Transglutaminase 6 Protein

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Transglutaminase 6 Protein

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title: Transglutaminase 6 Protein

Transglutaminase 6 (TG6)

<div class="infobox infobox-protein"> [@wang2010]

| Property | Value | [@guan2019]
|----------|-------| [@hadjivassiliou2013]
| Protein Name | Transglutaminase 6 | [@iismaa2009]
| Aliases | TG6, TGY, Transglutaminase Y | [@boscolo2010]
| Gene | [TGM6](/genes/tgm6) |
| UniProt ID | [O95932](https://www.uniprot.org/uniprot/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 |

</div>

Overview

Transglutaminase 6 is a protein encoded by the [TGM6](/genes/tgm6) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.

Structure

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)](/proteins/tg2-protein):

Domain Organization

...

title: Transglutaminase 6 Protein

Transglutaminase 6 (TG6)

<div class="infobox infobox-protein"> [@wang2010]

| Property | Value | [@guan2019]
|----------|-------| [@hadjivassiliou2013]
| Protein Name | Transglutaminase 6 | [@iismaa2009]
| Aliases | TG6, TGY, Transglutaminase Y | [@boscolo2010]
| Gene | [TGM6](/genes/tgm6) |
| UniProt ID | [O95932](https://www.uniprot.org/uniprot/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 |

</div>

Overview

Transglutaminase 6 is a protein encoded by the [TGM6](/genes/tgm6) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.

Structure

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)](/proteins/tg2-protein):

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

Catalytic Mechanism

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

Conformational States

Like [TG2](/proteins/tg2-protein), 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

Protein Substrates

TG6 cross-links multiple neuronal and glial substrates:

Cytoskeletal proteins — [Tubulin](/proteins/tubulin), [actin](/proteins/actin), [neurofilaments](/proteins/neurofilament-light); cross-linking stabilizes the neuronal cytoskeleton
Myelin basic protein (MBP) — Cross-linking by TG6 in [oligodendrocytes](/cell-types/oligodendrocytes) may stabilize myelin sheaths
[Tau](/proteins/tau) — [Tau protein](/proteins/tau) is a substrate for transglutaminase-mediated cross-linking; cross-linked tau is resistant to proteolytic degradation and may contribute to [tangle](/mechanisms/tau-aggregation) formation
Alpha-synuclein — [α-Synuclein](/proteins/alpha-synuclein) cross-linking promotes oligomerization and may accelerate [Lewy body](/mechanisms/lewy-body-formation) pathology
Histones — Nuclear TG6 can modify histones, potentially affecting epigenetic regulation

Protein-Protein Interactions

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](/mechanisms/mitochondrial-dysfunction)
ER chaperones — [BiP/GRP78](/proteins/grp78-protein), [calnexin](/proteins/calnexin-protein); interaction increases when mutant TG6 triggers [ER stress](/mechanisms/er-stress-pathway)mechanisms/er-stress-neurodegeneration)

Role in Neurodegeneration

SCA35 (Genetic TG6 Dysfunction)

[TGM6](/genes/tgm6) mutations cause [spinocerebellar ataxia type 35](/diseases/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)](/mechanisms/endoplasmic-reticulum-stress))))))))))))))))))) through all three branches (IRE1α, PERK, ATF6), eventually triggering pro-apoptotic CHOP signaling

Autophagic overload — TG6 aggregates are targeted for clearance by [autophagy](/mechanisms/autophagy), but chronic aggregate burden exhausts autophagic capacity in Purkinje cells

Mitochondrial dysfunction — Mutant TG6 disrupts mitochondrial membrane potential, increases [reactive oxygen species](/entities/reactive-oxygen-species) (ROS) production, and impairs respiratory chain function

Gluten Ataxia (Autoimmune TG6 Targeting)

In gluten ataxia, anti-TG6 antibodies mediate cerebellar damage:

Anti-TG6 IgA antibodies are deposited on cerebellar [neurons](/entities/neurons) and perivascular regions
Complement activation leads to neuronal injury
Antibody-dependent cellular cytotoxicity (ADCC) by [microglia](/cell-types/microglia) and infiltrating immune cells
Inhibition of TG6 enzymatic activity by blocking antibodies may compound the damage

Role in Other Neurodegenerative Diseases

Alzheimer's disease — Transglutaminase-mediated cross-linking of [tau](/proteins/tau) and [Aβ](/proteins/amyloid-beta) promotes aggregation; TG6 may contribute alongside the more abundant [TG2](/proteins/tg2-protein)
Parkinson's disease — Cross-linking of [α-synuclein](/proteins/alpha-synuclein) by transglutaminases (TG2 and potentially TG6) promotes oligomer formation
Huntington's disease — [Huntingtin](/proteins/huntingtin) polyglutamine expansions are excellent transglutaminase substrates; cross-linking may contribute to aggregate stability

Comparison with TG2

| Feature | TG6 | [TG2](/proteins/tg2-protein) |
|---------|-----|-----|
| 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) |

Therapeutic Targeting

| 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](/entities/autophagy) enhancers | SCA35 | Clear TG6 aggregates | Preclinical |
| Gene therapy (AAV-TGM6) | SCA35 | Replace mutant TG6 with wild-type | Proof-of-concept |
| [UPR](/entities/unfolded-protein-response) modulators | SCA35 | Reduce ER stress-mediated [apoptosis](/entities/apoptosis) | Early research |

External Links

[UniProt: O95932](https://www.uniprot.org/uniprot/O95932)
[PDB structures](https://www.rcsb.org/search?q=uniprot:O95932)
[GeneCards: TGM6](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TGM6)

References

[Thomas et al., Transglutaminase 6: a protein associated with central nervous system development and motor function (2013) (2013)](https://doi.org/10.1007/s00726-013-1593-y)

[Hadjivassiliou et al., Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase (2008) (2008)](https://doi.org/10.1002/ana.21450)

[Tripathy et al., Mutations in TGM6 induce the unfolded protein response in SCA35 (2017) (2017)](https://doi.org/10.1093/hmg/ddx227)

[Wang et al., TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing (2010) (2010)](https://doi.org/10.1093/brain/awq323)

[Guan et al., Spinocerebellar ataxia type 35 (SCA35): a review and call to action (2019) (2019)](https://doi.org/10.1002/mds.27833)

[Hadjivassiliou et al., Transglutaminase 6 antibodies in the diagnosis of gluten ataxia (2013) (2013)](https://doi.org/10.1212/WNL.0b013e3182a1eae4)

[Iismaa et al., Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders (2009) (2009)](https://doi.org/10.1152/physrev.00044.2007)

[Boscolo et al., Anti transglutaminase antibodies cause ataxia in mice (2010) (2010)](https://doi.org/10.1371/journal.pone.0009698)

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Related Entities

TGM6PROTEIN

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slug	proteins-tgm6-protein
kg_node_id	TGM6PROTEIN
entity_type	protein
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source_table	wiki_pages
wiki_page_id	wp-c2408e78aa08
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-tgm6-protein'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

11

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Transglutaminase 6 Protein

Transglutaminase 6 (TG6)

Overview

Structure

Domain Organization

Transglutaminase 6 (TG6)

Overview

Structure

Domain Organization

Catalytic Mechanism

Conformational States

Substrates and Interactions

Protein Substrates

Protein-Protein Interactions

Role in Neurodegeneration

SCA35 (Genetic TG6 Dysfunction)

Gluten Ataxia (Autoimmune TG6 Targeting)

Role in Other Neurodegenerative Diseases

Comparison with TG2

Therapeutic Targeting

See Also

External Links

References

💬 Discussion