P21981 · TGM2_MOUSE
- ProteinProtein-glutamine gamma-glutamyltransferase 2
- GeneTgm2
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids686 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
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 (By similarity).
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:11113189, PubMed:11274171, PubMed:20489165).
Under physiological conditions, the protein cross-linking activity is inhibited by GTP; inhibition is relieved by Ca2+ 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 (PubMed:12810961, PubMed:15905580).
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:32116663).
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 (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 (PubMed:32116663).
Also acts as a protein deamidase by mediating the side chain deamidation of specific glutamine residues of proteins to glutamate (By similarity).
Catalyzes specific deamidation of protein gliadin, a component of wheat gluten in the diet (By similarity).
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 (PubMed:11274171).
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:11113189, PubMed:11274171, PubMed:20489165).
Under physiological conditions, the protein cross-linking activity is inhibited by GTP; inhibition is relieved by Ca2+ 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 (PubMed:12810961, PubMed:15905580).
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:32116663).
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 (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 (PubMed:32116663).
Also acts as a protein deamidase by mediating the side chain deamidation of specific glutamine residues of proteins to glutamate (By similarity).
Catalyzes specific deamidation of protein gliadin, a component of wheat gluten in the diet (By similarity).
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 (PubMed:11274171).
Catalytic activity
- L-glutaminyl-[protein] + L-lysyl-[protein] = [protein]-L-lysyl-N6-5-L-glutamyl-[protein] + NH4+This reaction proceeds in the forward direction.
- L-glutaminyl-[protein] + serotonin = 5-serotonyl-L-glutamyl-[protein] + NH4+This reaction proceeds in the forward direction.
- dopamine + L-glutaminyl-[protein] = 5-dopaminyl-L-glutamyl-[protein] + NH4+This reaction proceeds in the forward direction.
- histamine + L-glutaminyl-[protein] = 5-histaminyl-L-glutamyl-[protein] + NH4+This reaction proceeds in the forward direction.
- (R)-noradrenaline + L-glutaminyl-[protein] = 5-(R)-noradrenalinyl-L-glutamyl-[protein] + NH4+This reaction proceeds in the forward direction.
Cofactor
Activity regulation
Acyltransferase activity is regulated by the binding of GTP and Ca2+: inactivated by GTP, which stabilizes its closed structure, thereby obstructing the accessibility of substrates to the active sites. In contrast, Ca2+ acts as a cofactor by inducing conformational change to the active open form. In absence of Ca2+, Mg2+ may bind Ca2+-binding sites, promoting GTP-binding and subsequent inhibition of the acyltransferase activity. Extracellularly reduced and activated by CLIC3.
Features
Showing features for active site, binding site, site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Active site | 277 | |||||
Sequence: C | ||||||
Active site | 335 | |||||
Sequence: H | ||||||
Active site | 358 | |||||
Sequence: D | ||||||
Binding site | 398 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: N | ||||||
Binding site | 400 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 437 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 447 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 452 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 476-483 | GTP (UniProtKB | ChEBI) | ||||
Sequence: RIRVGDSM | ||||||
Site | 516 | Important for catalytic activity | ||||
Sequence: Y | ||||||
Binding site | 538 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 579-582 | GTP (UniProtKB | ChEBI) | ||||
Sequence: RDLY |
GO annotations
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameProtein-glutamine gamma-glutamyltransferase 2
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionP21981
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
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.
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
No visible phenotype in normal conditions (PubMed:11113189, PubMed:11274171).
During apoptosis, mice display defective clearance of apoptotic cells in the thymus (PubMed:12810961).
Moreover, inflammatory as well as autoimmune reactions develop spontaneously with age (PubMed:12810961).
Defective clearance of apoptotic cells is caused by an impaired capacity of macrophages to engulf, but not to bind, apoptotic cells (PubMed:15905580).
Mice also show glucose intolerance after intraperitoneal glucose loading: mice manifest a tendency to develop hypoglycemia after administration of exogenous insulin as a consequence of enhanced IRS2 phosphorylation (PubMed:12205028).
