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| Property | Value |
|----------|-------|
| Protein Name | Transglutaminase 6 |
| Aliases | TG6, TGY, Transglutaminase Y |
| Gene | TGM6 |
| UniProt ID | O95932 |
| PDB IDs | Not yet determined experimentally |
| Molecular Weight | ~79 kDa |
| Amino Acids | 706 |
| Protein Family | Transglutaminase family (protein-glutamine γ-glutamyltransferases) |
| Enzyme Classification | EC 2.3.2.13 |
| Subcellular Localization | Cytoplasm, cell surface, extracellular |
Transglutaminase 6 is a protein encoded by the TGM6 gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Transglutaminase 6 (TG6) shares the canonical four-domain architecture characteristic of the transglutaminase family, based on homology with the crystal structure of tissue transglutaminase (TG2):
¶ Domain Organization
- N-terminal β-sandwich domain (aa 1-139) — Fibronectin type III-like fold; involved in protein-protein interactions and substrate recognition; contains the R111C SCA35 mutation site
- Catalytic core domain (aa 140-460) — Contains the catalytic triad (Cys-His-Asp) essential for transamidation; harbors the L517W SCA35 mutation and the active site cysteine (C274)
- β-barrel 1 domain (aa 461-585) — Immunoglobulin-like fold; contributes to GTP/GDP binding pocket (inactive state regulation)
- β-barrel 2 domain (aa 586-706) — C-terminal domain; contains the D598N mutation site; involved in intramolecular regulation and substrate access
TG6 catalyzes a two-step transamidation reaction:
- Acyl-enzyme intermediate formation — The active-site Cys274 attacks the γ-carboxamide group of a protein-bound glutamine residue, releasing ammonia and forming a thioester intermediate
- Acyl transfer — The ε-amino group of a lysine residue from a second protein attacks the thioester, forming an ε-(γ-glutamyl)lysine isopeptide bond and regenerating the free enzyme
Catalytic requirements:
- Calcium (Ca²⁺) — Binding of calcium ions (multiple sites) induces a conformational change from the compact/closed (inactive) to the extended/open (active) form, exposing the catalytic site
- GTP/GDP — Binding of GTP/GDP stabilizes the compact inactive conformation, opposing calcium activation (allosteric regulation)
- Reducing conditions — The active-site cysteine must be in the reduced (thiol) form
Like TG2, TG6 exists in two major conformational states:
- Closed/compact form — GTP/GDP-bound; catalytically inactive; β-barrel domains packed against the catalytic core, blocking substrate access
- Open/extended form — Ca²⁺-bound; catalytically active; β-barrels swing away from the core, exposing the active site and substrate-binding groove
¶ Substrates and Interactions
TG6 cross-links multiple neuronal and glial substrates:
- Cytoskeletal proteins — Tubulin, actin, neurofilaments; cross-linking stabilizes the neuronal cytoskeleton
- Myelin basic protein (MBP) — Cross-linking by TG6 in oligodendrocytes may stabilize myelin sheaths
- Tau — Tau protein is a substrate for transglutaminase-mediated cross-linking; cross-linked tau is resistant to proteolytic degradation and may contribute to tangle formation
- Alpha-synuclein — α-Synuclein cross-linking promotes oligomerization and may accelerate Lewy body pathology
- Histones — Nuclear TG6 can modify histones, potentially affecting epigenetic regulation
- Calmodulin — Calcium-dependent interaction that modulates TG6 activity
- 14-3-3 proteins — May regulate TG6 subcellular localization
- Mitochondrial import receptors — TG6 interacts with outer mitochondrial membrane proteins, linking it to mitochondrial function
- ER chaperones — BiP/GRP78, calnexin; interaction increases when mutant TG6 triggers ER stressmechanisms/er-stress-neurodegeneration)
TGM6 mutations cause spinocerebellar ataxia type 35 through:
- Loss of catalytic function — SCA35 mutations (L517W, D327G) reduce transglutaminase activity by 50-90%, impairing protein cross-linking essential for Purkinje cell cytoskeletal integrity
- Protein misfolding — Mutant TG6 forms perinuclear aggregates that co-localize with ER markers, indicating ER retention and misfolding
- ER stress activation — Accumulated misfolded TG6 activates the unfolded protein response (UPR))))))))))))))))))) through all three branches (IRE1α, PERK, ATF6), eventually triggering pro-apoptotic CHOP signaling
- Autophagic overload — TG6 aggregates are targeted for clearance by autophagy, but chronic aggregate burden exhausts autophagic capacity in Purkinje cells
- Mitochondrial dysfunction — Mutant TG6 disrupts mitochondrial membrane potential, increases reactive oxygen species (ROS) production, and impairs respiratory chain function
In gluten ataxia, anti-TG6 antibodies mediate cerebellar damage:
- Anti-TG6 IgA antibodies are deposited on cerebellar neurons and perivascular regions
- Complement activation leads to neuronal injury
- Antibody-dependent cellular cytotoxicity (ADCC) by microglia and infiltrating immune cells
- Inhibition of TG6 enzymatic activity by blocking antibodies may compound the damage
- Alzheimer's disease — Transglutaminase-mediated cross-linking of tau and Aβ promotes aggregation; TG6 may contribute alongside the more abundant TG2
- Parkinson's disease — Cross-linking of α-synuclein by transglutaminases (TG2 and potentially TG6) promotes oligomer formation
- Huntington's disease — Huntingtin polyglutamine expansions are excellent transglutaminase substrates; cross-linking may contribute to aggregate stability
| Feature |
TG6 |
TG2 |
| Expression |
Brain-specific (cerebellum enriched) |
Ubiquitous |
| Molecular weight |
~79 kDa |
~78 kDa |
| GTPase activity |
Predicted (not confirmed) |
Yes (G-protein signaling) |
| Disease mutations |
SCA35 (LOF) |
None established |
| Autoimmune target |
Gluten ataxia |
Celiac disease |
| Cell surface |
Yes (neurons) |
Yes (many cell types) |
| Approach |
Indication |
Mechanism |
Status |
| Gluten-free diet |
Gluten ataxia |
Reduces anti-TG6 antibody titers |
Clinical practice |
| Rituximab (anti-CD20) |
Refractory gluten ataxia |
B-cell depletion reduces anti-TG6 antibodies |
Case reports |
| TG6 stabilizers |
SCA35 |
Prevent mutant TG6 misfolding |
Early research |
| Autophagy enhancers |
SCA35 |
Clear TG6 aggregates |
Preclinical |
| Gene therapy (AAV-TGM6) |
SCA35 |
Replace mutant TG6 with wild-type |
Proof-of-concept |
| UPR modulators |
SCA35 |
Reduce ER stress-mediated apoptosis |
Early research |