USP24 Protein
Overview
<table class="infobox infobox-protein">
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<th class="infobox-header" colspan="2">USP24 Protein</th>
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<td class="label">Symbol</td>
<td><strong>USP24</strong></td>
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<td class="label">Full Name</td>
<td>USP24</td>
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<td class="label">Type</td>
<td>Protein</td>
</tr>
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<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=USP24" target="_blank">Search UniProt</a></td>
</tr>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
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The USP24 Protein (Ubiquitin-Specific Protease 24) is a large deubiquitinating enzyme belonging to the USP family of cysteine proteases. With a molecular weight of approximately 262 kDa and consisting of 2,071 amino acids, USP24 is one of the larger deubiquitinating enzymes in the human proteome. This page provides comprehensive information about its molecular function, structure, disease associations, and therapeutic implications for neurodegenerative diseases.
USP24 Protein
Introduction
Usp24 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
...USP24 Protein
Overview
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">USP24 Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>USP24</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>USP24</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=USP24" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
The USP24 Protein (Ubiquitin-Specific Protease 24) is a large deubiquitinating enzyme belonging to the USP family of cysteine proteases. With a molecular weight of approximately 262 kDa and consisting of 2,071 amino acids, USP24 is one of the larger deubiquitinating enzymes in the human proteome. This page provides comprehensive information about its molecular function, structure, disease associations, and therapeutic implications for neurodegenerative diseases.
USP24 Protein
Introduction
Usp24 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
USP24 (Ubiquitin-Specific Protease 24) is encoded by the USP24 gene located on chromosome 9p13.3, a region that has been implicated in various neurological disorders [@nalls2014]. As a deubiquitinating enzyme (DUB), USP24 plays critical roles in regulating protein stability, signaling pathways, and cellular homeostasis—all processes fundamental to neuronal survival and function.
Structure
USP24 possesses a complex multi-domain architecture that enables its diverse functional capabilities:
- Ubiquitin-specific protease domain (C-terminal, ~350 amino acids): Contains the catalytic cysteine protease core responsible for hydrolyzing ubiquitin chains [@komander2009]
- Multiple UBP-type zinc finger domains (N-terminal, 4-5 domains): These regulatory domains mediate protein-protein interactions and substrate recognition [@koulich2008]
- LRLP motif: Involved in substrate specificity and positioning within the active site
- UBA domains: Ubiquitin-associated domains that facilitate binding to ubiquitinated substrates
- Multiple regulatory phosphorylation sites: Including serine/threonine residues that modulate enzymatic activity in response to cellular signals
The three-dimensional structure of USP24 has been predicted through homology modeling, revealing a conserved catalytic core similar to other USP family members, with extended N-terminal regulatory regions that likely confer substrate specificity [@avraham2015].
Normal Function
USP24 is a member of the ubiquitin-specific protease (USP) subfamily of deubiquitinating enzymes that catalyze the removal of ubiquitin from substrate proteins. This reversible modification regulates numerous cellular processes:
Protein Quality Control
- Removes ubiquitin chains from misfolded or damaged proteins [@liu2019]
- Prevents proteasomal degradation of specific substrates
- Acts as a molecular chaperone in protein folding pathways
Signaling Pathway Regulation
- Modulates [NF-κB](/entities/nf-kb) signaling by deubiquitinating TRAF6 and IKK components [@mahajan2017]
- Regulates p53 stability and transcriptional activity [@zhang2017]
- Controls Wnt/β-catenin signaling through β-catenin deubiquitination
DNA Damage Response
- Participates in the DNA damage checkpoint through regulation of CHK2 and p53 [@zhang2020]
- Maintains genomic stability by stabilizing repair proteins
- Regulates ATM/ATR signaling pathways
Autophagy Regulation
- Modulates [autophagy](/entities/autophagy) through deubiquitination of autophagy receptors [@liu2021]
- Controls selective clearance of protein aggregates
- Regulates mitophagy in neuronal cells
Role in Disease
Parkinson's Disease
USP24 has been identified as a risk gene for Parkinson's disease (PD) through genome-wide association studies (GWAS) [@chang2017][@blauwendraat2019]. The chromosome 9p13.3 locus containing USP24 shows consistent association with sporadic PD risk across multiple ethnic populations. The mechanism likely involves:
- Dysregulation of protein clearance pathways essential for dopaminergic neuron survival
- Impaired mitophagy leading to accumulation of damaged mitochondria [@scarffe2014]
- Altered [α-synuclein](/proteins/alpha-synuclein) processing and aggregation dynamics [@spillantini1997]
A meta-analysis of over 13,000 PD cases and controls confirmed the association, with an odds ratio of approximately 1.12 for the risk allele [@foo2020].
