Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.
Identifieur interne : 000541 ( PubMed/Checkpoint ); précédent : 000540; suivant : 000542Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.
Auteurs : Atul Kumar [Royaume-Uni] ; Jacob D. Aguirre [Canada] ; Tara E C. Condos [Canada] ; R Julio Martinez-Torres [Royaume-Uni] ; Viduth K. Chaugule [Royaume-Uni] ; Rachel Toth [Royaume-Uni] ; Ramasubramanian Sundaramoorthy [Royaume-Uni] ; Pascal Mercier [Canada] ; Axel Knebel [Royaume-Uni] ; Donald E. Spratt [Canada] ; Kathryn R. Barber [Canada] ; Gary S. Shaw [Canada] ; Helen Walden [Canada]Source :
- The EMBO journal [ 1460-2075 ] ; 2015.
English descriptors
- KwdEn :
- Binding Sites (genetics), Calorimetry, Catalysis, Chromatography, Gel, Crystallization, Enzyme Activation (genetics), Humans, Models, Biological, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Phosphorylation, Protein Conformation, Ubiquitin (metabolism), Ubiquitin-Protein Ligases (chemistry), Ubiquitin-Protein Ligases (metabolism).
- MESH :
- chemical , chemistry : Ubiquitin-Protein Ligases.
- chemical , metabolism : Ubiquitin, Ubiquitin-Protein Ligases.
- genetics : Binding Sites, Enzyme Activation.
- Calorimetry, Catalysis, Chromatography, Gel, Crystallization, Humans, Models, Biological, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Phosphorylation, Protein Conformation.
Abstract
The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N-terminal ubiquitin-like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 Å crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin-binding interface, provide a model for the phosphoubiquitin-parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin-binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin.
DOI: 10.15252/embj.201592337
PubMed: 26254304
Affiliations:
Links toward previous steps (curation, corpus...)
Links to Exploration step
pubmed:26254304Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.</title><author><name sortKey="Kumar, Atul" sort="Kumar, Atul" uniqKey="Kumar A" first="Atul" last="Kumar">Atul Kumar</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Aguirre, Jacob D" sort="Aguirre, Jacob D" uniqKey="Aguirre J" first="Jacob D" last="Aguirre">Jacob D. Aguirre</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Condos, Tara E C" sort="Condos, Tara E C" uniqKey="Condos T" first="Tara E C" last="Condos">Tara E C. Condos</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Martinez Torres, R Julio" sort="Martinez Torres, R Julio" uniqKey="Martinez Torres R" first="R Julio" last="Martinez-Torres">R Julio Martinez-Torres</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Chaugule, Viduth K" sort="Chaugule, Viduth K" uniqKey="Chaugule V" first="Viduth K" last="Chaugule">Viduth K. Chaugule</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Toth, Rachel" sort="Toth, Rachel" uniqKey="Toth R" first="Rachel" last="Toth">Rachel Toth</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Sundaramoorthy, Ramasubramanian" sort="Sundaramoorthy, Ramasubramanian" uniqKey="Sundaramoorthy R" first="Ramasubramanian" last="Sundaramoorthy">Ramasubramanian Sundaramoorthy</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Mercier, Pascal" sort="Mercier, Pascal" uniqKey="Mercier P" first="Pascal" last="Mercier">Pascal Mercier</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Knebel, Axel" sort="Knebel, Axel" uniqKey="Knebel A" first="Axel" last="Knebel">Axel Knebel</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Spratt, Donald E" sort="Spratt, Donald E" uniqKey="Spratt D" first="Donald E" last="Spratt">Donald E. Spratt</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Barber, Kathryn R" sort="Barber, Kathryn R" uniqKey="Barber K" first="Kathryn R" last="Barber">Kathryn R. Barber</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Shaw, Gary S" sort="Shaw, Gary S" uniqKey="Shaw G" first="Gary S" last="Shaw">Gary S. Shaw</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada gshaw1@uwo.ca h.walden@dundee.ac.uk.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Walden, Helen" sort="Walden, Helen" uniqKey="Walden H" first="Helen" last="Walden">Helen Walden</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK gshaw1@uwo.ca h.walden@dundee.ac.uk.