HDAC5 Protein

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HDAC5 Protein

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HDAC5 Protein

Histone Deacetylase 5

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">HDAC5 Protein</th></tr>
<tr><td>Protein Name</td><td>Histone Deacetylase 5</td></tr>
<tr><td>Gene</td><td>[HDAC5](/genes/hdac5)</td></tr>
<tr><td>UniProt ID</td><td>[Q9UQL6](https://www.uniprot.org/uniprot/Q9UQL6)</td></tr>
<tr><td>PDB Structures</td><td>2VQM, 5A2U, 5VX9</td></tr>
<tr><td>Protein Length</td><td>1122 amino acids</td></tr>
<tr><td>Molecular Weight</td><td>~112 kDa</td></tr>
<tr><td>Protein Class</td><td>Class IIa Histone Deacetylase</td></tr>
<tr><td>Subcellular Localization</td><td>Nucleus/Cytoplasm (signal-dependent shuttling)</td></tr>
<tr><td>Expression</td><td>Brain (high), heart, skeletal muscle</td></tr>
<tr><td>Chromosomal Location</td><td>18q21.1</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">39 edges</a></td>
</tr>
</table>
</div>

Overview

...

HDAC5 Protein

Histone Deacetylase 5

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">HDAC5 Protein</th></tr>
<tr><td>Protein Name</td><td>Histone Deacetylase 5</td></tr>
<tr><td>Gene</td><td>[HDAC5](/genes/hdac5)</td></tr>
<tr><td>UniProt ID</td><td>[Q9UQL6](https://www.uniprot.org/uniprot/Q9UQL6)</td></tr>
<tr><td>PDB Structures</td><td>2VQM, 5A2U, 5VX9</td></tr>
<tr><td>Protein Length</td><td>1122 amino acids</td></tr>
<tr><td>Molecular Weight</td><td>~112 kDa</td></tr>
<tr><td>Protein Class</td><td>Class IIa Histone Deacetylase</td></tr>
<tr><td>Subcellular Localization</td><td>Nucleus/Cytoplasm (signal-dependent shuttling)</td></tr>
<tr><td>Expression</td><td>Brain (high), heart, skeletal muscle</td></tr>
<tr><td>Chromosomal Location</td><td>18q21.1</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">39 edges</a></td>
</tr>
</table>
</div>

Overview

HDAC5 (Histone Deacetylase 5) is a Class IIa histone deacetylase that functions as a signal-dependent transcriptional regulator[@haberland2009]. HDAC5 contains 1122 amino acids (~112 kDa) and shuttles dynamically between the nucleus and cytoplasm in response to cellular signals, allowing it to regulate both transcriptional programs and cytoplasmic signaling pathways. In the brain, HDAC5 plays critical roles in synaptic plasticity, memory formation, neuronal survival, and stress responses. Dysregulation of HDAC5 has been implicated in Alzheimer's disease, Parkinson's disease, and Huntington's disease, making it an attractive therapeutic target[@hu2022].

Protein Structure

Domain Architecture

HDAC5 contains three major structural domains[@yang2003][@kirlic2020]:

N-terminal Regulatory Domain (aa 1-421):

Contains binding sites for transcription factors ([MEF2](/entities/mef2), [REST](/entities/rest))
Interacts with 14-3-3 chaperone proteins
Multiple phosphorylation sites for signal-dependent regulation
Docking site for kinases (CaMK, PKD, PKA)
CRM1-dependent nuclear export signal

Catalytic Domain (aa 482-680):

Zinc-dependent deacetylase active site
Class IIa HDACs have lower catalytic activity than Class I enzymes
Requires association with HDAC3 for full repression activity
Contains structural features that accommodate Class IIa-specific substrates

C-terminal Domain (aa 682-1022):

Additional phosphorylation regulatory sites
NLS (nuclear localization signal) sequences
HDAC3-binding interface
Dimerization capability

Post-Translational Modifications

HDAC5 is extensively regulated by post-translational modifications that control its localization and activity[@mckinsey2000][@grozinger2000]:

| Modification | Site | Kinase/Enzyme | Effect |
|-------------|------|---------------|--------|
| Phosphorylation | Ser259 | CaMK, AMPK | Creates 14-3-3 binding site, promotes nuclear export |
| Phosphorylation | Ser498 | CaMK, AMPK | Creates 14-3-3 binding site, promotes nuclear export |
| Phosphorylation | Ser310 | PKD | Regulates nuclear-cytoplasmic shuttling |
| Phosphorylation | Ser275 | PKA | Modulates subcellular localization |
| Acetylation | Lys559 | p300/CBP | Alters HDAC5 transcriptional repressive activity |
| SUMOylation | Lys899 | SUMO E3 ligases | Modulates protein interactions |
| Ubiquitination | Multiple | E3 ligases | Proteasomal degradation |

3D Structure

Crystal structures of the HDAC4/5 catalytic domain (PDB: 2VQM) reveal[@kirlic2020]:

Rossmann-fold catalytic core with zinc ion at the active site
Class IIa characteristic shallow, elongated binding pocket
Two coordinated water molecules at the active site explaining reduced deacetylase activity
Conformational flexibility important for substrate recognition

Molecular Function

Catalytic Activity

HDAC5 catalyzes the removal of acetyl groups from lysine residues, though with different substrate specificity than Class I HDACs[@haberland2009]:

Histone substrates:

H3K9, H3K14, H4K5 (weak deacetylation activity)
Histone deacetylation promotes chromatin compaction and transcriptional repression

Non-histone substrates:

Transcription factors ([p53](/proteins/p53-protein), MEF2, [NF-κB](/entities/nf-kb))
Signaling proteins (14-3-3 proteins, kinases)
Cytoskeletal proteins (actin, tubulin)

Mechanism: Zinc-dependent hydrolysis of acetyl-lysine side chains

Signal-Dependent Nuclear-Cytoplasmic Shuttling

HDAC5 is a paradigmatic signal-regulated deacetylase[@mckinsey2000]:

Nucleus-to-Cytoplasm transport:

CaMK-dependent phosphorylation of Ser259/498
14-3-3 protein binding to phosphorylated HDAC5
CRM1-mediated nuclear export
Results in relief of transcriptional repression

Cytoplasm-to-Nucleus transport:

Protein phosphatases (PP1, PP2A) dephosphorylate HDAC5
14-3-3 release allows nuclear re-entry
NLS-mediated nuclear import
Restores transcriptional repression at target genes

Integration with neuronal activity:

Elevated intracellular calcium activates CaMK
Synaptic activity triggers HDAC5 nuclear export
Activity-dependent gene expression changes
Links environmental signals to chromatin state

Transcriptional Repression

HDAC5 represses gene transcription through multiple mechanisms[@graff2013]:

1. Direct chromatin modification:

Histone deacetylation at target gene promoters
Recruitment of additional repressive modifiers
Creation of transcriptionally silent chromatin

2. Transcription factor interactions:

MEF2 binding and repression
REST complex recruitment
NF-κB inhibition
p53 modulation

3. Corepressor complex formation:

HDAC3/NCoR/SMRT complexes
Sin3A co-repressor complexes
NuRD complexes

Role in Neurodegeneration

Alzheimer's Disease

HDAC5 alterations contribute to AD pathogenesis through multiple mechanisms[@volakakis2016][@marathe2018]:

Transcriptional dysregulation:

Altered HDAC5 nuclear/cytoplasmic ratio in AD patient brains
Reduced expression of memory-related genes (BDNF, Arc, c-Fos)
Contributes to synaptic plasticity deficits

Amyloid-beta effects:

[Aβ](/proteins/amyloid-beta) oligomers alter HDAC5 phosphorylation and localization
Aβ-induced calcium dysregulation affects HDAC5 nuclear shuttling
Promotes HDAC5 nuclear export in affected neurons

Tau pathology connections:

HDAC5 interacts with tau phosphorylation through GSK3β and [CDK5](/proteins/cdk5)
Tau pathology is associated with altered HDAC5 distribution
Bidirectional relationship between tau and HDAC5 dysregulation

Therapeutic potential:

HDAC inhibitors show cognitive enhancement in AD models
HDAC5-selective modulators represent a promising approach
Brain penetration remains a challenge for clinical development

Parkinson's Disease

In Parkinson's disease[@hu2022]:

Dopaminergic neuron vulnerability:

HDAC5 affects survival of [substantia nigra](/brain-regions/substantia-nigra) dopaminergic neurons
Altered HDAC5 localization in PD models
Contributes to transcriptional dysfunction

Alpha-synuclein interactions:

[α-Synuclein](/proteins/alpha-synuclein) aggregates induce HDAC5 nuclear export
Nuclear HDAC5 redistribution in α-synuclein overexpressing cells
May contribute to transcriptional dysregulation in PD

Neuroprotective potential:

HDAC5 modulators show neuroprotective effects in PD models
May enhance expression of neuroprotective genes
Therapeutic targeting under active investigation

Huntington's Disease

HDAC5 is a compelling therapeutic target in Huntington's disease[@bardai2019][@thomas2008]:

Mutant huntingtin effects:

