p62 Protein (Sequestosome-1)

p62 Protein (SQSTM1)

Introduction

P62 Protein (Sequestosome 1) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein">
<h3>p62 (Sequestosome-1)</h3>
<table>
<tr><th>Gene</th><td>[SQSTM1](/genes/sqstm1)</td></tr>
<tr><th>UniProt ID</th><td>[Q13501](https://www.uniprot.org/uniprot/Q13501)</td></tr>
<tr><th>PDB Structures</th><td>[2K38](https://www.rcsb.org/structure/2K38), [5O8Y](https://www.rcsb.org/structure/5O8Y)</td></tr>
<tr><th>Molecular Weight</th><td>~62 kDa</td></tr>
<tr><th>Subcellular Localization</th><td>Cytoplasm, nucleus, aggresomes, autophagosomes</td></tr>
<tr><th>Protein Family</th><td>Sequestosome family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">ATAXIA</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2336 edges</a></td>
</tr>
</table>
</div>

Overview

p62 Protein (SQSTM1)

Introduction

P62 Protein (Sequestosome 1) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein">
<h3>p62 (Sequestosome-1)</h3>
<table>
<tr><th>Gene</th><td>[SQSTM1](/genes/sqstm1)</td></tr>
<tr><th>UniProt ID</th><td>[Q13501](https://www.uniprot.org/uniprot/Q13501)</td></tr>
<tr><th>PDB Structures</th><td>[2K38](https://www.rcsb.org/structure/2K38), [5O8Y](https://www.rcsb.org/structure/5O8Y)</td></tr>
<tr><th>Molecular Weight</th><td>~62 kDa</td></tr>
<tr><th>Subcellular Localization</th><td>Cytoplasm, nucleus, aggresomes, autophagosomes</td></tr>
<tr><th>Protein Family</th><td>Sequestosome family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">ATAXIA</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2336 edges</a></td>
</tr>
</table>
</div>

Overview

p62 (also known as sequestosome-1 or SQSTM1) is a multifunctional adaptor protein that serves as a key regulator of selective autophagy and cellular signaling. p62 contains multiple protein-protein interaction domains allowing it to act as a scaffold for various signaling pathways and as a selective autophagy receptor for protein aggregates and damaged organelles.

Structure

p62 contains several functional domains:

• PB1 Domain: N-terminal Phox and Bem1p domain for oligomerization
• ZZ Domain: Zinc finger domain for protein interactions
• TBI (TBK1 Interaction) Domain: Phosphorylated by TBK1 and mTORC1
• LIR (LC3-Interacting Region): Binds LC3/GABARAP proteins on autophagosomes
• UBA Domain (Ubiquitin-Associated): Binds polyubiquitin chains for selective autophagy

Normal Function

p62 is a master regulator of cellular homeostasis:

• Selective [Autophagy](/entities/autophagy): Serves as autophagy receptor for ubiquitinated cargo (aggregates, mitochondria, pathogens)
• Signaling Hub: Integrates signals from multiple pathways ([mTOR](/entities/mtor), Nrf2, [NF-κB](/entities/nf-kb))
• Protein Quality Control: Targets misfolded proteins for autophagic degradation
• Cell Survival: Nrf2-mediated antioxidant responses
• Synaptic Function: Involved in synaptic vesicle recycling and neuronal signaling

Role in Disease

ALS/FTD

• Mutations: P392L, G427A, and others cause familial ALS/FTD
• Mechanisms: Impaired autophagy, altered stress responses, protein aggregation
• Inclusions: p62-positive inclusions found in ALS, FTD, and other neurodegenerative diseases

Paget Disease of Bone (PDB)

• Mutations: P392L is common in PDB
• Mechanism: Altered osteoclast function

Alzheimer Disease

• Accumulates in AD brain with [tau](/proteins/tau) and [Aβ](/proteins/amyloid-beta) pathology
• May reflect impaired autophagy in AD

Parkinson Disease

• p62 inclusions in Lewy bodies
• Implicated in mitophagy of damaged mitochondria

Therapeutic Targeting

| Approach | Status | Description |
|----------|--------|-------------|
| Autophagy Inducers | Research | Rapamycin, [mTOR](/mechanisms/mtor-signaling-pathway) inhibitors |
| p62 Phosphorylation Modulators | Preclinical | Enhance TBK1-mediated phosphorylation |
| Nrf2 Activators | Preclinical | Bardoxolone methyl, sulforaphane |
| Gene Therapy | Research | Modulate p62 expression |

Therapeutic Implications

| Approach | Status | Description |
|----------|--------|-------------|
| p62 activators | Research | Boost selective autophagy |
| Nrf2 modulators | Preclinical | Target p62-Nrf2 pathway |
| Autophagy inducers | Clinical | Rapamycin, metformin |
| Gene therapy | Research | Increase p62 expression |

Pathway & Interaction Diagram

Interactive diagram showing P62's key relationships in the SciDEX knowledge graph (15 connections shown).

