Journal
MOLECULAR CELL
Volume 82, Issue 1, Pages 44-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.11.012
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Funding
- Canada Foundation for Innovation (CFI)
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- National Research Council of Canada
- Canadian Institutes of Health Research (CIHR)
- Government of Saskatchewan
- University of Saskatchewan
- Canada Research Chair (Tier 2) in Structural Pharmacology
- NSERC [06497-2015]
- CIHR [153274]
- Parkinson Canada [2017-1277]
- Michael J. Fox Foundation [12119]
- Parkinson Canada
- Centre de Recherche en Biologie Structurale (Fond de Recherche du Quebec - Sante)
- Foundation grant from the CIHR [FDN-154301]
- Canada Research Chair (Tier 1) in Parkinson's Disease
- CIHR Banting Fellowship
- FRQS postdoctoral fellowship
- Cystic Fibrosis Foundation US
- CIHR
- CFI
- Canada Research Chair (Tier I) in Molecular and Cellular Biology of Cystic Fibrosis and Other Conformational Diseases
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Mutations in PINK1 lead to Parkinson's disease. The study shows that PINK1 is imported into the translocase of the outer mitochondrial membrane (TOM) complex, leading to its activation by autophosphorylation and initiation of mitochondrial clearance. The crystal structures provide insights into the dimeric autophosphorylation complex and the stabilization mechanism of PINK1 on the core TOM complex.
Mutations in PINK1 cause autosomal-recessive Parkinson's disease. Mitochondrial damage results in PINK1 import arrest on the translocase of the outer mitochondrial membrane (TOM) complex, resulting in the activation of its ubiquitin kinase activity by autophosphorylation and initiation of Parkin-dependent mitochondrial clearance. Herein, we report crystal structures of the entire cytosolic domain of insect PINK1. Our structures reveal a dimeric autophosphorylation complex targeting phosphorylation at the invariant Ser205 (human Ser228). The dimer interface requires insert 2, which is unique to PINK1. The structures also reveal how an N-terminal helix binds to the C-terminal extension and provide insights into stabilization of PINK1 on the core TOM complex.
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