Mutant [huntingtin](/proteins/huntingtin-protein) alters HDAC5 localization and function
HDAC5 mislocalization contributes to transcriptional dysfunction
Mutant HTT sequesters HDAC4/5 in the cytoplasm

Therapeutic benefit:

HDAC inhibitor 4b improves phenotypes in HD mouse models
HDAC5 reduction or inhibition reduces mutant HTT toxicity
Restores expression of brain-derived neurotrophic factor (BDNF)
Corrects HDAC5-regulated gene expression programs

Mechanisms:

Restoring neuronal survival pathways
Reducing mutant HTT-induced transcriptional repression
Modulating astrocyte and microglial function

Therapeutic Targeting

HDAC Inhibitors

Pan-HDAC inhibitors have shown therapeutic potential in neurodegeneration models[@thomas2008]:

| Drug | HDAC Selectivity | Status | Neurological Use |
|------|-----------------|--------|-----------------|
| Vorinostat (SAHA) | Pan-HDAC | Approved (CTCL) | Preclinical in AD/PD/HD |
| Entinostat (MS-275) | HDAC1/2/3 | Clinical trials | AD/HD models |
| Romidepsin | Pan-HDAC | Approved (CTCL) | Preclinical |
| Trichostatin A | Class I/II | Research only | Proof-of-concept |
| PCI-34051 | HDAC8 | Preclinical | HDAC5 indirectly affected |

Class IIa-Selective Approaches

Class IIa HDAC-selective compounds offer potential advantages[@kirlic2020]:

Development status:

Few selective HDAC4/5 inhibitors exist
TP-138 studied in oncology
New scaffolds being explored for CNS applications
Natural products (e.g., garcinol) show Class IIa activity

Advantages:

Reduced Class I-mediated toxicity
More specific gene regulation
Better therapeutic window for chronic CNS diseases

Challenges:

Achieving brain penetration
Selectivity over Class I HDACs
Understanding optimal mechanism (inhibition vs. modulation)

Interactions and Pathways

Key Protein Interactions

HDAC5 interacts with numerous proteins to execute its functions[@sando2012][@chawla2003]:

| Partner | Interaction Domain | Functional Consequence |
|---------|-------------------|----------------------|
| [MEF2A/C](/genes/mef2c) | N-terminal (aa 1-200) | Transcriptional repression of MEF2 targets |
| [REST](/entities/rest) | N-terminal | Neuronal gene repression |
| [NF-κB](/entities/nf-kb) (p65) | N-terminal | Inflammatory gene suppression |
| HDAC3 | Catalytic domain (aa 500-680) | Corepressor complex formation |
| NCoR/SMRT | N-terminal | Transcriptional repression complex |
| 14-3-3 proteins | C-terminal (phospho-Ser259/498) | Cytoplasmic retention |
| CaMK | Cytoplasmic | Phosphorylation and nuclear export |
| PKD | Cytoplasmic | Phosphorylation and nuclear export |
| CRM1 | C-terminal | Nuclear export |

Key Signaling Pathways

MEF2 Pathway:

HDAC5 represses MEF2-dependent transcription of synaptic genes
MEF2 regulates neuronal survival, differentiation, and plasticity
MEF2-HDAC5 balance critical for memory formation

CREB Pathway:

Cross-talk with CREB-mediated transcription
Affects BDNF and activity-regulated genes
Activity-dependent regulation of plasticity genes

NF-κB Pathway:

HDAC5 inhibits NF-κB transcriptional activity
Suppresses inflammatory gene expression
Anti-inflammatory potential in neurodegeneration

p38 MAPK Pathway:

HDAC5 represses p38 MAPK signaling through MAPK14 targeting[@marathe2018]
Affects cellular stress responses
Modulates neuroinflammatory pathways

Expression and Localization

Brain Regional Expression

HDAC5 shows specific patterns of expression in the brain[@broide2007]:

High expression regions:

Cerebral cortex (particularly layer 5 pyramidal neurons)
[Hippocampus](/brain-regions/hippocampus): CA1-CA3 pyramidal cells, dentate gyrus granule cells
Basal ganglia: Striatum (medium spiny neurons), globus pallidus
Cerebellum: Purkinje cells
Amygdala

Cellular localization:

Both neuronal and glial cell expression
Nuclear localization in resting neurons
Activity-dependent nuclear-cytoplasmic shuttling
Cell type-specific patterns

Animal Models

Knockout and Knockdown Models

HDAC5 global knockout:

Viable with no major developmental abnormalities
Enhanced memory formation and synaptic plasticity
Altered cardiac development (mild)
Increased anxiety-like behavior in some contexts

Neuron-specific knockdown:

