Ubiquitin is phosphorylated by PINK1 to activate parkin.
Identifieur interne : 000732 ( PubMed/Curation ); précédent : 000731; suivant : 000733Ubiquitin is phosphorylated by PINK1 to activate parkin.
Auteurs : Fumika Koyano [Japon] ; Kei Okatsu [Japon] ; Hidetaka Kosako [Japon] ; Yasushi Tamura [Japon] ; Etsu Go [Japon] ; Mayumi Kimura [Japon] ; Yoko Kimura [Japon] ; Hikaru Tsuchiya [Japon] ; Hidehito Yoshihara [Japon] ; Takatsugu Hirokawa [Japon] ; Toshiya Endo [Japon] ; Edward A. Fon [Canada] ; Jean-François Trempe [Canada] ; Yasushi Saeki [Japon] ; Keiji Tanaka [Japon] ; Noriyuki Matsuda [Japon]Source :
- Nature [ 1476-4687 ] ; 2014.
English descriptors
- KwdEn :
- Animals, Enzyme Activation, Fibroblasts, HeLa Cells, Humans, Membrane Potential, Mitochondrial, Mice, Mitochondria (metabolism), Mutation (genetics), Parkinson Disease, Phosphorylation, Phosphoserine (metabolism), Protein Kinases (metabolism), Ubiquitin (chemistry), Ubiquitin (metabolism), Ubiquitin-Protein Ligases (genetics), Ubiquitin-Protein Ligases (metabolism), Ubiquitination.
- MESH :
- chemical , chemistry : Ubiquitin.
- chemical , genetics : Ubiquitin-Protein Ligases.
- chemical , metabolism : Phosphoserine, Protein Kinases, Ubiquitin, Ubiquitin-Protein Ligases.
- genetics : Mutation.
- metabolism : Mitochondria.
- Animals, Enzyme Activation, Fibroblasts, HeLa Cells, Humans, Membrane Potential, Mitochondrial, Mice, Parkinson Disease, Phosphorylation, Ubiquitination.
Abstract
PINK1 (PTEN induced putative kinase 1) and PARKIN (also known as PARK2) have been identified as the causal genes responsible for hereditary recessive early-onset Parkinsonism. PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. PINK1 acts as an upstream factor for parkin and is essential both for the activation of latent E3 parkin activity and for recruiting parkin onto depolarized mitochondria. Recently, mechanistic insights into mitochondrial quality control mediated by PINK1 and parkin have been revealed, and PINK1-dependent phosphorylation of parkin has been reported. However, the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation, and how PINK1 accelerates the E3 activity of parkin on damaged mitochondria is still obscure. Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (also known as UBE2L3) and ubiquitin (UBCH7∼ubiquitin) in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.
DOI: 10.1038/nature13392
PubMed: 24784582
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wicri:level="1"><nlm:affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561</wicri:regionArea></affiliation></author><author><name sortKey="Kosako, Hidetaka" sort="Kosako, Hidetaka" uniqKey="Kosako H" first="Hidetaka" last="Kosako">Hidetaka Kosako</name><affiliation wicri:level="1"><nlm:affiliation>Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima 770-8503, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima 770-8503</wicri:regionArea></affiliation></author><author><name sortKey="Tamura, Yasushi" sort="Tamura, Yasushi" uniqKey="Tamura Y" first="Yasushi" last="Tamura">Yasushi Tamura</name><affiliation wicri:level="1"><nlm:affiliation>Research Center for Materials Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Research Center for Materials Science, Nagoya University, Nagoya, Aichi 464-8602</wicri:regionArea></affiliation></author><author><name sortKey="Go, Etsu" sort="Go, Etsu" uniqKey="Go E" first="Etsu" last="Go">Etsu Go</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Kimura, Mayumi" sort="Kimura, Mayumi" uniqKey="Kimura M" first="Mayumi" last="Kimura">Mayumi Kimura</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Kimura, Yoko" sort="Kimura, Yoko" uniqKey="Kimura Y" first="Yoko" last="Kimura">Yoko Kimura</name><affiliation wicri:level="1"><nlm:affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Agriculture, Shizuoka University, 836 Ohya, Shizuoka 422-8529, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Agriculture, Shizuoka University, 836 Ohya, Shizuoka 422-8529</wicri:regionArea></affiliation></author><author><name sortKey="Tsuchiya, Hikaru" sort="Tsuchiya, Hikaru" uniqKey="Tsuchiya H" first="Hikaru" last="Tsuchiya">Hikaru Tsuchiya</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Yoshihara, Hidehito" sort="Yoshihara, Hidehito" uniqKey="Yoshihara H" first="Hidehito" last="Yoshihara">Hidehito Yoshihara</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Hirokawa, Takatsugu" sort="Hirokawa, Takatsugu" uniqKey="Hirokawa T" first="Takatsugu" last="Hirokawa">Takatsugu Hirokawa</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064</wicri:regionArea></affiliation></author><author><name sortKey="Endo, Toshiya" sort="Endo, Toshiya" uniqKey="Endo