Tissue transglutaminase

Source: Wikipedia, the free encyclopedia.
TGM2
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000198959

ENSMUSG00000037820

UniProt

P21980

P21981

RefSeq (mRNA)

NM_004613
NM_198951
NM_001323316
NM_001323317
NM_001323318

NM_009373

RefSeq (protein)

NP_001310245
NP_001310246
NP_001310247
NP_004604
NP_945189

NP_033399

Location (UCSC)Chr 20: 38.13 – 38.17 MbChr 2: 157.96 – 157.99 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Protein-glutamine gamma-glutamyltransferase
Identifiers
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

Tissue transglutaminase (abbreviated as tTG or TG2) is a 78-kDa, calcium-dependent

mitochondria.[6] Intracellular tTG is thought to play an important role in apoptosis.[8] In the extracellular space, tTG binds to proteins of the extracellular matrix (ECM),[9] binding particularly tightly to fibronectin.[10] Extracellular tTG has been linked to cell adhesion, ECM stabilization, wound healing, receptor signaling, cellular proliferation, and cellular motility.[6]

tTG is the

celiac disease, a lifelong illness in which the consumption of dietary gluten causes a pathological immune response resulting in the inflammation of the small intestine and subsequent villous atrophy.[11][12][13] It has also been implicated in the pathophysiology of many other diseases, including such as many different cancers and neurogenerative diseases.[14]

Structure

Gene

The human tTG gene is located on the 20th chromosome (20q11.2-q12).

Protein

TG2 is a multifunctional enzyme that belongs to

Crystal structures of TG2 with bound GDP, GTP, or ATP have demonstrated that these forms of TG2 adopt a "closed" conformation, whereas TG2 with the active site occupied by an inhibitory gluten peptide mimic or other similar inhibitors adopts an "open" conformation.[17][18][19] In the open conformation the four domains of TG2 are arranged in an extended configuration, allowing for catalytic activity, whereas in the closed conformation the two C-terminal domains are folded in on the catalytic core domain which includes the residue Cys-277.[20] The N-terminal domain only shows minor structural changes between the two different conformations.[21]

Mechanism

The catalytic mechanism for crosslinking in human tTG involves the

isopeptide bond between the two substrates (i.e. crosslinking). Alternatively, the thioester intermediate can be hydrolyzed, resulting in the net conversion of the glutamine residue to glutamic acid (i.e. deamidation).[6] The deamidation of glutamine residues catalyzed by tTG is thought to be linked to the pathological immune response to gluten in celiac disease.[12]
A schematic for the crosslinking and the deamidation reactions is provided in Figure 1.

reaction mechanism of tTG
Figure 1: Transamidation (crosslinking) and deamidation mechanisms of tissue transglutaminase

Regulation

The expression of tTG is regulated at the transcriptional level depending on complex signal cascades. Once synthesized, most of the protein is found in the cytoplasm, plasma membrane and ECM, but a small fraction is translocated to the nucleus, where it participates in the control of its own expression through the regulation of transcription factors.[22]

Crosslinking activity by tTG requires the binding of Ca2+ ions.

nucleotides and the high levels of calcium in the extracellular space, evidence has shown that extracellular tTG is mostly inactive.[6][12][23] Recent studies suggest that extracellular tTG is kept inactive by the formation of a disulfide bond between two vicinal cysteine residues, namely Cys 370 and Cys 371.[24] When this disulfide bond forms, the enzyme remains in an open confirmation but becomes catalytically inactive.[24] The, oxidation/reduction of the disulfide bond serves as a third allosteric regulatory mechanism (along with GTP/GDP and Ca2+) for the activation of tTG.[12] Thioredoxin-1 has been shown to activate extracellular tTG by reducing the disulfide bond.[23] Another disuplhide bond can form in tTG, between the residues Cys-230 and Cys-370. While this bond does not exist in the enzyme's native state, it appears when the enzyme is inactivated via oxidation.[20] The presence of calcium protects against the formation of both disulfide bonds, thus making the enzyme more resistant to oxidation.[20]

Figure 2: Cystein residues relevant in tTG activity. The disulfide bond between Cys 370 and Cys 371 has formed, therefore the enzyme is in an active conformation. The distance between Cys 370 and Cys 230 is 11.3 Å. Cys 277 is the cystein located within the active site of the enzyme.

Recent studies have suggested that interferon-γ may serve as an activator of extracellular tTG in the small intestine; these studies have a direct implication to the pathogenesis of celiac disease.[12] Activation of tTG has been shown to be accompanied by large conformational changes, switching from a compact (inactive) to an extended (active) conformation. (see Figure 3)[23][25][26]

X-ray crystallography images of tissue transglutaminase in two different conformations
Figure 3: Compact (inactive) and extended (active) conformations of tTG

In the extracellular matrix, TG2 is "turned off", due primarily to the oxidizing activity of endoplasmic reticulum protein 57 (ERp57).[24] Thus, tTG is allosterically regulated by two separate proteins, Erp57 and TRX-1.[24] (See Figure 4).

Figure 4: The proteins that allosterically regulate tTG. On the left Erp57 which oxidizes tTG and on the right TRX-1 which reduces tTG.

