO:0000269|Ref.6}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 479..486; /note=GTP; /evidence=ECO:0000250|UniProtKB:P21980; NP_BIND 583..586; /note=GTP; /evidence=ECO:0000250|UniProtKB:P21980 |
| Features | Active site (3); Chain (1); Cross-link (1); Disulfide bond (2); Initiator methionine (1); Metal binding (6); Modified residue (2); Nucleotide binding (2); Sequence conflict (3); Site (1) |
| Keywords | Acetylation;Acyltransferase;Calcium;Cell membrane;Chromosome;Cytoplasm;Direct protein sequencing;Disulfide bond;Extracellular matrix;GTP-binding;Hydrolase;Isopeptide bond;Membrane;Metal-binding;Mitochondrion;Nucleotide-binding;Nucleus;Protease;S-nitrosylation;Secreted;Transferase |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000250|UniProtKB:P21980}. Nucleus {ECO:0000250|UniProtKB:P21980}. Chromosome {ECO:0000250|UniProtKB:P21980}. Secreted, extracellular space, extracellular matrix {ECO:0000250|UniProtKB:P21980}. Cell membrane {ECO:0000250|UniProtKB:Q9WVJ6}. Mitochondrion {ECO:0000250|UniProtKB:P21980}. Note=Mainly localizes to the cytosol. Present at much lower level in the nucleus and chromatin. Also secreted via a non-classical secretion pathway to the extracellular matrix. {ECO:0000250|UniProtKB:P21980}. |
| Modified Residue | MOD_RES 2; /note=N-acetylalanine; /evidence=ECO:0000269|PubMed:2566328; MOD_RES 467; /note=N6-acetyllysine; /evidence=ECO:0000250|UniProtKB:P21981 |
| Post Translational Modification | PTM: Disulfide bond formation inactivates the calcium-dependent acyltransferase activity. 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. May also form interchain disulfids between Cys-230 and Cys-370. Ca(2+) protects against disulfide bond formation and inactivation. {ECO:0000250|UniProtKB:P21980}.; PTM: Auto-transglutaminated: Forms covalent cross-links mediated by transglutaminase between Gln-636 and the epsilon-amino group of a lysine residue of itself or HMGB1, forming homopolymers and heteropolymers, respectively. {ECO:0000269|PubMed:29618516}.; PTM: S-nitrosylated, leading to inactivation of the acyltransferase activity. {ECO:0000250|UniProtKB:P21981}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 19542224; 19931242; 21625219; 9060478; 9541024; |
| Motif | |
| Gene Encoded By | |
| Mass | 77,141 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=794.1 nM for serotonin (for protein-glutamine serotonyltransferase activity) {ECO:0000269|PubMed:22858378}; |
| Metal Binding | METAL 398; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P00488; METAL 400; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P00488; METAL 436; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P21980; METAL 446; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P00488; METAL 451; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P00488; METAL 542; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P21980 |
| Rhea ID | RHEA:54816; RHEA:54817; RHEA:66552; RHEA:66553; RHEA:66556; RHEA:66557; RHEA:66564; RHEA:66565; RHEA:66560; RHEA:66561; RHEA:16441; RHEA:16442 |
| Cross Reference Brenda | 2.3.2.13; |