During apoptosis, mice display defective clearance of apoptotic cells in the thymus (PubMed:12810961).
Moreover, inflammatory as well as autoimmune reactions develop spontaneously with age (PubMed:12810961).
Defective clearance of apoptotic cells is caused by an impaired capacity of macrophages to engulf, but not to bind, apoptotic cells (PubMed:15905580).
Mice also show glucose intolerance after intraperitoneal glucose loading: mice manifest a tendency to develop hypoglycemia after administration of exogenous insulin as a consequence of enhanced IRS2 phosphorylation (PubMed:12205028).
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 37 variants from UniProt as well as other sources including ClinVar and dbSNP.
Chemistry
PTM/Processing
Features
Showing features for initiator methionine, modified residue, chain, disulfide bond, cross-link.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Initiator methionine | 1 | Removed | ||||
Sequence: M | ||||||
Modified residue | 2 | N-acetylalanine | ||||
Sequence: A | ||||||
Chain | PRO_0000213708 | 2-686 | Protein-glutamine gamma-glutamyltransferase 2 | |||
Sequence: AEELLLERCDLEIQANGRDHHTADLCQEKLVLRRGQRFRLTLYFEGRGYEASVDSLTFGAVTGPDPSEEAGTKARFSLSDNVEEGSWSASVLDQQDNVLSLQLCTPANAPIGLYRLSLEASTGYQGSSFVLGHFILLYNAWCPADDVYLDSEEERREYVLTQQGFIYQGSVKFIKSVPWNFGQFEDGILDTCLMLLDMNPKFLKNRSRDCSRRSSPIYVGRVVSAMVNCNDDQGVLLGRWDNNYGDGISPMAWIGSVDILRRWKEHGCQQVKYGQCWVFAAVACTVLRCLGIPTRVVTNYNSAHDQNSNLLIEYFRNEFGELESNKSEMIWNFHCWVESWMTRPDLQPGYEGWQAIDPTPQEKSEGTYCCGPVSVRAIKEGDLSTKYDAPFVFAEVNADVVDWIRQEDGSVLKSINRSLVVGQKISTKSVGRDDREDITHTYKYPEGSPEEREVFTKANHLNKLAEKEETGVAMRIRVGDSMSMGNDFDVFAHIGNDTSETRECRLLLCARTVSYNGVLGPECGTEDINLTLDPYSENSIPLRILYEKYSGCLTESNLIKVRGLLIEPAANSYLLAERDLYLENPEIKIRVLGEPKQNRKLVAEVSLKNPLSDPLYDCIFTVEGAGLTKEQKSVEVSDPVPAGDLVKARVDLFPTDIGLHKLVVNFQCDKLKSVKGYRNVIIGPA | ||||||
Disulfide bond | 230↔370 | Alternate | ||||
Sequence: CNDDQGVLLGRWDNNYGDGISPMAWIGSVDILRRWKEHGCQQVKYGQCWVFAAVACTVLRCLGIPTRVVTNYNSAHDQNSNLLIEYFRNEFGELESNKSEMIWNFHCWVESWMTRPDLQPGYEGWQAIDPTPQEKSEGTYC | ||||||
Disulfide bond | 370↔371 | Alternate | ||||
Sequence: CC | ||||||
Modified residue | 468 | N6-acetyllysine | ||||
Sequence: K | ||||||
Cross-link | 632 | Isoglutamyl lysine isopeptide (Gln-Lys) (interchain with K-?) | ||||
Sequence: Q |
Post-translational modification
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. Ca2+ protects against disulfide bond formation and inactivation.
