title: Molecular mechanisms underlying PINK1 and Parkin catalyzed ubiquitylation of substrates on damaged mitochondria.
abstract: PINK1 and Parkin are gene products that cause genetic recessive Parkinsonism. PINK1 is a protein kinase and Parkin is a ubiquitin ligase (E3) that links ubiquitin to a substrate. Importantly, under steady state conditions, the enzymatic activity of Parkin is completely suppressed, but is activated when mitochondria become abnormal. In 2013 and 2014, biochemical and structure-function analyses revealed a number of critical mechanistic insights. First, Parkin is a self-inhibitory E3 that suppresses its E3 activity via intramolecular interactions. Second, in response to a decrease in mitochondrial membrane potential, PINK1 phosphorylates Ser65 in both the Parkin ubiquitin-like domain and ubiquitin itself. These phosphorylation events cooperate to relieve the Parkin autoinhibition. Third, activated Parkin forms a ubiquitin-thioester bond at Cys431 to produce a reaction intermediate that catalyzes ubiquitylation of substrates on damaged mitochondria. While the molecular mechanism regulating Parkin enzymatic activity has largely eluded clarification, a complete picture is now emerging.
authors.affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Room 202, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Fumika
authors.initials: F
authors.lastname: Koyano
authors.affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Room 202, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. Electronic address: matsuda-nr@igakuken.or.jp.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D024101:Mitochondrial Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: Activation; E3; PINK1; Parkin; Ubiquitin