PICK1 inhibits the E3 ubiquitin ligase activity of Parkin and reduces its neuronal protective effect

Parkin functions as a multipurpose E3 ubiquitin ligase, and Parkin loss of function is associated with both sporadic and familial Parkinson’s disease (PD). We report that the Bin/Amphiphysin/Rvs (BAR) domain of protein interacting with PRKCA1 (PICK1) bound to the really interesting new gene 1 (RING1...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2018-07, Vol.115 (30), p.E7193-E7201
Main Authors: He, Jing, Xia, Mengying, Yeung, Patrick K. K., Li, Jiahua, Li, Zhifang, Chung, Kenny K., Chung, Sookja K., Xia, Jun
Format: Article
Language:English
Subjects:
Biological Sciences
Inhibitor drugs
Medical treatment
Mice
Mitochondria
Movement disorders
MPTP
Neurodegenerative diseases
Neurons
Parkin protein
Parkinson's disease
PNAS Plus
Proteins
Substrates
Toxicity
Ubiquitin
Ubiquitin-protein ligase
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Summary:Parkin functions as a multipurpose E3 ubiquitin ligase, and Parkin loss of function is associated with both sporadic and familial Parkinson’s disease (PD). We report that the Bin/Amphiphysin/Rvs (BAR) domain of protein interacting with PRKCA1 (PICK1) bound to the really interesting new gene 1 (RING1) domain of Parkin and potently inhibited the E3 ligase activity of Parkin by disrupting its interaction with UbcH7. Parkin translocated to damaged mitochondria and led to their degradation in neurons, whereas PICK1 robustly inhibited this process. PICK1 also impaired the protective function of Parkin against stresses in SH-SY5Y cells and neurons. The protein levels of several Parkin substrates were reduced in young PICK1-knockout mice, and these mice were resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated toxicity. Taken together, the results indicate that PICK1 is a potent inhibitor of Parkin, and the reduction of PICK1 enhances the protective effect of Parkin.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1716506115