A molecular explanation for the recessive nature of parkin-linked Parkinson’s disease
Identifieur interne : 000E69 ( Main/Exploration ); précédent : 000E68; suivant : 000E70A molecular explanation for the recessive nature of parkin-linked Parkinson’s disease
Auteurs : Donald E. Spratt [Canada] ; R. Julio Martinez-Torres [Royaume-Uni] ; Yeong J. Noh [Canada] ; Pascal Mercier [Canada] ; Noah Manczyk [Canada] ; Kathryn R. Barber [Canada] ; Jacob D. Aguirre [Canada] ; Lynn Burchell [Royaume-Uni] ; Andrew Purkiss [Royaume-Uni] ; Helen Walden [Royaume-Uni] ; Gary S. Shaw [Canada]Source :
- Nature Communications [ 2041-1723 ] ; 2013.
English descriptors
- KwdEn :
- Amino Acid Sequence, Animals, Biocatalysis, Drosophila melanogaster, Genes, Recessive (genetics), Humans, Models, Molecular, Molecular Sequence Data, Mutation (genetics), Parkinson Disease (genetics), Protein Binding, Protein Structure, Tertiary, Sequence Alignment, Substrate Specificity, Ubiquitin-Conjugating Enzymes (metabolism), Ubiquitin-Protein Ligases (chemistry), Ubiquitin-Protein Ligases (genetics).
- MESH :
- chemical , chemistry : Ubiquitin-Protein Ligases.
- chemical , genetics : Ubiquitin-Protein Ligases.
- chemical , metabolism : Ubiquitin-Conjugating Enzymes.
- genetics : Genes, Recessive, Mutation, Parkinson Disease.
- Amino Acid Sequence, Animals, Biocatalysis, Drosophila melanogaster, Humans, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Sequence Alignment, Substrate Specificity.
Abstract
Mutations in the
Url:
DOI: 10.1038/ncomms2983
PubMed: 23770917
PubMed Central: 3709501
Affiliations:
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Spratt</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario</institution>, London, Ontario,<country>Canada</country> N6A 5C1</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation><nlm:aff id="a3">These authors contributed equally to this work</nlm:aff></affiliation></author><author><name sortKey="Julio Martinez Torres, R" sort="Julio Martinez Torres, R" uniqKey="Julio Martinez Torres R" first="R" last="Julio Martinez-Torres">R. Julio Martinez-Torres</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Protein Structure and Function Laboratory, Cancer Research UK, London Research Institute</institution>, 44 Lincoln’s Inn Fields, London WC2A 3LY,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation><nlm:aff id="a3">These authors contributed equally to this work</nlm:aff></affiliation></author><author><name sortKey="Noh, Yeong J" sort="Noh, Yeong J" uniqKey="Noh Y" first="Yeong J." last="Noh">Yeong J. Noh</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario</institution>, London, Ontario,<country>Canada</country> N6A 5C1</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation><nlm:aff id="a3">These authors contributed equally to this work</nlm:aff></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:aff id="a1"><institution>Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario</institution>, London, Ontario,<country>Canada</country> N6A 5C1</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Manczyk, Noah" sort="Manczyk, Noah" uniqKey="Manczyk N" first="Noah" last="Manczyk">Noah Manczyk</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario</institution>, London, Ontario,<country>Canada</country> N6A 5C1</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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:aff id="a1"><institution>Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario</institution>, London, Ontario,<country>Canada</country> N6A 5C1</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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:aff id="a1"><institution>Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario</institution>, London, Ontario,<country>Canada</country> N6A 5C1</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Burchell, Lynn" sort="Burchell, Lynn" uniqKey="Burchell L" first="Lynn" last="Burchell">Lynn Burchell</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Protein Structure and Function Laboratory, Cancer Research UK, London Research Institute</institution>, 44 Lincoln’s Inn Fields, London WC2A 3LY,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Purkiss, Andrew" sort="Purkiss, Andrew" uniqKey="Purkiss A" first="Andrew" last="Purkiss">Andrew Purkiss</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Protein Structure and Function Laboratory, Cancer Research UK, London Research Institute</institution>, 44 Lincoln’s Inn Fields, London WC2A 3LY,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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:aff id="a2"><institution>Protein Structure and Function Laboratory, Cancer Research UK, London Research Institute</institution>, 44 Lincoln’s Inn Fields, London WC2A 3LY,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></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:aff id="a1"><institution>Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario</institution>, London, Ontario,<country>Canada</country> N6A 5C1</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Biocatalysis</term><term>Drosophila melanogaster</term><term>Genes, Recessive (genetics)</term><term>Humans</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Mutation (genetics)</term><term>Parkinson Disease (genetics)</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>Sequence Alignment</term><term>Substrate Specificity</term><term>Ubiquitin-Conjugating Enzymes (metabolism)</term><term>Ubiquitin-Protein Ligases (chemistry)</term><term>Ubiquitin-Protein Ligases (genetics)</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-Conjugating Enzymes</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Genes, Recessive</term><term>Mutation</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Animals</term><term>Biocatalysis</term><term>Drosophila melanogaster</term><term>Humans</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>Sequence Alignment</term><term>Substrate Specificity</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Mutations in the <italic>park2</italic> gene, encoding the RING-inBetweenRING-RING E3 ubiquitin ligase parkin, cause 50% of autosomal recessive juvenile Parkinsonism cases. More than 70 known pathogenic mutations occur throughout parkin, many of which cluster in the inhibitory amino-terminal ubiquitin-like domain, and the carboxy-terminal RING2 domain that is indispensable for ubiquitin transfer. A structural rationale showing how autosomal recessive juvenile Parkinsonism mutations alter parkin function is still lacking. Here we show that the structure of parkin RING2 is distinct from canonical RING E3 ligases and lacks key elements required for E2-conjugating enzyme recruitment. Several pathogenic mutations in RING2 alter the environment of a single surface-exposed catalytic cysteine to inhibit ubiquitination. Native parkin adopts a globular inhibited conformation in solution facilitated by the association of the ubiquitin-like domain with the RING-inBetweenRING-RING C-terminus. Autosomal recessive juvenile Parkinsonism mutations disrupt this conformation. Finally, parkin autoubiquitinates only in <italic>cis</italic>, providing a molecular explanation for the recessive nature of autosomal recessive juvenile Parkinsonism.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Kitada, T" uniqKey="Kitada T">T. Kitada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lucas, J I" uniqKey="Lucas J">J. I. Lucas</name></author><author><name sortKey="Arnau, V" uniqKey="Arnau V">V. Arnau</name></author><author><name sortKey="Marin, I" uniqKey="Marin I">I. Marin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marin, I" uniqKey="Marin I">I. Marin</name></author><author><name sortKey="Lucas, J I" uniqKey="Lucas J">J. I. Lucas</name></author><author><name sortKey="Gradilla, A C" uniqKey="Gradilla A">A. C. Gradilla</name></author><author><name sortKey="Ferrus, A" uniqKey="Ferrus A">A. 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Schwieters</name></author><author><name sortKey="Kuszewski, J J" uniqKey="Kuszewski J">J. J. Kuszewski</name></author><author><name sortKey="Clore, G M" uniqKey="Clore G">G. M. Clore</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Konarev, P V" uniqKey="Konarev P">P. V. Konarev</name></author><author><name sortKey="Volkov, V V" uniqKey="Volkov V">V. V. Volkov</name></author><author><name sortKey="Sokolova, A V" uniqKey="Sokolova A">A. V. Sokolova</name></author><author><name sortKey="Koch, M H J" uniqKey="Koch M">M. H. J. Koch</name></author><author><name sortKey="Svergun, D I" uniqKey="Svergun D">D. I. Svergun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Svergun, D I" uniqKey="Svergun D">D. I. Svergun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Franke, D" uniqKey="Franke D">D. Franke</name></author><author><name sortKey="Dammif, Svergun D I" uniqKey="Dammif S">Svergun D. I. DAMMIF</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pettersen, E F" uniqKey="Pettersen E">E. F. Pettersen</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Canada</li><li>Royaume-Uni</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Spratt, Donald E" sort="Spratt, Donald E" uniqKey="Spratt D" first="Donald E." last="Spratt">Donald E. Spratt</name></noRegion><name sortKey="Aguirre, Jacob D" sort="Aguirre, Jacob D" uniqKey="Aguirre J" first="Jacob D." last="Aguirre">Jacob D. Aguirre</name><name sortKey="Barber, Kathryn R" sort="Barber, Kathryn R" uniqKey="Barber K" first="Kathryn R." last="Barber">Kathryn R. Barber</name><name sortKey="Manczyk, Noah" sort="Manczyk, Noah" uniqKey="Manczyk N" first="Noah" last="Manczyk">Noah Manczyk</name><name sortKey="Mercier, Pascal" sort="Mercier, Pascal" uniqKey="Mercier P" first="Pascal" last="Mercier">Pascal Mercier</name><name sortKey="Noh, Yeong J" sort="Noh, Yeong J" uniqKey="Noh Y" first="Yeong J." last="Noh">Yeong J. Noh</name><name sortKey="Shaw, Gary S" sort="Shaw, Gary S" uniqKey="Shaw G" first="Gary S." last="Shaw">Gary S. Shaw</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Julio Martinez Torres, R" sort="Julio Martinez Torres, R" uniqKey="Julio Martinez Torres R" first="R" last="Julio Martinez-Torres">R. Julio Martinez-Torres</name></noRegion><name sortKey="Burchell, Lynn" sort="Burchell, Lynn" uniqKey="Burchell L" first="Lynn" last="Burchell">Lynn Burchell</name><name sortKey="Purkiss, Andrew" sort="Purkiss, Andrew" uniqKey="Purkiss A" first="Andrew" last="Purkiss">Andrew Purkiss</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)
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