A Ubl/ubiquitin switch in the activation of Parkin.
Identifieur interne : 000848 ( Main/Exploration ); précédent : 000847; suivant : 000849A Ubl/ubiquitin switch in the activation of Parkin.
Auteurs : Véronique Sauvé [Canada] ; Asparouh Lilov [Canada] ; Marjan Seirafi [Canada] ; Marta Vranas [Canada] ; Shafqat Rasool [Canada] ; Guennadi Kozlov [Canada] ; Tara Sprules [Canada] ; Jimin Wang [États-Unis] ; Jean-François Trempe [Canada] ; Kalle Gehring [Canada]Source :
- The EMBO journal [ 1460-2075 ] ; 2015.
English descriptors
- KwdEn :
- Cloning, Molecular, Crystallization, Enzyme Activation (genetics), Humans, Mitochondria (metabolism), Models, Molecular, Mutagenesis, Nuclear Magnetic Resonance, Biomolecular, Phosphorylation, Protein Binding, Protein Conformation, Protein Kinases (chemistry), Protein Kinases (metabolism), Protein Structure, Tertiary, Scattering, Small Angle, Ubiquitin (metabolism), Ubiquitin-Conjugating Enzymes (metabolism), Ubiquitin-Protein Ligases (chemistry), Ubiquitin-Protein Ligases (metabolism).
- MESH :
- chemical , chemistry : Protein Kinases, Ubiquitin-Protein Ligases.
- genetics : Enzyme Activation.
- metabolism : Mitochondria, Protein Kinases, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases.
- Cloning, Molecular, Crystallization, Humans, Models, Molecular, Mutagenesis, Nuclear Magnetic Resonance, Biomolecular, Phosphorylation, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Scattering, Small Angle.
Abstract
Mutations in Parkin and PINK1 cause an inherited early-onset form of Parkinson's disease. The two proteins function together in a mitochondrial quality control pathway whereby PINK1 accumulates on damaged mitochondria and activates Parkin to induce mitophagy. How PINK1 kinase activity releases the auto-inhibited ubiquitin ligase activity of Parkin remains unclear. Here, we identify a binding switch between phospho-ubiquitin (pUb) and the ubiquitin-like domain (Ubl) of Parkin as a key element. By mutagenesis and SAXS, we show that pUb binds to RING1 of Parkin at a site formed by His302 and Arg305. pUb binding promotes disengagement of the Ubl from RING1 and subsequent Parkin phosphorylation. A crystal structure of Parkin Δ86-130 at 2.54 Å resolution allowed the design of mutations that specifically release the Ubl domain from RING1. These mutations mimic pUb binding and promote Parkin phosphorylation. Measurements of the E2 ubiquitin-conjugating enzyme UbcH7 binding to Parkin and Parkin E3 ligase activity suggest that Parkin phosphorylation regulates E3 ligase activity downstream of pUb binding.
DOI: 10.15252/embj.201592237
PubMed: 26254305
Affiliations:
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Parkin.</title><author><name sortKey="Sauve, Veronique" sort="Sauve, Veronique" uniqKey="Sauve V" first="Véronique" last="Sauvé">Véronique Sauvé</name><affiliation wicri:level="4"><nlm:affiliation>Groupe de recherché axé sur la structure des protéines and Department of Biochemistry, McGill University, Montréal, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Groupe de recherché axé sur la structure des protéines and Department of Biochemistry, McGill University, Montréal, QC</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="Lilov, Asparouh" sort="Lilov, Asparouh" uniqKey="Lilov A" first="Asparouh" last="Lilov">Asparouh Lilov</name><affiliation wicri:level="4"><nlm:affiliation>Groupe de recherché axé sur la structure des protéines and Department of Biochemistry, McGill University, 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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>Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pharmacology and Therapeutics, McGill University, Montréal, QC</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="Rasool, Shafqat" sort="Rasool, Shafqat" uniqKey="Rasool S" first="Shafqat" last="Rasool">Shafqat Rasool</name><affiliation wicri:level="4"><nlm:affiliation>Groupe de recherché axé sur la structure des protéines and Department of Biochemistry, McGill University, Montréal, QC, Canada Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Groupe de recherché axé sur la structure des protéines and Department of Biochemistry, McGill University, Montréal, QC, Canada Department of Pharmacology and Therapeutics, McGill University, Montréal, QC</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="Kozlov, Guennadi" sort="Kozlov, Guennadi" uniqKey="Kozlov G" first="Guennadi" last="Kozlov">Guennadi Kozlov</name><affiliation wicri:level="4"><nlm:affiliation>Groupe de recherché axé sur la structure des protéines and Department of Biochemistry, McGill University, Montréal, QC, Canada.