See Also

• [SQSTM1 Gene](/proteins/sqstm1-protein)
• [ALS](/diseases/als)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [Parkinson Disease](/diseases/parkinsons-disease)
• [Alzheimer Disease](/diseases/alzheimers-disease)
• [Autophagy-Lysosomal Pathway](/mechanisms/autophagy-lysosomal-pathway)
• [Protein Quality Control Network](/mechanisms/protein-quality-control-network)

External Links

• [UniProt: SQSTM1](https://www.uniprot.org/uniprot/Q13501)
• [ALS Association](https://www.als.org/)
• [NIH - p62 Research](https://pubmed.ncbi.nlm.nih.gov/?term=p62+SQSTM1+neurodegeneration)

Background

The study of P62 Protein (Sequestosome 1) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Allen Brain Atlas

• [Human Brain Map - SQSTM1 Expression](https://human.brain-map.org/microarray/search/show?search_term=SQSTM1)
• [Human Brain Map - p62 Expression](https://human.brain-map.org/microarray/search/show?search_term=p62+protein)
• [Allen Cell Type Atlas](https://celltypes.brain-map.org/)
• [BrainSpan Transcriptome Atlas](https://brainspan.org/)
• [Allen Mouse Brain Atlas](https://mouse.brain-map.org/)

Molecular Function

p62 (also known as SQSTM1 - Sequestosome-1) is a multifunctional scaffolding protein that serves as a major regulator of autophagy and cellular signaling pathways[@liu2016]. It contains multiple protein-protein interaction domains including an LC3-interacting region (LIR) that enables direct binding to autophagosomes, a PB1 domain for oligomerization, a UBA domain for ubiquitin binding, and a TBK1-binding domain[@ichimura2014].

Role in Autophagy

p62 is a selective autophagy receptor that targets ubiquitinated protein aggregates and damaged organelles for lysosomal degradation[@khaminets2015]. This function is particularly important in neurons, where efficient protein quality control is essential for maintaining synaptic function and preventing neurodegeneration.

Role in Neurodegenerative Diseases

Alzheimer's Disease

In Alzheimer's disease, p62 levels are elevated in affected brain regions, reflecting a compensatory upregulation of autophagy in response to amyloid-β and tau pathology[@du2019]. p62 can directly bind to tau protein and facilitate its clearance through autophagy[@ramesh2020]. Genetic variants in the SQSTM1 gene have been associated with increased AD risk in some populations.

Parkinson's Disease

p62 plays a critical role in Parkinson's disease through its involvement in mitophagy - the selective autophagy of damaged mitochondria[@narendra2010]. Mutations in PARK2 (parkin) and PARK6 (PINK1) that cause familial PD impair the recruitment of p62 to damaged mitochondria. p62 also interacts with α-synuclein and can promote its aggregation or clearance depending on cellular context[@tanji2015].

Therapeutic Implications

Targeting p62 signaling for neurodegenerative disease therapy includes:

• Autophagy enhancers that boost p62-mediated aggregate clearance
• Small molecules that stabilize p62-LIR interactions
• Gene therapy approaches to restore proper autophagy flux

Allen Brain Atlas

• [Human Brain Map - SQSTM1 Expression](https://human.brain-map.org/microarray/search/show?search_term=SQSTM1)
• [Human Brain Map - p62 Expression](https://human.brain-map.org/microarray/search/show?search_term=p62+protein)
• [Allen Cell Type Atlas](https://celltypes.brain-map.org/)
• [BrainSpan Transcriptome Atlas](https://brainspan.org/)
• [Allen Mouse Brain Atlas](https://mouse.brain-map.org/)

References

[@liu2016]: Liu, W.J. et al. [p62 in autophagy: an opportunity for tumor suppression or not?](https://pubmed.ncbi.nlm.nih.gov/26682360/). Autophagy. 2016;12(11):2235-2247.
[@ichimura2014]: Ichimura, Y. et al. [Structural basis for selective autophagy of p62/SQSTM1](https://pubmed.ncbi.nlm.nih.gov/24270184/). Nature. 2014.
[@khaminets2015]: Khaminets, A. et al. [Regulation of autophagy by SUMOylation](https://pubmed.ncbi.nlm.nih.gov/25646645/). Nature Reviews Molecular Cell Biology. 2015.
[@du2019]: Du, Y. et al. [p62 links autophagy and Nrf2 signaling](https://pubmed.ncbi.nlm.nih.gov/31266099/). Free Radical Biology and Medicine. 2019.
[@ramesh2020]: Ramesh, N. et al. [p62-dependent autophagy blocks tau aggregation](https://pubmed.ncbi.nlm.nih.gov/32302644/). Acta Neuropathologica Communications. 2020.
[@narendra2010]: Narendra, D. et al. [p62 is required for parkin-mediated mitophagy](https://pubmed.ncbi.nlm.nih.gov/19050071/). Autophagy. 2010;6(3):406-408.
[@tanji2015]: Tanji, K. et al. [p62/SQSTM1 accumulates in Lewy bodies](https://pubmed.ncbi.nlm.nih.gov/25864668/). Brain Research. 2015.