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.
| Gene | SQSTM1 |
|---|---|
| UniProt ID | Q13501 |
| PDB Structures | 2K38, 5O8Y |
| Molecular Weight | ~62 kDa |
| Subcellular Localization | Cytoplasm, nucleus, aggresomes, autophagosomes |
| Protein Family | Sequestosome family |
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.
p62 contains several functional domains:
p62 is a master regulator of cellular homeostasis:
| Approach | Status | Description |
|---|---|---|
| Autophagy Inducers | Research | Rapamycin, mTOR inhibitors |
| p62 Phosphorylation Modulators | Preclinical | Enhance TBK1-mediated phosphorylation |
| Nrf2 Activators | Preclinical | Bardoxolone methyl, sulforaphane |
| Gene Therapy | Research | Modulate p62 expression |
| 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 |
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.
p62 (also known as SQSTM1 - Sequestosome-1) is a multifunctional scaffolding protein that serves as a major regulator of autophagy and cellular signaling pathways[1]. 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[2].
p62 is a selective autophagy receptor that targets ubiquitinated protein aggregates and damaged organelles for lysosomal degradation[3]. This function is particularly important in neurons, where efficient protein quality control is essential for maintaining synaptic function and preventing neurodegeneration.
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[4]. p62 can directly bind to tau protein and facilitate its clearance through autophagy[5]. Genetic variants in the SQSTM1 gene have been associated with increased AD risk in some populations.
p62 plays a critical role in Parkinson's disease through its involvement in mitophagy - the selective autophagy of damaged mitochondria[6]. 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[7].
Targeting p62 signaling for neurodegenerative disease therapy includes:
Liu, W.J. et al. p62 in autophagy: an opportunity for tumor suppression or not?. Autophagy. 2016. ↩︎
Ichimura, Y. et al. Structural basis for selective autophagy of p62/SQSTM1. Nature. 2014. ↩︎
Khaminets, A. et al. Regulation of autophagy by SUMOylation. Nature Reviews Molecular Cell Biology. 2015. ↩︎
Du, Y. et al. p62 links autophagy and Nrf2 signaling. Free Radical Biology and Medicine. 2019. ↩︎
Ramesh, N. et al. p62-dependent autophagy blocks tau aggregation. Acta Neuropathologica Communications. 2020. ↩︎
Narendra, D. et al. p62 is required for parkin-mediated mitophagy. Autophagy. 2010. ↩︎
Tanji, K. et al. p62/SQSTM1 accumulates in Lewy bodies. Brain Research. 2015. ↩︎