Autoregulation of Parkin activity through its ubiquitin‐like domain
Open accessAbstract
Parkin is an E3-ubiquitin ligase belonging to the RBR (RING-InBetweenRING-RING family), and is involved in the neurodegenerative disorder Parkinson's disease. Autosomal recessive juvenile Parkinsonism, which is one of the most common familial forms of the disease, is directly linked to mutations in the parkin gene. However, the molecular mechanisms of Parkin dysfunction in the disease state remain to be established. We now demonstrate that the ubiquitin-like domain of Parkin functions to inhibit its autoubiquitination. Moreover pathogenic Parkin mutations disrupt this autoinhibition, resulting in a constitutively active molecule. In addition, we show that the mechanism of autoregulation involves ubiquitin binding by a C-terminal region of Parkin. Our observations provide important molecular insights into the underlying basis of Parkinson's disease, and in the regulation of RBR E3-ligase activity.
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Proteasomal degradation of parkin occurs during mitophagy due to autoubiquitination, halting its activity.
“Proteasomal degradation of parkin was demonstrated during mitophagy due to autoubiquitination, halting its activity28,29,33,34.”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [33]
The Discussion (page unavailable) describes proteasomal degradation of Parkin mutants and proposes that autoubiquitination may lead to Parkin degradation and inactivation. It does not demonstrate that this occurs during mitophagy; it instead suggests that autoubiquitination and degradation of wild-type Parkin are absent or prevented in normal cellular conditions. (LLM, conf=0.88)
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- Authors
- Chaugule, V. K., Burchell, L., Barber, K. R., Sidhu, A., Leslie, S. J., Shaw, G. S., & Walden, H.
- Affiliations
- Cancer Research UK (GB)
- Western University (CA)
- Corresponding author
- Walden, Helen
- Venue
- The EMBO Journal
- Published
- 2011-06-21
- Volume
- 30
- Issue
- 14
- Pages
- 2853-2867
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC3160258
- OpenAlex
- W2113440807
- Cited by
- 339
- References
- 5
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 24 · 2023: 27 · 2022: 16 · 2021: 22 · 2020: 23 · 2019: 14 · 2018: 23 · 2017: 22 · 2016: 28 · 2015: 33 · 2014: 28 · 2013: 27 · 2012: 19
- FWCI
- 15.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Funders
- Cancer Research UK
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkin, ubiquitin-like domain, autoubiquitination, autoinhibition, RBR E3 ubiquitin ligase, Parkinson's disease, autosomal recessive juvenile parkinsonism, parkin mutations, ubiquitin binding
- MeSH terms
- Amino Acid Sequence, Homeostasis, Humans, Molecular Sequence Data, Mutation, Parkinson Disease, Peptide Fragments, Protein Conformation, Gene Expression Regulation, Enzymologic, Sequence Homology, Amino Acid, Ubiquitin, Ubiquitin-Protein Ligases
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