Auto-transglutaminated: Forms covalent cross-links mediated by transglutaminase between Gln-632 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.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Gene expression databases
Structure
Sequence
- Sequence statusComplete
- Length686
- Mass (Da)77,061
- Last updated2008-03-18 v4
- Checksum9B64B074D3F837DE
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
G3UXE8 | G3UXE8_MOUSE | Tgm2 | 146 |
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 32-33 | in Ref. 1; AAA40420 | ||||
Sequence: VL → LV | ||||||
Sequence conflict | 51 | in Ref. 1; AAA40420 and 2; AAD37501 | ||||
Sequence: E → Q | ||||||
Sequence conflict | 186 | in Ref. 1; AAA40420 | ||||
Sequence: E → Q | ||||||
Sequence conflict | 226 | in Ref. 1; AAA40420 | ||||
Sequence: A → D | ||||||
Sequence conflict | 325 | in Ref. 1; AAA40420 | ||||
Sequence: S → T | ||||||
Sequence conflict | 357 | in Ref. 1; AAA40420 and 2; AAD37501 | ||||
Sequence: I → L | ||||||
Sequence conflict | 396 | in Ref. 4; BAC40899 | ||||
Sequence: E → K | ||||||
Sequence conflict | 408-409 | in Ref. 1; AAA40420 | ||||
Sequence: ED → DE | ||||||
Sequence conflict | 415-416 | in Ref. 1; AAA40420 | ||||
Sequence: SI → WM | ||||||
Sequence conflict | 421 | in Ref. 1; AAA40420 | ||||
Sequence: V → I | ||||||
Sequence conflict | 481-485 | in Ref. 1; AAA40420 | ||||
Sequence: DSMSM → QYEH | ||||||
Sequence conflict | 539 | in Ref. 4; BAE38690 | ||||
Sequence: N → K | ||||||
Sequence conflict | 552 | in Ref. 1; AAA40420 | ||||
Sequence: G → D | ||||||
Sequence conflict | 583 | in Ref. 1; AAA40420 and 2; AAD37501 | ||||
Sequence: L → V | ||||||
Sequence conflict | 654 | in Ref. 1; AAA40420 | ||||
Sequence: F → S |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
M55154 EMBL· GenBank· DDBJ | AAA40420.1 EMBL· GenBank· DDBJ | mRNA | ||
AF114266 EMBL· GenBank· DDBJ | AAD37501.1 EMBL· GenBank· DDBJ | mRNA | ||
AF076928 EMBL· GenBank· DDBJ | AAC62014.1 EMBL· GenBank· DDBJ | mRNA | ||
AK052912 EMBL· GenBank· DDBJ | BAC35200.1 EMBL· GenBank· DDBJ | mRNA | ||
AK080224 EMBL· GenBank· DDBJ | BAC37852.1 EMBL· GenBank· DDBJ | mRNA | ||
AK080593 EMBL· GenBank· DDBJ | BAC37952.1 EMBL· GenBank· DDBJ | mRNA | ||
AK089481 EMBL· GenBank· DDBJ | BAC40899.1 EMBL· GenBank· DDBJ | mRNA | ||
AK143712 EMBL· GenBank· DDBJ | BAE25511.1 EMBL· GenBank· DDBJ | mRNA | ||
AK151776 EMBL· GenBank· DDBJ | BAE30682.1 EMBL· GenBank· DDBJ | mRNA | ||
AK152152 EMBL· GenBank· DDBJ | BAE30987.1 EMBL· GenBank· DDBJ | mRNA | ||
AK152627 EMBL· GenBank· DDBJ | BAE31370.1 EMBL· GenBank· DDBJ | mRNA | ||
AK159255 EMBL· GenBank· DDBJ | BAE34936.1 EMBL· GenBank· DDBJ | mRNA | ||
AK166302 EMBL· GenBank· DDBJ | BAE38690.1 EMBL· GenBank· DDBJ | mRNA | ||
AK168990 EMBL· GenBank· DDBJ | BAE40790.1 EMBL· GenBank· DDBJ | mRNA | ||
AK169356 EMBL· GenBank· DDBJ | BAE41105.1 EMBL· GenBank· DDBJ | mRNA | ||
AL669824 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC016492 EMBL· GenBank· DDBJ | AAH16492.1 EMBL· GenBank· DDBJ | mRNA | ||
U24148 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. |