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26254304</idno><idno type="pmid">26254304</idno><idno type="doi">10.15252/embj.201592337</idno><idno type="wicri:Area/PubMed/Corpus">000386</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000386</idno><idno type="wicri:Area/PubMed/Curation">000386</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000386</idno><idno type="wicri:Area/PubMed/Checkpoint">000386</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000386</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.</title><author><name sortKey="Kumar, Atul" sort="Kumar, Atul" uniqKey="Kumar A" first="Atul" last="Kumar">Atul Kumar</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Aguirre, Jacob D" sort="Aguirre, Jacob D" uniqKey="Aguirre J" first="Jacob D" last="Aguirre">Jacob D. Aguirre</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Condos, Tara E C" sort="Condos, Tara E C" uniqKey="Condos T" first="Tara E C" last="Condos">Tara E C. Condos</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Martinez Torres, R Julio" sort="Martinez Torres, R Julio" uniqKey="Martinez Torres R" first="R Julio" last="Martinez-Torres">R Julio Martinez-Torres</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Chaugule, Viduth K" sort="Chaugule, Viduth K" uniqKey="Chaugule V" first="Viduth K" last="Chaugule">Viduth K. Chaugule</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Toth, Rachel" sort="Toth, Rachel" uniqKey="Toth R" first="Rachel" last="Toth">Rachel Toth</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Sundaramoorthy, Ramasubramanian" sort="Sundaramoorthy, Ramasubramanian" uniqKey="Sundaramoorthy R" first="Ramasubramanian" last="Sundaramoorthy">Ramasubramanian Sundaramoorthy</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Mercier, Pascal" sort="Mercier, Pascal" uniqKey="Mercier P" first="Pascal" last="Mercier">Pascal Mercier</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Knebel, Axel" sort="Knebel, Axel" uniqKey="Knebel A" first="Axel" last="Knebel">Axel Knebel</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author><author><name sortKey="Spratt, Donald E" sort="Spratt, Donald E" uniqKey="Spratt D" first="Donald E" last="Spratt">Donald E. Spratt</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Barber, Kathryn R" sort="Barber, Kathryn R" uniqKey="Barber K" first="Kathryn R" last="Barber">Kathryn R. Barber</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Shaw, Gary S" sort="Shaw, Gary S" uniqKey="Shaw G" first="Gary S" last="Shaw">Gary S. Shaw</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada gshaw1@uwo.ca h.walden@dundee.ac.uk.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Walden, Helen" sort="Walden, Helen" uniqKey="Walden H" first="Helen" last="Walden">Helen Walden</name><affiliation wicri:level="1"><nlm:affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK gshaw1@uwo.ca h.walden@dundee.ac.uk.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee</wicri:regionArea><wicri:noRegion>Dundee</wicri:noRegion></affiliation></author></analytic><series><title level="j">The EMBO journal</title><idno type="eISSN">1460-2075</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Binding Sites (genetics)</term><term>Calorimetry</term><term>Catalysis</term><term>Chromatography, Gel</term><term>Crystallization</term><term>Enzyme Activation (genetics)</term><term>Humans</term><term>Models, Biological</term><term>Models, Molecular</term><term>Nuclear Magnetic Resonance, Biomolecular</term><term>Phosphorylation</term><term>Protein Conformation</term><term>Ubiquitin (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>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Ubiquitin</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Binding Sites</term><term>Enzyme Activation</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Calorimetry</term><term>Catalysis</term><term>Chromatography, Gel</term><term>Crystallization</term><term>Humans</term><term>Models, Biological</term><term>Models, Molecular</term><term>Nuclear Magnetic Resonance, Biomolecular</term><term>Phosphorylation</term><term>Protein Conformation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N-terminal ubiquitin-like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 Å crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin-binding interface, provide a model for the phosphoubiquitin-parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin-binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26254304</PMID><DateCreated><Year>2015</Year><Month>10</Month><Day>15</Day></DateCreated><DateCompleted><Year>2016</Year><Month>02</Month><Day>02</Day></DateCompleted><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1460-2075</ISSN><JournalIssue CitedMedium="Internet"><Volume>34</Volume><Issue>20</Issue><PubDate><Year>2015</Year><Month>Oct</Month><Day>14</Day></PubDate></JournalIssue><Title>The EMBO journal</Title><ISOAbbreviation>EMBO J.