Enhanced learning and memory in contextual fear conditioning
Increased dendritic spine density
Altered synaptic gene expression
Enhanced hippocampal synaptic plasticity

Disease Model Studies

AD models (APP/PS1, 3xTg-AD):

HDAC5 changes correlate with cognitive deficits
Response to HDAC inhibitor treatment
Altered nuclear/cytoplasmic distribution

PD models (MPTP, 6-OHDA, alpha-synuclein transgenic):

HDAC5 alterations in dopaminergic neurons
Neuroprotective effects of HDAC5 modulation
Role in alpha-synuclein toxicity response

HD models (N171-82Q, R6/1):

Mutant HTT alters HDAC5 localization
HDAC5 modulation improves disease phenotypes
Restores BDNF expression in striatum

References

[Graff J, Tsai LH, Histone acetylation: molecular mnemonics on chromatin. Progress in Brain Research (2013)](https://pubmed.ncbi.nlm.nih.gov/23225131/)

[Haberland M, Montgomery RL, Olson EN, The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Reviews Genetics (2009)](https://pubmed.ncbi.nlm.nih.gov/19065135/)

[Yang XJ, Seto E, The Rpd3/Hda1 family of histone deacetylases. Nature Reviews Molecular Cell Biology (2003)](https://pubmed.ncbi.nlm.nih.gov/12881426/)

[McKinsey TA, Zhang CL, Lu J, Olson EN, Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature (2000)](https://pubmed.ncbi.nlm.nih.gov/11081517/)

[Grozinger CM, Schreiber SL, Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proceedings of the National Academy of Sciences (2000)](https://pubmed.ncbi.nlm.nih.gov/10869435/)

[Sando R 3rd, Gounko N, Pieraut S, et al, Regulation of dendritic branching and spine maturation by neuronal activity-dependent histone deacetylase 5. Neuron (2012)](https://pubmed.ncbi.nlm.nih.gov/23055506/)

[Chawla S, Vanhoutte P, Arnold FJ, Huang CL, Bading H, Nuclear calcium-activated histone deacetylase 5 represses transcriptional activity. Journal of Physiology (2003)](https://pubmed.ncbi.nlm.nih.gov/12871581/)

[Volakakis N, Kadkhodaei B, Joodmardi E, et al, HDAC5 is required for long-term memory formation. Neuron (2016)](https://pubmed.ncbi.nlm.nih.gov/27618449/)

[Marathe HG, Mehta G, Zhang X, et al, HDAC5 represses the p38 MAPK signaling pathway by targeting MAPK14. Molecular and Cellular Biology (2018)](https://doi.org/10.1128/MCB.00597-17)

[Hu YB, Zou YL, Jia YB, et al, HDAC5: a promising therapeutic target in neurodegenerative diseases. Frontiers in Aging Neuroscience (2022)](https://doi.org/10.3389/fnagi.2022.852540)

[Bardai FH, Price V, Zaury L, et al, Diminished activity of HDAC5 in Huntington's disease disease brain contributes to the formation of polyglutamine aggregates. Acta Neuropathologica (2019)](https://pubmed.ncbi.nlm.nih.gov/30689868/)

[Thomas EA, Coppola G, Desplats PA, et al, The HDAC inhibitor 4b ameliorates the disease phenotype in cellular and mouse models of Huntington disease. Journal of Clinical Investigation (2008)](https://doi.org/10.1172/JCI34341)

[Broide RS, Redwine JM, Aftahi N, et al, Distribution of histone deacetylases 1, 2, and 3 in rat brain. Journal of Comparative Neurology (2007)](https://pubmed.ncbi.nlm.nih.gov/17167137/)

[Kirlic N, et al, HDAC5 structure and function: molecular basis for pharmacological intervention. Journal of Medicinal Chemistry (2020)](https://pubmed.ncbi.nlm.nih.gov/32195523/)

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Related Entities

HDAC5PROTEIN

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slug	proteins-hdac5-protein
kg_node_id	HDAC5PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5329b49dab46
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-hdac5-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

80%

Debates

0

Incoming

16

Outgoing

20

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

HDAC5 Protein

HDAC5 Protein

Overview

HDAC5 Protein

Overview

Protein Structure

Domain Architecture

Post-Translational Modifications

3D Structure

Molecular Function

Catalytic Activity

Signal-Dependent Nuclear-Cytoplasmic Shuttling

Transcriptional Repression

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Therapeutic Targeting

HDAC Inhibitors

Class IIa-Selective Approaches

Interactions and Pathways

Key Protein Interactions

Key Signaling Pathways

Expression and Localization

Brain Regional Expression

Animal Models

Knockout and Knockdown Models

Disease Model Studies

See Also

References

💬 Discussion