Structure of parkin reveals mechanisms for ubiquitin ligase activation.
Identifieur interne : 000C63 ( Main/Exploration ); précédent : 000C62; suivant : 000C64Structure of parkin reveals mechanisms for ubiquitin ligase activation.
Auteurs : Jean-François Trempe [Canada] ; Véronique Sauvé ; Karl Grenier ; Marjan Seirafi ; Matthew Y. Tang ; Marie Ménade ; Sameer Al-Abdul-Wahid ; Jonathan Krett ; Kathy Wong ; Guennadi Kozlov ; Bhushan Nagar ; Edward A. Fon ; Kalle GehringSource :
- Science (New York, N.Y.) [ 1095-9203 ] ; 2013.
English descriptors
- KwdEn :
- Amino Acid Sequence, Animals, Catalytic Domain, Crystallography, X-Ray, Enzyme Activation, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Sequence Data, Mutation, Parkinson Disease, Parkinsonian Disorders, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Rats, Ubiquitin-Protein Ligases (chemistry), Ubiquitin-Protein Ligases (genetics), Ubiquitin-Protein Ligases (metabolism), Ubiquitination, Zinc Fingers.
- MESH :
- chemical , chemistry : Ubiquitin-Protein Ligases.
- chemical , genetics : Ubiquitin-Protein Ligases.
- chemical , metabolism : Ubiquitin-Protein Ligases.
- Amino Acid Sequence, Animals, Catalytic Domain, Crystallography, X-Ray, Enzyme Activation, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Sequence Data, Mutation, Parkinson Disease, Parkinsonian Disorders, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Rats, Ubiquitination, Zinc Fingers.
Abstract
Mutations in the PARK2 (parkin) gene are responsible for an autosomal recessive form of Parkinson's disease. The parkin protein is a RING-in-between-RING E3 ubiquitin ligase that exhibits low basal activity. We describe the crystal structure of full-length rat parkin. The structure shows parkin in an autoinhibited state and provides insight into how it is activated. RING0 occludes the ubiquitin acceptor site Cys(431) in RING2, whereas a repressor element of parkin binds RING1 and blocks its E2-binding site. Mutations that disrupted these inhibitory interactions activated parkin both in vitro and in cells. Parkin is neuroprotective, and these findings may provide a structural and mechanistic framework for enhancing parkin activity.
DOI: 10.1126/science.1237908
PubMed: 23661642
Affiliations:
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Tang</name></author><author><name sortKey="Menade, Marie" sort="Menade, Marie" uniqKey="Menade M" first="Marie" last="Ménade">Marie Ménade</name></author><author><name sortKey="Al Abdul Wahid, Sameer" sort="Al Abdul Wahid, Sameer" uniqKey="Al Abdul Wahid S" first="Sameer" last="Al-Abdul-Wahid">Sameer Al-Abdul-Wahid</name></author><author><name sortKey="Krett, Jonathan" sort="Krett, Jonathan" uniqKey="Krett J" first="Jonathan" last="Krett">Jonathan Krett</name></author><author><name sortKey="Wong, Kathy" sort="Wong, Kathy" uniqKey="Wong K" first="Kathy" last="Wong">Kathy Wong</name></author><author><name sortKey="Kozlov, Guennadi" sort="Kozlov, Guennadi" uniqKey="Kozlov G" first="Guennadi" last="Kozlov">Guennadi Kozlov</name></author><author><name sortKey="Nagar, Bhushan" sort="Nagar, Bhushan" uniqKey="Nagar B" first="Bhushan" last="Nagar">Bhushan Nagar</name></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name></author><author><name sortKey="Gehring, Kalle" sort="Gehring, Kalle" uniqKey="Gehring K" first="Kalle" last="Gehring">Kalle Gehring</name></author></analytic><series><title level="j">Science (New York, N.Y.)