</ISOAbbreviation></Journal><ArticleTitle>Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.</ArticleTitle><Pagination><MedlinePgn>2506-21</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.15252/embj.201592337</ELocationID><Abstract><AbstractText>The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N-terminal ubiquitin-like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 Å crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin-binding interface, provide a model for the phosphoubiquitin-parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin-binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin.</AbstractText><CopyrightInformation>© 2015 The Authors. Published under the terms of the CC BY 4.0 license.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kumar</LastName><ForeName>Atul</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Aguirre</LastName><ForeName>Jacob D</ForeName><Initials>JD</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Condos</LastName><ForeName>Tara E C</ForeName><Initials>TE</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martinez-Torres</LastName><ForeName>R Julio</ForeName><Initials>RJ</Initials><AffiliationInfo><Affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chaugule</LastName><ForeName>Viduth K</ForeName><Initials>VK</Initials><AffiliationInfo><Affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Toth</LastName><ForeName>Rachel</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sundaramoorthy</LastName><ForeName>Ramasubramanian</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mercier</LastName><ForeName>Pascal</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Knebel</LastName><ForeName>Axel</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Spratt</LastName><ForeName>Donald E</ForeName><Initials>DE</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Barber</LastName><ForeName>Kathryn R</ForeName><Initials>KR</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shaw</LastName><ForeName>Gary S</ForeName><Initials>GS</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, Schulich School of Medicine & Dentistry University of Western Ontario, London, ON, Canada gshaw1@uwo.ca h.walden@dundee.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Walden</LastName><ForeName>Helen</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK gshaw1@uwo.ca h.walden@dundee.ac.uk.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>A17739</GrantID><Agency>Cancer Research UK</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>MOP-14606</GrantID><Agency>Canadian Institutes of Health Research</Agency><Country>Canada</Country></Grant><Grant><Agency>Medical Research Council</Agency><Country>United Kingdom</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>2015</Year><Month>08</Month><Day>07</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>EMBO J</MedlineTA><NlmUniqueID>8208664</NlmUniqueID><ISSNLinking>0261-4189</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D025801">Ubiquitin</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></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentIn"><RefSource>EMBO J. 2015 Oct 14;34(20):2486-8</RefSource><PMID Version="1">26346274</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3095-100</RefSource><PMID Version="1">17360614</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Biochemistry. 1994 May 17;33(19):5984-6003</RefSource><PMID Version="1">7514039</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Structure. 2013 Jun 4;21(6):1030-41</RefSource><PMID Version="1">23707686</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Nature. 2014 Jun 5;510(7503):162-6</RefSource><PMID Version="1">24784582</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Biomol NMR. 1995 Nov;6(3):277-93</RefSource><PMID Version="1">8520220</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Cell Res. 2013 Jul;23(7):886-97</RefSource><PMID Version="1">23670163</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>PLoS Genet. 2014 Jun;10(6):e1004391</RefSource><PMID Version="1">24901221</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Hum Mol Genet. 