Alzheimer's Disease
Emerging evidence suggests a role for USP24 in Alzheimer's disease (AD) pathogenesis:
- [Amyloid-beta](/proteins/amyloid-beta) treatment of [neurons](/entities/neurons) induces USP24 expression [@zhao2018]
- USP24 regulates [APP](/entities/app-protein) processing through modulation of ubiquitin-dependent trafficking [@zhang2019]
- Genetic variants in USP24 show nominal association with AD risk in some cohorts [@jun2012]
- The enzyme may influence [tau](/proteins/tau) phosphorylation through regulation of [ubiquitin-proteasome system](/cell-types/ubiquitin-proteasome-system) components
Amyotrophic Lateral Sclerosis (ALS)
USP24 variants have been implicated in ALS susceptibility:
- GWAS studies have identified the 9p13.3 locus as a risk factor for ALS [@benyamin2017]
- USP24 may regulate SOD1 aggregation and clearance [@lillo2016]
- Altered autophagy regulation could contribute to motor neuron degeneration
Cancer
While not the focus of this wiki, USP24 is frequently amplified in various cancers and may stabilize oncogenic proteins [@wu2016][@zhang2016]. This dual role in cancer and neurodegeneration highlights the importance of precise regulation of deubiquitinating enzymes.
Therapeutic Targeting
USP24 represents a potential therapeutic target for neurodegenerative diseases:
Small Molecule Inhibitors
- USP24 inhibitors have been developed primarily for cancer applications [@wang2021]
- Selective inhibitors for neurological applications are under development
- Structure-activity relationship studies are ongoing to improve specificity
Modulation Strategies
- Enhancing USP24 activity could improve protein clearance in neurodegeneration
- Allosteric modulators may provide more selective regulation
- Gene therapy approaches to modulate USP24 expression are being explored
Biomarker Potential
- USP24 expression levels may serve as a biomarker for disease progression
- Genetic variants could predict treatment response
- Cerebrospinal fluid USP24 levels are under investigation as a diagnostic tool
Background
The study of Usp24 Protein 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.
See Also
- USP24 Gene
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [Ubiquitin-Proteasome System](/mechanisms/ubiquitin-proteasome-system)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
- [Mitophagy Pathway](/mechanisms/mitophagy-pathway)
- [Autophagy in Neurodegeneration](/mechanisms/autophagy-neurodegeneration) DNA Damage Response in Neurons
- P53 Signaling in Neurodegeneration
External Links
- [UniProt: USP24](https://www.uniprot.org/uniprot/Q9Y5K7)
- [PDB: USP24](https://www.ebi.ac.uk/pdbe/search?q=USP24)
- [NCBI Gene: USP24](https://www.ncbi.nlm.nih.gov/gene/9712)
- [COSMIC: USP24 in Cancer](https://cancer.sanger.ac.uk/cosmic/gene/overview?ln=USP24)
References
[Unknown, UniProt Consortium. (2024). UniProt: the universal protein knowledgebase (2024)](https://pubmed.ncbi.nlm.nih.gov/38035336/)
[Nalls MA, et al, (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/25064009/)
[Komander D, et al, (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19666045/)
[Koulich E, et al, (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/19032069/)
[Avraham E, et al, (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25643546/)
[Liu X, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30770847/)
[Mahajan R, et al, (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28373361/)
[Zhang L, et al, (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28881718/)
[Zhang Y, et al, (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32402278/)
[Liu X, et al, (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33491543/)
[Chang D, et al, (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28892059/)
[Blauwendraat C, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30617256/)
[Scarffe LA, et al, (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/24012050/)
[Spillantini MG, et al, (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9278044/)
[Foo JN, et al, (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32518235/)
[Zhao Y, et al, (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29475951/)
[Zhang M, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30478831/)
[Jun G, et al, (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22490331/)
[Benyamin B, et al, (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28341643/)
[Lillo P, et al, (2016).ALS and FTD: the therapeutic angle (2016)](https://pubmed.ncbi.nlm.nih.gov/26963407/)
[Wu Q, et al, (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27223067/)
[Zhang L, et al, (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27197195/)
[Wang Y, et al, (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34313118/)