Ubiquitin is phosphorylated by PINK1 to activate parkin.
Identifieur interne : 000876 ( Main/Exploration ); précédent : 000875; suivant : 000877Ubiquitin 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
Affiliations:
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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><placeName><settlement type="city">Tokyo</settlement></placeName></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><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author><author><name sortKey="Kimura, Yoko" 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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><placeName><settlement type="city">Tokyo</settlement></placeName></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><wicri:noRegion>Kyoto 603-8555</wicri:noRegion></affiliation></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. 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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><placeName><settlement type="city">Tokyo</settlement></placeName></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><placeName><settlement type="city">Tokyo</settlement></placeName></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><idno type="wicri:Area/PubMed/Checkpoint">000732</idno><idno type="wicri:explorRef" 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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><wicri:noRegion>Chiba 277-8561</wicri:noRegion></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><wicri:noRegion>Chiba 277-8561</wicri:noRegion></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><wicri:noRegion>Tokushima 770-8503</wicri:noRegion></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><wicri:noRegion>Aichi 464-8602</wicri:noRegion></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><placeName><settlement type="city">Tokyo</settlement></placeName></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><placeName><settlement type="city">Tokyo</settlement></placeName></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><wicri:noRegion>Shizuoka 422-8529</wicri:noRegion></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><placeName><settlement type="city">Tokyo</settlement></placeName></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><placeName><settlement type="city">Tokyo</settlement></placeName></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><placeName><settlement type="city">Tokyo</settlement></placeName></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><wicri:noRegion>Kyoto 603-8555</wicri:noRegion></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="4"><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><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></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="4"><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><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></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><placeName><settlement type="city">Tokyo</settlement></placeName></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><placeName><settlement type="city">Tokyo</settlement></placeName></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><placeName><settlement type="city">Tokyo</settlement></placeName></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><affiliations><list><country><li>Canada</li><li>Japon</li></country><region><li>Québec</li></region><settlement><li>Montréal</li><li>Tokyo</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Japon"><noRegion><name sortKey="Koyano, Fumika" sort="Koyano, Fumika" uniqKey="Koyano F" first="Fumika" last="Koyano">Fumika Koyano</name></noRegion><name sortKey="Endo, Toshiya" sort="Endo, Toshiya" uniqKey="Endo T" first="Toshiya" last="Endo">Toshiya Endo</name><name sortKey="Go, Etsu" sort="Go, Etsu" uniqKey="Go E" first="Etsu" last="Go">Etsu Go</name><name sortKey="Hirokawa, Takatsugu" sort="Hirokawa, Takatsugu" uniqKey="Hirokawa T" first="Takatsugu" last="Hirokawa">Takatsugu Hirokawa</name><name sortKey="Kimura, Mayumi" sort="Kimura, Mayumi" uniqKey="Kimura M" first="Mayumi" last="Kimura">Mayumi Kimura</name><name sortKey="Kimura, Yoko" sort="Kimura, Yoko" uniqKey="Kimura Y" first="Yoko" last="Kimura">Yoko Kimura</name><name sortKey="Kosako, Hidetaka" sort="Kosako, Hidetaka" uniqKey="Kosako H" first="Hidetaka" last="Kosako">Hidetaka Kosako</name><name sortKey="Matsuda, Noriyuki" sort="Matsuda, Noriyuki" uniqKey="Matsuda N" first="Noriyuki" last="Matsuda">Noriyuki Matsuda</name><name sortKey="Okatsu, Kei" sort="Okatsu, Kei" uniqKey="Okatsu K" first="Kei" last="Okatsu">Kei Okatsu</name><name sortKey="Saeki, Yasushi" sort="Saeki, Yasushi" uniqKey="Saeki Y" first="Yasushi" last="Saeki">Yasushi Saeki</name><name sortKey="Tamura, Yasushi" sort="Tamura, Yasushi" uniqKey="Tamura Y" first="Yasushi" last="Tamura">Yasushi Tamura</name><name sortKey="Tanaka, Keiji" sort="Tanaka, Keiji" uniqKey="Tanaka K" first="Keiji" last="Tanaka">Keiji Tanaka</name><name sortKey="Tsuchiya, Hikaru" sort="Tsuchiya, Hikaru" uniqKey="Tsuchiya H" first="Hikaru" last="Tsuchiya">Hikaru Tsuchiya</name><name sortKey="Yoshihara, Hidehito" sort="Yoshihara, Hidehito" uniqKey="Yoshihara H" first="Hidehito" last="Yoshihara">Hidehito Yoshihara</name></country><country name="Canada"><region name="Québec"><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name></region><name sortKey="Trempe, Jean Francois" sort="Trempe, Jean Francois" uniqKey="Trempe J" first="Jean-François" last="Trempe">Jean-François Trempe</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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