Journal
EMBO REPORTS
Volume 19, Issue 4, Pages -Publisher
WILEY
DOI: 10.15252/embr.201744981
Keywords
Parkin; Parkinson; phosphorylation; PINK1; ubiquitin
Categories
Funding
- National Science Foundation
- National Institutes of Health/National Institute of General Medical Sciences under NSF [DMR-0936384]
- National Institutes of Health, through its National Institute of General Medical Sciences [GM-103485]
- Parkinson Canada
- Michael J. Fox Foundation
- Natural Science AMP
- Engineering Research Council of Canada
- Canadian Fund for Innovation
- Canada Research Chair Program
- Canadian Institute of Health Research
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Mutations in PINK1 cause autosomal recessive Parkinson's disease (PD), a neurodegenerative movement disorder. PINK1 is a kinase that acts as a sensor of mitochondrial damage and initiates Parkin-mediated clearance of the damaged organelle. PINK1 phosphorylates Ser65 in both ubiquitin and the ubiquitin-like (Ubl) domain of Parkin, which stimulates its E3 ligase activity. Autophosphorylation of PINK1 is required for Parkin activation, but how this modulates the ubiquitin kinase activity is unclear. Here, we show that autophosphorylation of Tribolium castaneum PINK1 is required for substrate recognition. Using enzyme kinetics and NMR spectroscopy, we reveal that PINK1 binds the Parkin Ubl with a 10-fold higher affinity than ubiquitin via a conserved interface that is also implicated in RING1 and SH3 binding. The interaction requires phosphorylation at Ser205, an invariant PINK1 residue (Ser228 in human). Using mass spectrometry, we demonstrate that PINK1 rapidly autophosphorylates in trans at Ser205. Small-angle X-ray scattering and hydrogen-deuterium exchange experiments provide insights into the structure of the PINK1 catalytic domain. Our findings suggest that multiple PINK1 molecules autophosphorylate first prior to binding and phosphorylating ubiquitin and Parkin.
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