T" first="Toshiya" last="Endo">Toshiya Endo</name><affiliation wicri:level="1"><nlm:affiliation>1] JST-CREST/Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan [2] JST-CREST/Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>1] JST-CREST/Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan [2] JST-CREST/Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555</wicri:regionArea></affiliation></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><affiliation wicri:level="1"><nlm:affiliation>McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec H3A 2B4, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec H3A 2B4</wicri:regionArea></affiliation></author><author><name sortKey="Trempe, Jean Francois" sort="Trempe, Jean Francois" uniqKey="Trempe J" first="Jean-François" last="Trempe">Jean-François Trempe</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology & Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology & Therapeutics, McGill University, Montréal, Québec H3G 1Y6</wicri:regionArea></affiliation></author><author><name sortKey="Saeki, Yasushi" sort="Saeki, Yasushi" uniqKey="Saeki Y" first="Yasushi" last="Saeki">Yasushi Saeki</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Tanaka, Keiji" sort="Tanaka, Keiji" uniqKey="Tanaka K" first="Keiji" last="Tanaka">Keiji Tanaka</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Matsuda, Noriyuki" sort="Matsuda, Noriyuki" uniqKey="Matsuda N" first="Noriyuki" last="Matsuda">Noriyuki Matsuda</name><affiliation wicri:level="1"><nlm:affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:24784582</idno><idno type="pmid">24784582</idno><idno type="doi">10.1038/nature13392</idno><idno type="wicri:Area/PubMed/Corpus">000732</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000732</idno><idno type="wicri:Area/PubMed/Curation">000732</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000732</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Ubiquitin is phosphorylated by PINK1 to activate parkin.</title><author><name sortKey="Koyano, Fumika" sort="Koyano, Fumika" uniqKey="Koyano F" first="Fumika" last="Koyano">Fumika Koyano</name><affiliation wicri:level="1"><nlm:affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561</wicri:regionArea></affiliation></author><author><name sortKey="Okatsu, Kei" sort="Okatsu, Kei" uniqKey="Okatsu K" first="Kei" last="Okatsu">Kei Okatsu</name><affiliation wicri:level="1"><nlm:affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561</wicri:regionArea></affiliation></author><author><name sortKey="Kosako, Hidetaka" sort="Kosako, Hidetaka" uniqKey="Kosako H" first="Hidetaka" last="Kosako">Hidetaka Kosako</name><affiliation wicri:level="1"><nlm:affiliation>Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima 770-8503, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima 770-8503</wicri:regionArea></affiliation></author><author><name sortKey="Tamura, Yasushi" sort="Tamura, Yasushi" uniqKey="Tamura Y" first="Yasushi" last="Tamura">Yasushi Tamura</name><affiliation wicri:level="1"><nlm:affiliation>Research Center for Materials Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Research Center for Materials Science, Nagoya University, Nagoya, Aichi 464-8602</wicri:regionArea></affiliation></author><author><name sortKey="Go, Etsu" sort="Go, Etsu" uniqKey="Go E" first="Etsu" last="Go">Etsu Go</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Kimura, Mayumi" sort="Kimura, Mayumi" uniqKey="Kimura M" first="Mayumi" last="Kimura">Mayumi Kimura</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Kimura, Yoko" sort="Kimura, Yoko" uniqKey="Kimura Y" first="Yoko" last="Kimura">Yoko Kimura</name><affiliation wicri:level="1"><nlm:affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Agriculture, Shizuoka University, 836 Ohya, Shizuoka 422-8529, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Agriculture, Shizuoka University, 836 Ohya, Shizuoka 422-8529</wicri:regionArea></affiliation></author><author><name sortKey="Tsuchiya, Hikaru" sort="Tsuchiya, Hikaru" uniqKey="Tsuchiya H" first="Hikaru" last="Tsuchiya">Hikaru Tsuchiya</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Yoshihara, Hidehito" sort="Yoshihara, Hidehito" uniqKey="Yoshihara H" first="Hidehito" last="Yoshihara">Hidehito Yoshihara</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Hirokawa, Takatsugu" sort="Hirokawa, Takatsugu" uniqKey="Hirokawa T" first="Takatsugu" last="Hirokawa">Takatsugu Hirokawa</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064</wicri:regionArea></affiliation></author><author><name sortKey="Endo, Toshiya" sort="Endo, Toshiya" uniqKey="Endo T" first="Toshiya" last="Endo">Toshiya Endo</name><affiliation