HERC2 — HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2

HERC2 — HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">HERC2 — HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>HERC2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>HERC2 — HECT and RLD Domain Containing E3 Ubiquitin Ligase 2</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=HERC2" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/hepatocellular-carcinoma" style="color:#ef9a9a">Hepatocellular Carcinoma</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</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">11 edges</a></td>
</tr>
</table>

HERC2 is a giant E3 ubiquitin ligase (~500 kDa) involved in protein ubiquitination, DNA repair, and cellular stress responses. It plays critical roles in genome stability and has been implicated in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. [@herc]

Structure

HERC2 — HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">HERC2 — HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase 2</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>HERC2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>HERC2 — HECT and RLD Domain Containing E3 Ubiquitin Ligase 2</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=HERC2" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/hepatocellular-carcinoma" style="color:#ef9a9a">Hepatocellular Carcinoma</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</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">11 edges</a></td>
</tr>
</table>

HERC2 is a giant E3 ubiquitin ligase (~500 kDa) involved in protein ubiquitination, DNA repair, and cellular stress responses. It plays critical roles in genome stability and has been implicated in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. [@herc]

Structure

HERC2 contains multiple functional domains: [@herca]

• HECT domain (~350 aa at C-terminus): Catalytic E3 ubiquitin ligase activity
• RING finger domain: E3 ligase activity for substrate recognition
• WD40 repeats: Protein-protein interactions
• HECT-like domain: Regulatory functions
• Multiple RCC1 repeats: Chromatin binding

Normal Cellular Functions

Ubiquitin-Proteasome System [@hercb]

HERC2 functions as an E3 ubiquitin ligase:

• Targets proteins for proteasomal degradation
• Catalyzes ubiquitin chain formation
• Regulates protein turnover
• Controls cellular protein homeostasis

DNA Repair [@hercc]

• Regulates p53 activity through MDM2
• DNA damage response coordination
• Cell cycle control
• Genome stability maintenance

Iron Metabolism

• Regulates iron homeostasis
• Affects transferrin receptor trafficking
• Links ubiquitination to iron metabolism
• Important for neuronal survival

Autophagy

• Regulates [autophagy](/entities/autophagy) initiation
• Controls selective autophagy receptors
• Degrades damaged organelles
• Maintains cellular quality control

Role in Neurodegenerative Diseases

Alzheimer's Disease [@hercd]

Evidence for Involvement

Molecular Mechanisms

• Altered expression in AD brain
• Interactions with AD-related proteins
• Potential role in amyloid clearance
• Mitochondrial quality control

Parkinson's Disease [@herce]

Connections to PD Pathways

Other Neurodegenerative Conditions

• Huntington's disease: Polyglutamine aggregate clearance
• Amyotrophic lateral sclerosis: Protein homeostasis
• Frontotemporal dementia: Ubiquitin pathology

Cellular Mechanisms

Protein Quality Control [@autophagy]

Proteasomal Degradation

• Targets misfolded proteins
• Regulates stress response proteins
• Controls transcription factors
• Maintains neuronal health

Autophagy Regulation

• Modulates [mTOR](/mechanisms/mtor-signaling-pathway) pathway
• Controls ULK1 complex
• Regulates selective autophagy
• Links to neurodegeneration

Signal Transduction

• [NF-κB](/entities/nf-kb) pathway regulation
• p53-dependent [apoptosis](/entities/apoptosis)
• MAPK/ERK signaling
• DNA damage responses

Therapeutic Implications

Drug Development

• HERC2 modulators (in development)
• Proteostasis enhancers
• Autophagy-inducing compounds
• Mitochondrial protectants

Biomarker Potential

• HERC2 expression as disease marker
• Activity in cerebrospinal fluid
• Genetic variants as risk factors

Research Highlights

Genetic Studies

• HERC2 variants associated with AD risk
• Expression quantitative trait loci (eQTLs) in brain
• Epigenetic regulation in disease

Model Systems

• Knockout mice: Lethal in embryonic stage
• Conditional knockouts: Neurodegeneration phenotype
• Cell models: Oxidative stress sensitivity

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References