Caspase-6
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Caspase-6</th>
</tr>
<tr> [@bhatt2022]
<td class="label">Gene</td> [@bhatt2012]
<td><a href="/genes/casp6">CASP6</a></td> [@bhatt2020]
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P55212" target="_blank">P55212</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/3OD5" target="_blank">3OD5</a>, <a href="https://www.rcsb.org/structure/4FXO" target="_blank">4FXO</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>~34 kDa (proenzyme), p18+p11 (active)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm, nucleus, mitochondria</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Caspase family (C14 clan, executioner caspase)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td><a href="/diseases/alzheimers">Alzheimer's Disease</a>, <a href="/diseases/huntingtons">Huntington's Disease</a>, <a href="/diseases/als">ALS</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer-disease" style="color:#ef9a9a">Alzheimer Disease</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/huntington-disease" style="color:#ef9a9a">Huntington Disease</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">24 edges</a></td>
</tr>
</table>
Caspase-6
Overview
Caspase-6 is an executioner cysteine-aspartate protease encoded by the [CASP6](/genes/casp6) gene. It is synthesized as a 34 kDa inactive zymogen (procaspase-6) that requires proteolytic processing to generate the active p18/p11 heterodimer. Caspase-6 occupies a unique position among executioner caspases due to its substrate specificity for neurodegeneration-critical proteins: it cleaves [tau](/proteins/tau) at Asp421, generating neurotoxic [tau](/proteins/tau) fragments found in Alzheimer's disease tangles, and cleaves [huntingtin](/proteins/huntingtin-protein) at Asp586, producing the toxic N-terminal fragments essential for Huntington's disease pathogenesis.
Structure
Proenzyme Architecture
Procaspase-6 (293 amino acids) comprises:
Prodomain (residues 1-23): Short N-terminal peptide removed during activation. Unlike initiator caspases, caspase-6 has a short prodomain without CARD or DED motifs.
Large subunit (p18) (residues 24-179): Contains the catalytic cysteine (Cys163) in the conserved QACQG pentapeptide motif
Intersubunit linker (residues 180-193): Removed during activation; contains the processing site Asp193
Small subunit (p11) (residues 194-293): Completes the active site and contributes to substrate bindingActive Enzyme
The mature enzyme is a homodimer of p18/p11 heterodimers (p18₂p11₂):
- Two active sites face the same direction in the dimer
- Each active site is formed at the interface between p18 and p11 subunits
- Crystal structures (PDB: 3OD5, 4FXO) reveal the typical caspase fold with a central β-sheet flanked by α-helices
- Substrate specificity pocket accommodates VEID/VEHD sequences (P4-P1 positions)
Unique Structural Features
Caspase-6 has several distinguishing structural properties:
- Self-activation capability: Unlike caspase-3/7, procaspase-6 can undergo intramolecular self-cleavage at Asp179, enabling activation without upstream caspases
- Zinc inhibition site: An allosteric zinc-binding site (His121, Cys163, Cys263) allows physiological regulation by zinc ions
- Conformational flexibility: The active-site loop (L2') adopts an extended conformation not seen in other executioner caspases, contributing to distinct substrate specificity
Substrate Specificity
Caspase-6 prefers the recognition sequence VEID↓X (Val-Glu-Ile-Asp):
- Optimal P4: hydrophobic (Val, Leu)
- P3: Glu (distinguishes from caspase-3 preference for Asp at P3)
- P2: Ile or hydrophobic
- P1: Asp (absolutely required)
- This sequence differs from caspase-3 (DEVD) and caspase-7 (DEVD), conferring distinct substrate selectivity
Function and Signaling
Apoptotic Execution
In the classical apoptotic cascade:
Intrinsic pathway: Cytochrome c → apoptosome → [caspase-9](/genes/casp9) → [caspase-3](/genes/casp3) → caspase-6
Extrinsic pathway: Death receptors → [caspase-8](/genes/casp8) → caspase-6 (direct) or → caspase-3 → caspase-6
[Caspase-1](/genes/casp1) can directly activate caspase-6, linking inflammation to [apoptosis](/entities/apoptosis)Feedback Amplification
Caspase-6 creates a positive feedback loop by cleaving and activating [caspase-8](/genes/casp8), which in turn activates more caspase-6. This caspase-6/caspase-8 amplification circuit is particularly active in [neurons](/entities/neurons) and contributes to the irreversibility of the apoptotic program.