wicri:level="1"><nlm:affiliation>1] JST-CREST/Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan [2] JST-CREST/Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>1] JST-CREST/Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan [2] JST-CREST/Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555</wicri:regionArea></affiliation></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><affiliation wicri:level="1"><nlm:affiliation>McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec H3A 2B4, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec H3A 2B4</wicri:regionArea></affiliation></author><author><name sortKey="Trempe, Jean Francois" sort="Trempe, Jean Francois" uniqKey="Trempe J" first="Jean-François" last="Trempe">Jean-François Trempe</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacology & Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology & Therapeutics, McGill University, Montréal, Québec H3G 1Y6</wicri:regionArea></affiliation></author><author><name sortKey="Saeki, Yasushi" sort="Saeki, Yasushi" uniqKey="Saeki Y" first="Yasushi" last="Saeki">Yasushi Saeki</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Tanaka, Keiji" sort="Tanaka, Keiji" uniqKey="Tanaka K" first="Keiji" last="Tanaka">Keiji Tanaka</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author><author><name sortKey="Matsuda, Noriyuki" sort="Matsuda, Noriyuki" uniqKey="Matsuda N" first="Noriyuki" last="Matsuda">Noriyuki Matsuda</name><affiliation wicri:level="1"><nlm:affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature</title><idno type="eISSN">1476-4687</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Enzyme Activation</term><term>Fibroblasts</term><term>HeLa Cells</term><term>Humans</term><term>Membrane Potential, Mitochondrial</term><term>Mice</term><term>Mitochondria (metabolism)</term><term>Mutation (genetics)</term><term>Parkinson Disease</term><term>Phosphorylation</term><term>Phosphoserine (metabolism)</term><term>Protein Kinases (metabolism)</term><term>Ubiquitin (chemistry)</term><term>Ubiquitin (metabolism)</term><term>Ubiquitin-Protein Ligases (genetics)</term><term>Ubiquitin-Protein Ligases (metabolism)</term><term>Ubiquitination</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Ubiquitin</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Phosphoserine</term><term>Protein Kinases</term><term>Ubiquitin</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mutation</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Mitochondria</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Enzyme Activation</term><term>Fibroblasts</term><term>HeLa Cells</term><term>Humans</term><term>Membrane Potential, Mitochondrial</term><term>Mice</term><term>Parkinson Disease</term><term>Phosphorylation</term><term>Ubiquitination</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">PINK1 (PTEN induced putative kinase 1) and PARKIN (also known as PARK2) have been identified as the causal genes responsible for hereditary recessive early-onset Parkinsonism. PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. PINK1 acts as an upstream factor for parkin and is essential both for the activation of latent E3 parkin activity and for recruiting parkin onto depolarized mitochondria. Recently, mechanistic insights into mitochondrial quality control mediated by PINK1 and parkin have been revealed, and PINK1-dependent phosphorylation of parkin has been reported. However, the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation, and how PINK1 accelerates the E3 activity of parkin on damaged mitochondria is still obscure. Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (also known as UBE2L3) and ubiquitin (UBCH7∼ubiquitin) in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24784582</PMID><DateCreated><Year>2014</Year><Month>06</Month><Day>06</Day></DateCreated><DateCompleted><Year>2014</Year><Month>07</Month><Day>10</Day></DateCompleted><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1476-4687</ISSN><JournalIssue CitedMedium="Internet"><Volume>510</Volume><Issue>7503</Issue><PubDate><Year>2014</Year><Month>Jun</Month><Day>05</Day></PubDate></JournalIssue><Title>Nature</Title><ISOAbbreviation>Nature</ISOAbbreviation></Journal><ArticleTitle>Ubiquitin is phosphorylated by PINK1 to activate parkin.