</nlm:affiliation><country 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type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cloning, Molecular</term><term>Crystallization</term><term>Enzyme Activation (genetics)</term><term>Humans</term><term>Mitochondria (metabolism)</term><term>Models, Molecular</term><term>Mutagenesis</term><term>Nuclear Magnetic Resonance, Biomolecular</term><term>Phosphorylation</term><term>Protein Binding</term><term>Protein Conformation</term><term>Protein Kinases (chemistry)</term><term>Protein Kinases (metabolism)</term><term>Protein Structure, Tertiary</term><term>Scattering, Small Angle</term><term>Ubiquitin (metabolism)</term><term>Ubiquitin-Conjugating Enzymes (metabolism)</term><term>Ubiquitin-Protein Ligases (chemistry)</term><term>Ubiquitin-Protein Ligases (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Protein Kinases</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Enzyme Activation</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Mitochondria</term><term>Protein Kinases</term><term>Ubiquitin</term><term>Ubiquitin-Conjugating Enzymes</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cloning, Molecular</term><term>Crystallization</term><term>Humans</term><term>Models, Molecular</term><term>Mutagenesis</term><term>Nuclear Magnetic Resonance, Biomolecular</term><term>Phosphorylation</term><term>Protein Binding</term><term>Protein Conformation</term><term>Protein Structure, Tertiary</term><term>Scattering, Small Angle</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in Parkin and PINK1 cause an inherited early-onset form of Parkinson's disease. The two proteins function together in a mitochondrial quality control pathway whereby PINK1 accumulates on damaged mitochondria and activates Parkin to induce mitophagy. How PINK1 kinase activity releases the auto-inhibited ubiquitin ligase activity of Parkin remains unclear. Here, we identify a binding switch between phospho-ubiquitin (pUb) and the ubiquitin-like domain (Ubl) of Parkin as a key element. By mutagenesis and SAXS, we show that pUb binds to RING1 of Parkin at a site formed by His302 and Arg305. pUb binding promotes disengagement of the Ubl from RING1 and subsequent Parkin phosphorylation. A crystal structure of Parkin Δ86-130 at 2.54 Å resolution allowed the design of mutations that specifically release the Ubl domain from RING1. These mutations mimic pUb binding and promote Parkin phosphorylation. Measurements of the E2 ubiquitin-conjugating enzyme UbcH7 binding to Parkin and Parkin E3 ligase activity suggest that Parkin phosphorylation regulates E3 ligase activity downstream of pUb binding.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Connecticut</li><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="Sauve, Veronique" sort="Sauve, Veronique" uniqKey="Sauve V" first="Véronique" last="Sauvé">Véronique Sauvé</name></region><name sortKey="Gehring, Kalle" sort="Gehring, Kalle" uniqKey="Gehring K" first="Kalle" last="Gehring">Kalle Gehring</name><name sortKey="Kozlov, Guennadi" sort="Kozlov, Guennadi" uniqKey="Kozlov G" first="Guennadi" last="Kozlov">Guennadi Kozlov</name><name sortKey="Lilov, Asparouh" sort="Lilov, Asparouh" uniqKey="Lilov A" first="Asparouh" last="Lilov">Asparouh Lilov</name><name sortKey="Rasool, Shafqat" sort="Rasool, Shafqat" uniqKey="Rasool S" first="Shafqat" last="Rasool">Shafqat Rasool</name><name sortKey="Seirafi, Marjan" sort="Seirafi, Marjan" uniqKey="Seirafi M" first="Marjan" last="Seirafi">Marjan Seirafi</name><name sortKey="Sprules, Tara" sort="Sprules, Tara" uniqKey="Sprules T" first="Tara" last="Sprules">Tara Sprules</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><country name="États-Unis"><region name="Connecticut"><name sortKey="Wang, Jimin" sort="Wang, Jimin" uniqKey="Wang J" first="Jimin" last="Wang">Jimin Wang</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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