Neuronal Substrate Cleavage
Tau cleavage (D421):
- Caspase-6 cleaves tau at Asp421, removing the C-terminal 20 amino acids
- Truncated tau (Tau-ΔC, 1-421) has:
- Enhanced aggregation propensity (~3-fold faster fibril formation)
- Increased toxicity to cultured neurons
- Greater ability to seed [tau aggregation](/mechanisms/tau-propagation)
- Reduced microtubule binding affinity
- Caspase-6-cleaved tau is one of the earliest post-translational modifications detected in AD brains
[Huntingtin](/proteins/huntingtin) cleavage (D586):
- Caspase-6 cleaves [huntingtin](/proteins/huntingtin-protein) at Asp586, generating:
- N-terminal fragment (1-586) that is toxic when it contains expanded polyQ
- The caspase-6 cleavage fragment is the predominant toxic species in HD models
- YAC128 mice with D586A-resistant huntingtin are completely protected from neurodegeneration
Other neuronal substrates:
- Lamin A/C: Nuclear envelope collapse
- α-Tubulin: Microtubule destabilization and axonal transport failure
- [Presenilin-1](/genes/psen1): Modulation of [γ-secretase](/entities/gamma-secretase) and [amyloid-β](/proteins/amyloid-beta-protein) production
- VDAC1: Mitochondrial permeabilization
- [DJ-1](/genes/park7): Oxidative stress response impairment
Non-Apoptotic Functions
Caspase-6 has important roles beyond cell death:
- Axon pruning: Mediates selective axon degeneration during development via localized activation
- Synaptic depression: Low-level caspase-6 activity at synapses participates in AMPA receptor internalization and long-term depression (LTD)
- Inflammasome signaling: Activates the [NLRP3](/genes/nlrp3) inflammasome complex
- B cell development: Required for normal B lymphocyte activation and differentiation
Role in Disease
Alzheimer's Disease Pathology
Active caspase-6 is intimately linked to [AD](/diseases/alzheimers-disease) pathology:
- Immunohistochemistry reveals active caspase-6 in neuritic plaques, neuropil threads, and neurofibrillary tangles
- Active caspase-6 is detected in mild cognitive impairment (MCI) cases before clinical AD diagnosis
- Caspase-6-cleaved tau (TauC6 neoepitope) colocalizes with PHF-1 (phospho-tau) in tangles
- Higher caspase-6 activity in hippocampal lysates predicts lower cognitive performance
- Caspase-6 activation correlates with [APOE](/genes/apoe) ε4 carrier status
Huntington's Disease
- Caspase-6 cleavage of mutant huntingtin at D586 is required for disease onset in mice
- Active caspase-6 is elevated in presymptomatic and symptomatic HD striatum
- Preventing caspase-6 cleavage of huntingtin is sufficient to prevent motor deficits, cognitive decline, and striatal atrophy in YAC128 mice
- This has made caspase-6-resistant huntingtin a therapeutic strategy for HD
Protein-Protein Interactions
| Partner | Interaction Type | Consequence |
|---|---|---|
| [Tau](/proteins/tau) | Substrate (D421) | Toxic truncated tau |
| [Huntingtin](/proteins/huntingtin-protein) | Substrate (D586) | Toxic N-terminal fragments |
| [Caspase-8](/genes/casp8) | Substrate + activator | Feedback amplification |
| [Caspase-3](/genes/casp3) | Upstream activator | Apoptotic cascade |
| [Caspase-1](/genes/casp1) | Upstream activator | Inflammation-apoptosis link |
| Lamin A/C | Substrate | Nuclear breakdown |
| XIAP | Inhibitor | Negative regulation |
| Zinc (Zn²⁺) | Allosteric inhibitor | Physiological regulation |
Pathway & Interaction Diagram
Interactive diagram showing CASPASE-6's key relationships in the SciDEX knowledge graph (8 connections shown).
Mermaid diagram (expand to render)
See Also
- [CASP6 Gene](/genes/casp6) — Encoding gene
- [CASP3](/genes/casp3) — Related executioner caspase
- [Tau Protein](/proteins/tau) — Critical substrate
- [Huntingtin](/proteins/huntingtin-protein) — HD substrate
- [Apoptosis](/mechanisms/apoptosis) — Cell death pathway
- [NLRP3 Inflammasome](/mechanisms/nlrp3-inflammasome) — Inflammatory activation
External Links
- [Caspase-6 at UniProt (P55212)](https://www.uniprot.org/uniprot/P55212)
- [Caspase-6 at PDB (3OD5)](https://www.rcsb.org/structure/3OD5)
- [Caspase-6 at Human Protein Atlas](https://www.proteinatlas.org/ENSG00000138794-CASP6)
- [Caspase-6 at MEROPS (C14.005)](https://www.ebi.ac.uk/merops/cgi-bin/pepsum?id=C14.005)
References
[Bhatt et al., The activated form of caspase-6 is detected at the earliest stages of Alzheimer's disease neuropathology (2014) (2014)](https://doi.org/10.1186/1750-1326-9-2)
[Graham et al., Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin (2006) (2006)](https://doi.org/10.1016/j.cell.2006.06.026)
[LeBlanc et al., Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease (1999) (1999)](https://doi.org/10.1074/jbc.274.33.23426)
[Bhatt et al., Caspase-6-cleaved tau is relevant in Alzheimer's disease (2019) (2019)](https://doi.org/10.3233/JAD-181059)
[Bhatt et al., Protective caspase-6 self-cleavage prevents self-activation (2022) (2022)](https://doi.org/10.1016/j.str.2022.01.007)
[Bhatt et al., Active caspase-6 in the hippocampus is associated with lower episodic memory in non-demented elderly (2012) (2012)](https://doi.org/10.1111/j.1365-2990.2012.01325.x)
[Bhatt et al., Caspase-6 is a key regulator of Alzheimer's disease pathology (2020) (2020)](https://doi.org/10.1016/j.celrep.2020.107652)