</ArticleTitle><Pagination><MedlinePgn>162-6</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/nature13392</ELocationID><Abstract><AbstractText>PINK1 (PTEN induced putative kinase 1) and PARKIN (also known as PARK2) have been identified as the causal genes responsible for hereditary recessive early-onset Parkinsonism. PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. PINK1 acts as an upstream factor for parkin and is essential both for the activation of latent E3 parkin activity and for recruiting parkin onto depolarized mitochondria. Recently, mechanistic insights into mitochondrial quality control mediated by PINK1 and parkin have been revealed, and PINK1-dependent phosphorylation of parkin has been reported. However, the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation, and how PINK1 accelerates the E3 activity of parkin on damaged mitochondria is still obscure. Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (also known as UBE2L3) and ubiquitin (UBCH7∼ubiquitin) in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Koyano</LastName><ForeName>Fumika</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Okatsu</LastName><ForeName>Kei</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kosako</LastName><ForeName>Hidetaka</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima 770-8503, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tamura</LastName><ForeName>Yasushi</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Research Center for Materials Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Go</LastName><ForeName>Etsu</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kimura</LastName><ForeName>Mayumi</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kimura</LastName><ForeName>Yoko</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Agriculture, Shizuoka University, 836 Ohya, Shizuoka 422-8529, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tsuchiya</LastName><ForeName>Hikaru</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yoshihara</LastName><ForeName>Hidehito</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hirokawa</LastName><ForeName>Takatsugu</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Endo</LastName><ForeName>Toshiya</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>1] JST-CREST/Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan [2] JST-CREST/Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fon</LastName><ForeName>Edward A</ForeName><Initials>EA</Initials><AffiliationInfo><Affiliation>McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec H3A 2B4, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Trempe</LastName><ForeName>Jean-François</ForeName><Initials>JF</Initials><AffiliationInfo><Affiliation>Department of Pharmacology & Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Saeki</LastName><ForeName>Yasushi</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tanaka</LastName><ForeName>Keiji</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Matsuda</LastName><ForeName>Noriyuki</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><Agency>Canadian Institutes of Health Research</Agency><Country>Canada</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>06</Month><Day>04</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Nature</MedlineTA><NlmUniqueID>0410462</NlmUniqueID><ISSNLinking>0028-0836</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D025801">Ubiquitin</NameOfSubstance></Chemical><Chemical><RegistryNumber>17885-08-4</RegistryNumber><NameOfSubstance UI="D010768">Phosphoserine</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.2.27</RegistryNumber><NameOfSubstance UI="D044767">Ubiquitin-Protein Ligases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.2.27</RegistryNumber><NameOfSubstance UI="C111567">parkin protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.-</RegistryNumber><NameOfSubstance UI="D011494">Protein Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="C433927">PTEN-induced 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Version="1">23770917</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004789" MajorTopicYN="N">Enzyme Activation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005347" MajorTopicYN="N">Fibroblasts</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006367" MajorTopicYN="N">HeLa Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053078" MajorTopicYN="N">Membrane Potential, Mitochondrial</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008928" MajorTopicYN="N">Mitochondria</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010300" MajorTopicYN="N">Parkinson Disease</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010766" MajorTopicYN="N">Phosphorylation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010768" MajorTopicYN="N">Phosphoserine</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011494" MajorTopicYN="N">Protein Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D025801" MajorTopicYN="N">Ubiquitin</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" 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