Function

tTG is expressed ubiquitously and is present in various cellular compartments, such as the cytosol, the nucleus, and the plasma membrane.[14] It requires calcium as a cofactor for transamidation activity. Transcription is increased by retinoic acid. Among its many supposed functions, it appears to play a role in wound healing, apoptosis, and extracellular matrix development[11] as well as differentiation and cell adhesion.[14] It has been noted that tTG may have very different activity in different cell types. For example, in neurons, tTG supports the survival of cells subjected to injury whereas in astrocytes knocking out the gene expression for tTG is beneficial to cell survival.[27]

tTG is thought to be involved in the regulation of the cytoskeleton by crosslinking various cytoskeletal proteins including myosin, actin, and spectrin.[28] Evidence shows that intracellular tTG crosslinks itself to myosin. It is also believed that tTG may stabilize the structure of the dying cells during apoptosis by polymerizing the components of the cytoskeleton, therefore preventing the leakage of the cellular contents into the extracellular space.[7]

tTG also has GTPase activity:[5] In the presence of GTP, it suggested to function as a G protein participating in signaling processes.[29] Besides its transglutaminase activity, tTG is proposed to also act as kinase,[30] and protein disulfide isomerase,[31] and deamidase.[32] This latter activity is important in the deamidation of gliadin peptides, thus playing important role in the pathology of coeliac disease.

tTG also presents PDI (Protein Disulfide Isomerase) activity.[33][34] Based on its PDI activity, tTG plays an important role in the regulation of proteostasis, by catalyzing the trimerization of HSF1 (Heat Shock Factor 1) and thus the body's response to heat shock. In the absence of tTG, the response to heat shock is impaired since the necessary trimer is not formed.[34]

Clinical significance

tTG is the most comprehensively studied transglutaminase and has been associated with many diseases. However, none of these diseases are related to an enzyme deficiency. Indeed, thus far no disease has been attributed to the lack of tTG activity and this has been attested through the study of tTG knockout mice.[35]

Celiac Disease

tTG is best known for its link with

T cells, initiating an adaptive immune response.[35]

Cancer

Recent studies suggest that tTG also plays a role in

Preclinical trials have showed promise in using tTG inhibitors as anti-cancer therapeutic agents.[38] However, other studies [33]
have noted that tTG transamidation activity could be linked to the inhibition of tumor cell invasiveness.

Other Diseases

tTG is believed to contribute to several neurodegenerative disorders including

Alzheimer, Parkinson and Huntington diseases by affecting transcription, differentiation and migration and adhesion .[39][40] Such neurological diseases are characterized in part by the abnormal aggregation of proteins due to the increased activity of protein crosslinking in the affected brain.[41] Additionally, specific proteins associated with these disorders have been found to be in vivo and in vitro substrates of tTG.[7]
Although tTG is up regulated in the areas of the brain affected by Huntington's disease, a recent study showed that increasing levels of tTG do not affect the onset and/or progression of the disease in mice.[42] Recent studies show that tTG may not be involved in AD as studies show it is associated with erythrocyte lysis and is a consequence of the disease rather than a cause.

tTG has also been linked to the pathogenesis of fibrosis in various organs including the lung and the kidney. Specifically, in kidney fibrosis, tTG contributes to the stabilization and accumulation of the ECM affecting TGF beta activity.[16]

Diagnostic

specificity (>90%) for identifying celiac disease. Modern anti-tTG assays rely on a human recombinant protein as an antigen.[43]

Therapeutic

It's still experimental to use tTG as a form of surgical glue. It is also being studied as an attenuator of

neurodegenerative diseases.[45] This indicates that tTG inhibitors could also serve as a tool to mitigate the progression of tTG brain related diseases.[45]

Interactions

TG2 participates in both enzymatic and non-enzymatic

interactions. Enzymatic interactions are formed between TG2 and its substrate proteins containing the glutamine donor and lysine donor groups in the presence of calcium. Substrates of TG2 are known to affect TG2 activity, which enables it to subsequently execute diverse biological functions in the cell. However, the importance of non-enzymatic interactions in regulating TG2 activities is yet to be revealed. Recent studies indicate that non-enzymatic interactions play physiological roles and enable diverse TG2 functions in a context-specific manner.[46]

Mouse Mutant Alleles for Tgm2
Marker Symbol for Mouse Gene. This symbol is assigned to the genomic locus by the MGI Tgm2
Mutant Mouse Embryonic Stem Cell Clones. These are the known targeted mutations for this gene in a mouse. Tgm2tm1a(KOMP)Wtsi
Example structure of targeted conditional mutant allele for this gene
Molecular structure of Tgm2 region with inserted mutation sequence
These Mutant ES Cells can be studied directly or used to generate mice with this gene knocked out. Study of these mice can shed light on the function of Tgm2: see Knockout mouse

Erp57

Endoplasmic reticulum protein 57 (Erp57), is a

MHC class I molecules in the endoplasmic reticulum
.

Transglutaminase 2 (TG2) is a ubiquitously expressed (intracellular as well as extracellular) protein, with multiple modes of Post-translational regulation, including an allosteric disulfide bond between Cys-370-Cys-371 that renders the enzyme inactive in the extracellular matrix.[24]

Endoplasmic reticulum (ER)-resident protein 57 (ERp57), a protein in the ER that promotes folding of nascent proteins and is also present in the extracellular environment, has the cellular and biochemical characteristics for inactivating TG2. We found that ERp57 colocalizes with extracellular TG2 in cultured human umbilical vein endothelial cells (HUVECs). ERp57 oxidized TG2 with a rate constant that was 400-2000-fold higher than those of the aforementioned small molecule oxidants. Moreover, its specificity for TG2 was also markedly higher than those of other secreted redox proteins, including protein disulfide isomerase (PDI), ERp72, TRX, and quiescin sulfhydryl oxidase 1 (QSOX1).

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198959 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037820 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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External links
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