</title><idno type="eISSN">1095-9203</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Catalytic Domain</term><term>Crystallography, X-Ray</term><term>Enzyme Activation</term><term>Hydrophobic and Hydrophilic Interactions</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Mutation</term><term>Parkinson Disease</term><term>Parkinsonian Disorders</term><term>Protein Binding</term><term>Protein Conformation</term><term>Protein Folding</term><term>Protein Structure, Tertiary</term><term>Rats</term><term>Ubiquitin-Protein Ligases (chemistry)</term><term>Ubiquitin-Protein Ligases (genetics)</term><term>Ubiquitin-Protein Ligases (metabolism)</term><term>Ubiquitination</term><term>Zinc Fingers</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Ubiquitin-Protein Ligases</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>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Catalytic Domain</term><term>Crystallography, X-Ray</term><term>Enzyme Activation</term><term>Hydrophobic and Hydrophilic Interactions</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Mutation</term><term>Parkinson Disease</term><term>Parkinsonian Disorders</term><term>Protein Binding</term><term>Protein Conformation</term><term>Protein Folding</term><term>Protein Structure, Tertiary</term><term>Rats</term><term>Ubiquitination</term><term>Zinc Fingers</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in the PARK2 (parkin) gene are responsible for an autosomal recessive form of Parkinson's disease. The parkin protein is a RING-in-between-RING E3 ubiquitin ligase that exhibits low basal activity. We describe the crystal structure of full-length rat parkin. The structure shows parkin in an autoinhibited state and provides insight into how it is activated. RING0 occludes the ubiquitin acceptor site Cys(431) in RING2, whereas a repressor element of parkin binds RING1 and blocks its E2-binding site. Mutations that disrupted these inhibitory interactions activated parkin both in vitro and in cells. Parkin is neuroprotective, and these findings may provide a structural and mechanistic framework for enhancing parkin activity.</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><noCountry><name sortKey="Al Abdul Wahid, Sameer" sort="Al Abdul Wahid, Sameer" uniqKey="Al Abdul Wahid S" first="Sameer" last="Al-Abdul-Wahid">Sameer Al-Abdul-Wahid</name><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><name sortKey="Gehring, Kalle" sort="Gehring, Kalle" uniqKey="Gehring K" first="Kalle" last="Gehring">Kalle Gehring</name><name sortKey="Grenier, Karl" sort="Grenier, Karl" uniqKey="Grenier K" first="Karl" last="Grenier">Karl Grenier</name><name sortKey="Kozlov, Guennadi" sort="Kozlov, Guennadi" uniqKey="Kozlov G" first="Guennadi" last="Kozlov">Guennadi Kozlov</name><name sortKey="Krett, Jonathan" sort="Krett, Jonathan" uniqKey="Krett J" first="Jonathan" last="Krett">Jonathan Krett</name><name sortKey="Menade, Marie" sort="Menade, Marie" uniqKey="Menade M" first="Marie" last="Ménade">Marie Ménade</name><name sortKey="Nagar, Bhushan" sort="Nagar, Bhushan" uniqKey="Nagar B" first="Bhushan" last="Nagar">Bhushan Nagar</name><name sortKey="Sauve, Veronique" sort="Sauve, Veronique" uniqKey="Sauve V" first="Véronique" last="Sauvé">Véronique Sauvé</name><name sortKey="Seirafi, Marjan" sort="Seirafi, Marjan" uniqKey="Seirafi M" first="Marjan" last="Seirafi">Marjan Seirafi</name><name sortKey="Tang, Matthew Y" sort="Tang, Matthew Y" uniqKey="Tang M" first="Matthew Y" last="Tang">Matthew Y. Tang</name><name sortKey="Wong, Kathy" sort="Wong, Kathy" uniqKey="Wong K" first="Kathy" last="Wong">Kathy Wong</name></noCountry><country name="Canada"><region name="Québec"><name sortKey="Trempe, Jean Francois" sort="Trempe, Jean Francois" uniqKey="Trempe J" first="Jean-François" last="Trempe">Jean-François Trempe</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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