2006 Jul 1;15(13):2059-75</RefSource><PMID Version="1">16714300</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>EMBO J. 2011 Jul 20;30(14):2853-67</RefSource><PMID Version="1">21694720</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Biochem J. 2014 May 15;460(1):127-39</RefSource><PMID Version="1">24660806</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Mol Cell. 2014 Nov 6;56(3):360-75</RefSource><PMID Version="1">25284222</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Nature. 2011 Jun 2;474(7349):105-8</RefSource><PMID Version="1">21532592</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Annu Rev Biochem. 2004;73:107-46</RefSource><PMID Version="1">15189138</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Comput Chem. 2004 Oct;25(13):1605-12</RefSource><PMID Version="1">15264254</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Biol Chem. 2009 May 29;284(22):14978-86</RefSource><PMID Version="1">19339245</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Hum Mol Genet. 2005 Dec 15;14(24):3885-97</RefSource><PMID Version="1">16278233</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>PLoS One. 2012;7(4):e34748</RefSource><PMID Version="1">22496854</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Biomol NMR. 1994 Sep;4(5):603-14</RefSource><PMID Version="1">22911360</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>EMBO J. 2013 Jul 31;32(15):2099-112</RefSource><PMID Version="1">23727886</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Cell Biol. 2014 Apr 28;205(2):143-53</RefSource><PMID Version="1">24751536</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Biochem J. 2014 Mar 15;458(3):421-37</RefSource><PMID Version="1">24576094</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Proc Natl Acad Sci U S A. 2015 May 26;112(21):6637-42</RefSource><PMID Version="1">25969509</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Neurol Sci. 2002 Sep;23 Suppl 2:S59-60</RefSource><PMID Version="1">12548343</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Open Biol. 2014;4:130213</RefSource><PMID Version="1">24647965</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Biochemistry. 2007 Dec 11;46(49):14162-9</RefSource><PMID Version="1">18004887</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>EMBO J. 2012 Oct 3;31(19):3833-44</RefSource><PMID Version="1">22863777</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12366-71</RefSource><PMID Version="1">9356455</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Nature. 2012 Sep 6;489(7414):115-20</RefSource><PMID Version="1">22842904</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>EMBO Rep. 2015 Aug;16(8):939-54</RefSource><PMID Version="1">26116755</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Nature. 2006 Jun 29;441(7097):1157-61</RefSource><PMID Version="1">16672980</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Science. 2013 Jun 21;340(6139):1451-5</RefSource><PMID Version="1">23661642</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3</RefSource><PMID Version="1">15299374</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Biomol NMR. 1999 Jan;13(1):3-10</RefSource><PMID Version="1">21080259</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Nature. 2015 Aug 20;524(7565):370-4</RefSource><PMID Version="1">26161729</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Open Biol. 2012 May;2(5):120080</RefSource><PMID Version="1">22724072</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Nat Rev Neurol. 2013 Jan;9(1):13-24</RefSource><PMID Version="1">23183883</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Nature. 2006 Jun 29;441(7097):1162-6</RefSource><PMID Version="1">16672981</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Biochemistry. 2011 Apr 5;50(13):2603-10</RefSource><PMID Version="1">21348451</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32</RefSource><PMID Version="1">15572765</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Sci Rep. 2012;2:1002</RefSource><PMID Version="1">23256036</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Nat Commun. 2013;4:1982</RefSource><PMID Version="1">23770887</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>EMBO Rep. 2012 Sep;13(9):840-6</RefSource><PMID Version="1">22791023</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Am Chem Soc. 2003 Feb 19;125(7):1731-7</RefSource><PMID Version="1">12580598</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Nat Commun. 