Parkin functions as an E2-dependent ubiquitin– protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1
Open accessAbstract
Parkinson's disease is a common neurodegenerative disorder in which familial-linked genes have provided novel insights into the pathogenesis of this disorder. Mutations in Parkin, a ring-finger-containing protein of unknown function, are implicated in the pathogenesis of autosomal recessive familial Parkinson's disease. Here, we show that Parkin binds to the E2 ubiquitin-conjugating human enzyme 8 (UbcH8) through its C-terminal ring-finger. Parkin has ubiquitin–protein ligase activity in the presence of UbcH8. Parkin also ubiquitinates itself and promotes its own degradation. We also identify and show that the synaptic vesicle-associated protein, CDCrel-1, interacts with Parkin through its ring-finger domains. Furthermore, Parkin ubiquitinates and promotes the degradation of CDCrel-1. Familial-linked mutations disrupt the ubiquitin–protein ligase function of Parkin and impair Parkin and CDCrel-1 degradation. These results suggest that Parkin functions as an E3 ubiquitin–protein ligase through its ring domains and that it may control protein levels via ubiquitination. The loss of Parkin's ubiquitin–protein ligase function in familial-linked mutations suggests that this may be the cause of familial autosomal recessive Parkinson's disease.
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Loss of Parkin activity due to mutations has been related to autosomal recessive early onset of Parkinson's disease.
“Loss of Parkin activity due to the mutations has been related to autosomal recessive early onset of Parkinson’s disease (Zhang et al. 2000).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Zhang et al. 2000
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- Authors
- Zhang, Y., Gao, J., Chung, K. K. K., Huang, H., Dawson, V. L., & Dawson, T. M.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Dawson, Valina L.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2000-11-14
- Volume
- 97
- Issue
- 24
- Pages
- 13354-13359
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC27228
- OpenAlex
- W1986188355
- Cited by
- 982
- References
- 49
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 12 · 2023: 11 · 2022: 15 · 2021: 17 · 2020: 20 · 2019: 21 · 2018: 18 · 2017: 37 · 2016: 28 · 2015: 33 · 2014: 34 · 2013: 32 · 2012: 44
- FWCI
- 41.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- U.S. Public Health Service
- National Institute of Neurological Disorders and Stroke (NS 38377, P50NS038377)
- 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, E3 ubiquitin ligase, UbcH8, E2 ubiquitin-conjugating enzyme, RING domain, synaptic vesicle proteins, protein degradation, ubiquitination, familial Parkinson's disease, autosomal recessive Parkinson's disease, parkin mutations
- MeSH terms
- Amino Acid Sequence, Binding Sites, Cell Line, Cloning, Molecular, Humans, Ligases, Methionine, Molecular Sequence Data, Nerve Tissue Proteins, Parkinson Disease, Recombinant Proteins, Synaptic Vesicles, Transfection, Ubiquitins, Sequence Alignment, Sequence Homology, Amino Acid, Cell Cycle Proteins, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Septins
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