Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation.
Identifieur interne : 000022 ( Main/Exploration ); précédent : 000021; suivant : 000023Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation.
Auteurs : Matthew Y. Tang [Canada] ; Marta Vranas [Canada] ; Andrea I. Krahn [Canada] ; Shayal Pundlik [Canada] ; Jean-François Trempe [Canada] ; Edward A. Fon [Canada]Source :
- Nature communications [ 2041-1723 ] ; 2017.
Abstract
Parkin and PINK1 function in a common pathway to clear damaged mitochondria. Parkin exists in an auto-inhibited conformation stabilized by multiple interdomain interactions. The binding of PINK1-generated phospho-ubiquitin and the phosphorylation of the ubiquitin-like (Ubl) domain of Parkin at Ser65 release its auto-inhibition, but how and when these events take place in cells remain to be defined. Here we show that mutations that we designed to activate Parkin by releasing the Repressor Element of Parkin (REP) domain, or by disrupting the interface between the RING0:RING2 domains, can completely rescue mutations in the Parkin Ubl that are defective in mitochondrial autophagy. Using a FRET reporter assay we show that Parkin undergoes a conformational change upon phosphorylation that can be mimicked by mutating Trp403 in the REP. We propose a hierarchical model whereby pUb binding on mitochondria enables Parkin phosphorylation, which, in turn, leads to REP removal, E3 ligase activation and mitophagy.
DOI: 10.1038/ncomms14697
PubMed: 28276439
Affiliations:
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Tang</name><affiliation wicri:level="4"><nlm:affiliation>McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4.</nlm:affiliation><country>Canada</country><wicri:regionArea>McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec</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="Vranas, Marta" sort="Vranas, Marta" uniqKey="Vranas M" first="Marta" last="Vranas">Marta Vranas</name><affiliation wicri:level="4"><nlm:affiliation>Groupe de Recherche Axé sur la Structure des Protéines, Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3G 1Y6.</nlm:affiliation><country>Canada</country><wicri:regionArea>Groupe de Recherche Axé sur la Structure des Protéines, Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec</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="Krahn, Andrea I" sort="Krahn, Andrea I" uniqKey="Krahn A" first="Andrea I" last="Krahn">Andrea I. Krahn</name><affiliation wicri:level="4"><nlm:affiliation>McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4.</nlm:affiliation><country>Canada</country><wicri:regionArea>McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec</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="Pundlik, Shayal" sort="Pundlik, Shayal" uniqKey="Pundlik S" first="Shayal" last="Pundlik">Shayal Pundlik</name><affiliation wicri:level="4"><nlm:affiliation>McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4.</nlm:affiliation><country>Canada</country><wicri:regionArea>McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec</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>Groupe de Recherche Axé sur la Structure des Protéines, Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3G 1Y6.</nlm:affiliation><country>Canada</country><wicri:regionArea>Groupe de Recherche Axé sur la Structure des Protéines, Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec</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="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, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4.</nlm:affiliation><country>Canada</country><wicri:regionArea>McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author></analytic><series><title level="j">Nature communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkin and PINK1 function in a common pathway to clear damaged mitochondria. Parkin exists in an auto-inhibited conformation stabilized by multiple interdomain interactions. The binding of PINK1-generated phospho-ubiquitin and the phosphorylation of the ubiquitin-like (Ubl) domain of Parkin at Ser65 release its auto-inhibition, but how and when these events take place in cells remain to be defined. Here we show that mutations that we designed to activate Parkin by releasing the Repressor Element of Parkin (REP) domain, or by disrupting the interface between the RING0:RING2 domains, can completely rescue mutations in the Parkin Ubl that are defective in mitochondrial autophagy. Using a FRET reporter assay we show that Parkin undergoes a conformational change upon phosphorylation that can be mimicked by mutating Trp403 in the REP. We propose a hierarchical model whereby pUb binding on mitochondria enables Parkin phosphorylation, which, in turn, leads to REP removal, E3 ligase activation and mitophagy.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Québec</li></region><settlement><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><region name="Québec"><name sortKey="Tang, Matthew Y" sort="Tang, Matthew Y" uniqKey="Tang M" first="Matthew Y" last="Tang">Matthew Y. Tang</name></region><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><name sortKey="Krahn, Andrea I" sort="Krahn, Andrea I" uniqKey="Krahn A" first="Andrea I" last="Krahn">Andrea I. Krahn</name><name sortKey="Pundlik, Shayal" sort="Pundlik, Shayal" uniqKey="Pundlik S" first="Shayal" last="Pundlik">Shayal Pundlik</name><name sortKey="Trempe, Jean Francois" sort="Trempe, Jean Francois" uniqKey="Trempe J" first="Jean-François" last="Trempe">Jean-François Trempe</name><name sortKey="Vranas, Marta" sort="Vranas, Marta" uniqKey="Vranas M" first="Marta" last="Vranas">Marta Vranas</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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