2013;4:1983</RefSource><PMID Version="1">23770917</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D001665" MajorTopicYN="N">Binding Sites</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002151" MajorTopicYN="N">Calorimetry</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002384" MajorTopicYN="N">Catalysis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002850" MajorTopicYN="N">Chromatography, Gel</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003460" MajorTopicYN="N">Crystallization</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004789" MajorTopicYN="N">Enzyme Activation</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008954" MajorTopicYN="Y">Models, Biological</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="Y">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019906" MajorTopicYN="N">Nuclear Magnetic Resonance, Biomolecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010766" MajorTopicYN="N">Phosphorylation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011487" MajorTopicYN="N">Protein Conformation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D025801" MajorTopicYN="N">Ubiquitin</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D044767" MajorTopicYN="N">Ubiquitin-Protein Ligases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><OtherID Source="NLM">PMC4609183</OtherID><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Parkinson's disease</Keyword><Keyword MajorTopicYN="N">enzyme mechanism</Keyword><Keyword MajorTopicYN="N">phosphorylation</Keyword><Keyword MajorTopicYN="N">ubiquitin ligase</Keyword><Keyword MajorTopicYN="N">ubiquitination</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>06</Month><Day>18</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>07</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>8</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>8</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>2</Month><Day>3</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26254304</ArticleId><ArticleId IdType="pii">embj.201592337</ArticleId><ArticleId IdType="doi">10.15252/embj.201592337</ArticleId><ArticleId IdType="pmc">PMC4609183</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Canada</li><li>Royaume-Uni</li></country></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Kumar, Atul" sort="Kumar, Atul" uniqKey="Kumar A" first="Atul" last="Kumar">Atul Kumar</name></noRegion><name sortKey="Chaugule, Viduth K" sort="Chaugule, Viduth K" uniqKey="Chaugule V" first="Viduth K" last="Chaugule">Viduth K. Chaugule</name><name sortKey="Knebel, Axel" sort="Knebel, Axel" uniqKey="Knebel A" first="Axel" last="Knebel">Axel Knebel</name><name sortKey="Martinez Torres, R Julio" sort="Martinez Torres, R Julio" uniqKey="Martinez Torres R" first="R Julio" last="Martinez-Torres">R Julio Martinez-Torres</name><name sortKey="Sundaramoorthy, Ramasubramanian" sort="Sundaramoorthy, Ramasubramanian" uniqKey="Sundaramoorthy R" first="Ramasubramanian" last="Sundaramoorthy">Ramasubramanian Sundaramoorthy</name><name sortKey="Toth, Rachel" sort="Toth, Rachel" uniqKey="Toth R" first="Rachel" last="Toth">Rachel Toth</name></country><country name="Canada"><noRegion><name sortKey="Aguirre, Jacob D" sort="Aguirre, Jacob D" uniqKey="Aguirre J" first="Jacob D" last="Aguirre">Jacob D. Aguirre</name></noRegion><name sortKey="Barber, Kathryn R" sort="Barber, Kathryn R" uniqKey="Barber K" first="Kathryn R" last="Barber">Kathryn R. Barber</name><name sortKey="Condos, Tara E C" sort="Condos, Tara E C" uniqKey="Condos T" first="Tara E C" last="Condos">Tara E C. Condos</name><name sortKey="Mercier, Pascal" sort="Mercier, Pascal" uniqKey="Mercier P" first="Pascal" last="Mercier">Pascal Mercier</name><name sortKey="Shaw, Gary S" sort="Shaw, Gary S" uniqKey="Shaw G" first="Gary S" last="Shaw">Gary S. Shaw</name><name sortKey="Spratt, Donald E" sort="Spratt, Donald E" uniqKey="Spratt D" first="Donald E" last="Spratt">Donald E. Spratt</name><name sortKey="Walden, Helen" sort="Walden, Helen" uniqKey="Walden H" first="Helen" last="Walden">Helen Walden</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Canada/explor/ParkinsonCanadaV1/Data/PubMed/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000541 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/PubMed/Checkpoint/biblio.hfd -nk 000541 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Canada
|area= ParkinsonCanadaV1
|flux= PubMed
|étape= Checkpoint
|type= RBID
|clé= pubmed:26254304
|texte= Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Checkpoint/RBID.i -Sk "pubmed:26254304" \
| HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Checkpoint/biblio.hfd \
| NlmPubMed2Wicri -a ParkinsonCanadaV1
| This area was generated with Dilib version V0.6.29. |  |