Protein-glutamine gamma-glutamyltransferase 2 (TGM2)
The protein contains 687 amino acids for an estimated molecular weight of 77329 Da.
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 clear (updated: April 7, 2021)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
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Biological Process
Apoptotic cell clearance
Blood vessel remodeling
Bone development
Branching involved in salivary gland morphogenesis
Cellular response to cocaine
Cellular response to dopamine
Cellular response to serotonin
Isopeptide cross-linking via N6-(L-isoglutamyl)-L-lysine
Negative regulation of endoplasmic reticulum calcium ion concentration
Peptide cross-linking
Phospholipase C-activating G protein-coupled receptor signaling pathway
Positive regulation of apoptotic process
Positive regulation of cell adhesion
Positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway
Positive regulation of GTPase activity
Positive regulation of I-kappaB kinase/NF-kappaB signaling
Positive regulation of inflammatory response
Positive regulation of mitochondrial calcium ion concentration
Positive regulation of neurogenesis
Positive regulation of small GTPase mediated signal transduction
Positive regulation of smooth muscle cell proliferation
Protein deamination
Protein homooligomerization
Regulation of apoptotic cell clearance
Regulation of apoptotic process
Salivary gland cavitation
Cellular Component
Chromatin
Collagen-containing extracellular matrix
Cytosol
Endoplasmic reticulum
Extracellular exosome
Extracellular matrix
Focal adhesion
Intrinsic component of plasma membrane
Mitochondrion
Nucleus
Obsolete cell
Perinuclear region of cytoplasm
Plasma membrane
Molecular Function
Calcium ion binding
GTP binding
Histone dopaminyltransferase activity
Histone serotonyltransferase activity
Identical protein binding
Metal ion binding
Peptidase activity
Peptide histaminyltransferase activity
Peptide noradrenalinyltransferase activity
Protein domain specific binding
Protein-glutamine gamma-glutamyltransferase activity
Protein-glutamine glutaminase activity
The reference OMIM entry for this protein is 190196
Transglutaminase 2; tgm2
Transglutaminase, tissue
Transglutaminase c; tgc
Guanine nucleotide-binding protein, h polypeptide; gnah
G protein, alpha subunit, gh class
G-alpha-h
DESCRIPTION
Transglutaminases (EC 2.3.2.13) catalyze the crosslinking of proteins by epsilon-gamma glutamyl lysine isopeptide bonds. The transglutaminases include factor XIII (plasma transglutaminase; 134570), keratinocyte transglutaminase (TGM1; 190195), hair follicle transglutaminase, prostate transglutaminase (TGM4; 600585), and tissue transglutaminase (TGM2). Although the overall primary structures of these enzymes are different, they all share a common amino acid sequence at the active site (YGQCW) and a strict calcium dependence for their activity. Differences in the primary structures of transglutaminases are probably responsible for their diverse biologic functions. The unique C terminus of TGM2, which is not involved in TGase activity, functions as a G protein (see GNAQ; 600998) in receptor signaling.CLONING
Gentile et al. (1991) isolated mouse and human cDNAs encoding tissue transglutaminase. The predicted 687-amino acid human protein is 84% and 81% identical to mouse and guinea pig tissue transglutaminase, respectively. In vitro translated human tissue transglutaminase has an apparent molecular mass of 85 kD by SDS-PAGE. The translated product exhibited calcium-dependent catalytic activity. Northern blot analysis revealed that tissue transglutaminase is expressed as a 3.6-kb mRNA in human endothelial cells. Hwang et al. (1995) cloned TGM2, which they called G-alpha-h, from a heart cDNA library. Transfected COS-1 cells expressed TGM2 protein at an apparent molecular mass of about 80 kD. Lu et al. (1995) cloned the promoter region of TGM2, ligated it to a reporter construct, and demonstrated its activity in transient transfection experiments. By RT-PCR and immunoblot analysis, Vezza et al. (1999) demonstrated that TGM2 was expressed in platelets, megakaryocytic cell lines, and endothelial and vascular smooth muscle cells. Antonyak et al. (2006) described a splice variant of TGM2 that encodes a 548-amino acid protein, which they called TGase-S. TGase-S contains the GTP-binding domain, transamidation domain, and Ca(2+)-binding domain of full-length TGase, but it lacks the C-terminal phospholipase C (PLC; see 604114)-binding domain.GENE FUNCTION
Fesus et al. (1987) observed a significant increase of tissue transglutaminase activity and enzyme concentration in programmed cell death of hepatocytes. Immunohistochemical examination showed transglutaminase within apoptotic hepatocytes, suggesting a role for the enzyme in apoptosis. In neonatal rat liver cells stimulated with epidermal growth factor (EGF; 131530), Piacentini et al. (1991) found that the proliferative phase was paralleled by a 10-fold increase in tissue transglutaminase mRNA levels. During the phase of involution, there were sequential increases in enzyme activity and increased levels of insoluble apoptotic bodies. Immunostaining localized the TGM2 protein within apoptotic bodies. The findings suggested that tissue transglutaminase leads to the formation of a detergent-insoluble cross-linked protein scaffold in cells undergoing apoptosis. This scaffold could stabilize cell membranes and prevent nonspecific release of harmful intracellular components, such as lysosomal enzymes. In human neuroblastoma cells, Melino et al. (1994) showed that overexpression of tissue transglutaminase resulted in a large increase in cell death rate with changes characteristic of cells undergoing apoptosis. Transfection of cells with TGM2 cDNA in antisense or ... More on the omim web site
April 10, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
Sept. 22, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 190196 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed