Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease

Autores
Miotto, Marco César; Rodriguez, Esaú E; Valiente Gabioud, Ariel Alejandro; Torres Monserrat, Valentina; Binolfi, Andrés; Quintanar, Liliana; Zweckstetter, Markus; Griesinger, Christian; Fernandez, Claudio Oscar
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The amyloid aggregation of alpha-synuclein (AS) has been linked to the pathological effects associated to Parkinson´s disease (PD). Cu(II) binds specifically at the N-terminus of AS and triggers its aggregation. Site-specific Cu(I)-catalyzed oxidation of AS has been proposed as a plausible mechanism for metal-enhanced AS amyloid formation. In this study, Cu(I) binding to AS was probed by NMR spectroscopy, in combination with synthetic peptide models, site- directed and C-terminal truncated protein variants. Our results demonstrate that both Met residues in the motif 1MDVFM5 constitute key structural determinants for the high-affinity binding of Cu(I) to the N-terminal region of AS. Replacement of one Met residue by Ile causes a dramatic decrease in binding affinity for Cu(I), whereas removal of both Met residues results in complete lack of binding. Moreover, these Met residues can be oxidized rapidly after air exposure of the AS-Cu(I) complex, whereas Met-116 and Met-127 in the C-terminal region remain unaffected. Met-1 displays higher susceptibility to oxidative damage compared to Met-5, as it is directly involved in both Cu(II) and Cu(I) coordination, resulting in a closer exposure to the reactive oxygen species that may be generated by the redox cycling of copper. Our findings support a mechanism where the interaction of AS with copper ions leads to site-specific metal catalyzed oxidation in the protein under physiologically relevant conditions. In light of recent biological findings, these results support a role for AS-copper interactions in neurodegeneration in PD.
Fil: Miotto, Marco César. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Rodriguez, Esaú E. Centro de Investigación y de Estudios Avanzado. DF; México
Fil: Valiente Gabioud, Ariel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario; Argentina
Fil: Torres Monserrat, Valentina. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Binolfi, Andrés. Leibniz Institute of Molecular Pharmacology. Berlin; Alemania
Fil: Quintanar, Liliana. Centro de Investigación y de Estudios Avanzado. DF; México
Fil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry, Gottingen; Alemania. Deutsches Zentrum für Neurodegenerative Erkrankung. Gottingen; Alemania. University Medical Center. Gottingen; Alemania
Fil: Griesinger, Christian. Max Planck Institute for Biophysical Chemistry, Gottingen; Alemania
Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario; Argentina
Materia
Alfa-Sinucleina
Cobre
Oxidación
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/31089
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/31089
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s DiseaseMiotto, Marco CésarRodriguez, Esaú EValiente Gabioud, Ariel AlejandroTorres Monserrat, ValentinaBinolfi, AndrésQuintanar, LilianaZweckstetter, MarkusGriesinger, ChristianFernandez, Claudio OscarAlfa-SinucleinaCobreOxidaciónhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The amyloid aggregation of alpha-synuclein (AS) has been linked to the pathological effects associated to Parkinson´s disease (PD). Cu(II) binds specifically at the N-terminus of AS and triggers its aggregation. Site-specific Cu(I)-catalyzed oxidation of AS has been proposed as a plausible mechanism for metal-enhanced AS amyloid formation. In this study, Cu(I) binding to AS was probed by NMR spectroscopy, in combination with synthetic peptide models, site- directed and C-terminal truncated protein variants. Our results demonstrate that both Met residues in the motif 1MDVFM5 constitute key structural determinants for the high-affinity binding of Cu(I) to the N-terminal region of AS. Replacement of one Met residue by Ile causes a dramatic decrease in binding affinity for Cu(I), whereas removal of both Met residues results in complete lack of binding. Moreover, these Met residues can be oxidized rapidly after air exposure of the AS-Cu(I) complex, whereas Met-116 and Met-127 in the C-terminal region remain unaffected. Met-1 displays higher susceptibility to oxidative damage compared to Met-5, as it is directly involved in both Cu(II) and Cu(I) coordination, resulting in a closer exposure to the reactive oxygen species that may be generated by the redox cycling of copper. Our findings support a mechanism where the interaction of AS with copper ions leads to site-specific metal catalyzed oxidation in the protein under physiologically relevant conditions. In light of recent biological findings, these results support a role for AS-copper interactions in neurodegeneration in PD.Fil: Miotto, Marco César. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Rodriguez, Esaú E. Centro de Investigación y de Estudios Avanzado. DF; MéxicoFil: Valiente Gabioud, Ariel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario; ArgentinaFil: Torres Monserrat, Valentina. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Binolfi, Andrés. Leibniz Institute of Molecular Pharmacology. Berlin; AlemaniaFil: Quintanar, Liliana. Centro de Investigación y de Estudios Avanzado. DF; MéxicoFil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry, Gottingen; Alemania. Deutsches Zentrum für Neurodegenerative Erkrankung. Gottingen; Alemania. University Medical Center. Gottingen; AlemaniaFil: Griesinger, Christian. Max Planck Institute for Biophysical Chemistry, Gottingen; AlemaniaFil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario; ArgentinaAmerican Chemical Society2014-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/31089Fernandez, Claudio Oscar; Griesinger, Christian; Zweckstetter, Markus; Quintanar, Liliana; Binolfi, Andrés; Torres Monserrat, Valentina; et al.; Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease; American Chemical Society; Inorganic Chemistry; 53; 4-2014; 4350-43580020-1669CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/ic4031377info:eu-repo/semantics/altIdentifier/doi/10.1021/ic4031377info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:06:47Zoai:ri.conicet.gov.ar:11336/31089instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:06:47.603CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease
title Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease
spellingShingle Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease
Miotto, Marco César
Alfa-Sinucleina
Cobre
Oxidación
title_short Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease
title_full Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease
title_fullStr Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease
title_full_unstemmed Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease
title_sort Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease
dc.creator.none.fl_str_mv Miotto, Marco César
Rodriguez, Esaú E
Valiente Gabioud, Ariel Alejandro
Torres Monserrat, Valentina
Binolfi, Andrés
Quintanar, Liliana
Zweckstetter, Markus
Griesinger, Christian
Fernandez, Claudio Oscar
author Miotto, Marco César
author_facet Miotto, Marco César
Rodriguez, Esaú E
Valiente Gabioud, Ariel Alejandro
Torres Monserrat, Valentina
Binolfi, Andrés
Quintanar, Liliana
Zweckstetter, Markus
Griesinger, Christian
Fernandez, Claudio Oscar
author_role author
author2 Rodriguez, Esaú E
Valiente Gabioud, Ariel Alejandro
Torres Monserrat, Valentina
Binolfi, Andrés
Quintanar, Liliana
Zweckstetter, Markus
Griesinger, Christian
Fernandez, Claudio Oscar
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alfa-Sinucleina
Cobre
Oxidación
topic Alfa-Sinucleina
Cobre
Oxidación
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The amyloid aggregation of alpha-synuclein (AS) has been linked to the pathological effects associated to Parkinson´s disease (PD). Cu(II) binds specifically at the N-terminus of AS and triggers its aggregation. Site-specific Cu(I)-catalyzed oxidation of AS has been proposed as a plausible mechanism for metal-enhanced AS amyloid formation. In this study, Cu(I) binding to AS was probed by NMR spectroscopy, in combination with synthetic peptide models, site- directed and C-terminal truncated protein variants. Our results demonstrate that both Met residues in the motif 1MDVFM5 constitute key structural determinants for the high-affinity binding of Cu(I) to the N-terminal region of AS. Replacement of one Met residue by Ile causes a dramatic decrease in binding affinity for Cu(I), whereas removal of both Met residues results in complete lack of binding. Moreover, these Met residues can be oxidized rapidly after air exposure of the AS-Cu(I) complex, whereas Met-116 and Met-127 in the C-terminal region remain unaffected. Met-1 displays higher susceptibility to oxidative damage compared to Met-5, as it is directly involved in both Cu(II) and Cu(I) coordination, resulting in a closer exposure to the reactive oxygen species that may be generated by the redox cycling of copper. Our findings support a mechanism where the interaction of AS with copper ions leads to site-specific metal catalyzed oxidation in the protein under physiologically relevant conditions. In light of recent biological findings, these results support a role for AS-copper interactions in neurodegeneration in PD.
Fil: Miotto, Marco César. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Rodriguez, Esaú E. Centro de Investigación y de Estudios Avanzado. DF; México
Fil: Valiente Gabioud, Ariel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario; Argentina
Fil: Torres Monserrat, Valentina. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Binolfi, Andrés. Leibniz Institute of Molecular Pharmacology. Berlin; Alemania
Fil: Quintanar, Liliana. Centro de Investigación y de Estudios Avanzado. DF; México
Fil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry, Gottingen; Alemania. Deutsches Zentrum für Neurodegenerative Erkrankung. Gottingen; Alemania. University Medical Center. Gottingen; Alemania
Fil: Griesinger, Christian. Max Planck Institute for Biophysical Chemistry, Gottingen; Alemania
Fil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario; Argentina
description The amyloid aggregation of alpha-synuclein (AS) has been linked to the pathological effects associated to Parkinson´s disease (PD). Cu(II) binds specifically at the N-terminus of AS and triggers its aggregation. Site-specific Cu(I)-catalyzed oxidation of AS has been proposed as a plausible mechanism for metal-enhanced AS amyloid formation. In this study, Cu(I) binding to AS was probed by NMR spectroscopy, in combination with synthetic peptide models, site- directed and C-terminal truncated protein variants. Our results demonstrate that both Met residues in the motif 1MDVFM5 constitute key structural determinants for the high-affinity binding of Cu(I) to the N-terminal region of AS. Replacement of one Met residue by Ile causes a dramatic decrease in binding affinity for Cu(I), whereas removal of both Met residues results in complete lack of binding. Moreover, these Met residues can be oxidized rapidly after air exposure of the AS-Cu(I) complex, whereas Met-116 and Met-127 in the C-terminal region remain unaffected. Met-1 displays higher susceptibility to oxidative damage compared to Met-5, as it is directly involved in both Cu(II) and Cu(I) coordination, resulting in a closer exposure to the reactive oxygen species that may be generated by the redox cycling of copper. Our findings support a mechanism where the interaction of AS with copper ions leads to site-specific metal catalyzed oxidation in the protein under physiologically relevant conditions. In light of recent biological findings, these results support a role for AS-copper interactions in neurodegeneration in PD.
publishDate 2014
dc.date.none.fl_str_mv 2014-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/31089
Fernandez, Claudio Oscar; Griesinger, Christian; Zweckstetter, Markus; Quintanar, Liliana; Binolfi, Andrés; Torres Monserrat, Valentina; et al.; Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease; American Chemical Society; Inorganic Chemistry; 53; 4-2014; 4350-4358
0020-1669
CONICET Digital
CONICET
url http://hdl.handle.net/11336/31089
identifier_str_mv Fernandez, Claudio Oscar; Griesinger, Christian; Zweckstetter, Markus; Quintanar, Liliana; Binolfi, Andrés; Torres Monserrat, Valentina; et al.; Site-Specific Copper-Catalyzed Oxidation of α-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson’s Disease; American Chemical Society; Inorganic Chemistry; 53; 4-2014; 4350-4358
0020-1669
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/ic4031377
info:eu-repo/semantics/altIdentifier/doi/10.1021/ic4031377
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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