title: PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy.
abstract: Parkinson's disease genes PINK1 and parkin encode kinase and ubiquitin ligase, respectively. The gene products PINK1 and Parkin are implicated in mitochondrial autophagy, or mitophagy. Upon the loss of mitochondrial membrane potential (ΔΨm), cytosolic Parkin is recruited to the mitochondria by PINK1 through an uncharacterised mechanism - an initial step triggering sequential events in mitophagy. This study reports that Ser65 in the ubiquitin-like domain (Ubl) of Parkin is phosphorylated in a PINK1-dependent manner upon depolarisation of ΔΨm. The introduction of mutations at Ser65 suggests that phosphorylation of Ser65 is required not only for the efficient translocation of Parkin, but also for the degradation of mitochondrial proteins in mitophagy. Phosphorylation analysis of Parkin pathogenic mutants also suggests Ser65 phosphorylation is not sufficient for Parkin translocation. Our study partly uncovers the molecular mechanism underlying the PINK1-dependent mitochondrial translocation and activation of Parkin as an initial step of mitophagy.
authors.affiliation: Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Kahori
authors.initials: K
authors.lastname: Shiba-Fukushima
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Imai
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Yoshida
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishihama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kanao
authors.forename: Shigeto
authors.initials: S
authors.lastname: Sato
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein