Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions

Autores
Miotto, Marco César; Binolfi, Andrés; Zweckstetter, Markus; Griesinger, Christian; Fernandez, Claudio Oscar
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. This process is selectively enhanced by copper in vitro and the interaction is proposed to play a potential role in vivo. Presently, the identity of the Cu(I) binding sites in AS and their relative affinities are under debate. In this work we have addressed unresolved details related to the structural binding specificity and affinity of Cu(I) to full-length AS. We demonstrated conclusively that: (i) the binding preferences of Cu(I) for the Met-binding sites at the N- (Kd = 20 μM) and C-terminus (Kd = 270 μM) of AS are widely different: (ii) the imidazole ring of His-50 acts as an effective anchoring residue (Kd = 50 μM) for Cu(I) binding to AS; and (iii) no major structural rearrangements occur in the protein upon Cu(I) binding. Overall, our work shows that Cu(I) binding to the N- and C-terminal regions of AS are two independent events, with substantial differences in their affinities, and suggest that protein oxidative damage derived from a misbalance in cellular copper homeostasis would target preferentially the N-terminal region of AS. This knowledge is key to understanding the structural-aggregation basis of the copper catalyzed oxidation of AS.
Fil: Miotto, Marco César. 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-institut Für Molekulare Pharmakologie; Alemania. 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: Zweckstetter, Markus. Universität Göttingen; Alemania
Fil: Griesinger, Christian. Max Planck Institute For Biophysical Chemistry; 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
Materia
ALPHA-SYNUCLEIN
CU(I)
MET-RICH SITES
PARKINSON
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:11336/94278
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactionsMiotto, Marco CésarBinolfi, AndrésZweckstetter, MarkusGriesinger, ChristianFernandez, Claudio OscarALPHA-SYNUCLEINCU(I)MET-RICH SITESPARKINSONhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. This process is selectively enhanced by copper in vitro and the interaction is proposed to play a potential role in vivo. Presently, the identity of the Cu(I) binding sites in AS and their relative affinities are under debate. In this work we have addressed unresolved details related to the structural binding specificity and affinity of Cu(I) to full-length AS. We demonstrated conclusively that: (i) the binding preferences of Cu(I) for the Met-binding sites at the N- (Kd = 20 μM) and C-terminus (Kd = 270 μM) of AS are widely different: (ii) the imidazole ring of His-50 acts as an effective anchoring residue (Kd = 50 μM) for Cu(I) binding to AS; and (iii) no major structural rearrangements occur in the protein upon Cu(I) binding. Overall, our work shows that Cu(I) binding to the N- and C-terminal regions of AS are two independent events, with substantial differences in their affinities, and suggest that protein oxidative damage derived from a misbalance in cellular copper homeostasis would target preferentially the N-terminal region of AS. This knowledge is key to understanding the structural-aggregation basis of the copper catalyzed oxidation of AS.Fil: Miotto, Marco César. 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-institut Für Molekulare Pharmakologie; Alemania. 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: Zweckstetter, Markus. Universität Göttingen; AlemaniaFil: Griesinger, Christian. Max Planck Institute For Biophysical Chemistry; 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; ArgentinaElsevier Science Inc2014-12info: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/11336/94278Miotto, Marco César; Binolfi, Andrés; Zweckstetter, Markus; Griesinger, Christian; Fernandez, Claudio Oscar; Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions; Elsevier Science Inc; Journal of Inorganic Biochemistry; 141; 12-2014; 208-2110162-0134CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0162013414002323info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jinorgbio.2014.08.012info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:35:33Zoai:ri.conicet.gov.ar:11336/94278instacron: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:34982025-10-15 15:35:33.448CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
title Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
spellingShingle Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
Miotto, Marco César
ALPHA-SYNUCLEIN
CU(I)
MET-RICH SITES
PARKINSON
title_short Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
title_full Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
title_fullStr Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
title_full_unstemmed Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
title_sort Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
dc.creator.none.fl_str_mv Miotto, Marco César
Binolfi, Andrés
Zweckstetter, Markus
Griesinger, Christian
Fernandez, Claudio Oscar
author Miotto, Marco César
author_facet Miotto, Marco César
Binolfi, Andrés
Zweckstetter, Markus
Griesinger, Christian
Fernandez, Claudio Oscar
author_role author
author2 Binolfi, Andrés
Zweckstetter, Markus
Griesinger, Christian
Fernandez, Claudio Oscar
author2_role author
author
author
author
dc.subject.none.fl_str_mv ALPHA-SYNUCLEIN
CU(I)
MET-RICH SITES
PARKINSON
topic ALPHA-SYNUCLEIN
CU(I)
MET-RICH SITES
PARKINSON
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. This process is selectively enhanced by copper in vitro and the interaction is proposed to play a potential role in vivo. Presently, the identity of the Cu(I) binding sites in AS and their relative affinities are under debate. In this work we have addressed unresolved details related to the structural binding specificity and affinity of Cu(I) to full-length AS. We demonstrated conclusively that: (i) the binding preferences of Cu(I) for the Met-binding sites at the N- (Kd = 20 μM) and C-terminus (Kd = 270 μM) of AS are widely different: (ii) the imidazole ring of His-50 acts as an effective anchoring residue (Kd = 50 μM) for Cu(I) binding to AS; and (iii) no major structural rearrangements occur in the protein upon Cu(I) binding. Overall, our work shows that Cu(I) binding to the N- and C-terminal regions of AS are two independent events, with substantial differences in their affinities, and suggest that protein oxidative damage derived from a misbalance in cellular copper homeostasis would target preferentially the N-terminal region of AS. This knowledge is key to understanding the structural-aggregation basis of the copper catalyzed oxidation of AS.
Fil: Miotto, Marco César. 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-institut Für Molekulare Pharmakologie; Alemania. 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: Zweckstetter, Markus. Universität Göttingen; Alemania
Fil: Griesinger, Christian. Max Planck Institute For Biophysical Chemistry; 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
description The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. This process is selectively enhanced by copper in vitro and the interaction is proposed to play a potential role in vivo. Presently, the identity of the Cu(I) binding sites in AS and their relative affinities are under debate. In this work we have addressed unresolved details related to the structural binding specificity and affinity of Cu(I) to full-length AS. We demonstrated conclusively that: (i) the binding preferences of Cu(I) for the Met-binding sites at the N- (Kd = 20 μM) and C-terminus (Kd = 270 μM) of AS are widely different: (ii) the imidazole ring of His-50 acts as an effective anchoring residue (Kd = 50 μM) for Cu(I) binding to AS; and (iii) no major structural rearrangements occur in the protein upon Cu(I) binding. Overall, our work shows that Cu(I) binding to the N- and C-terminal regions of AS are two independent events, with substantial differences in their affinities, and suggest that protein oxidative damage derived from a misbalance in cellular copper homeostasis would target preferentially the N-terminal region of AS. This knowledge is key to understanding the structural-aggregation basis of the copper catalyzed oxidation of AS.
publishDate 2014
dc.date.none.fl_str_mv 2014-12
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/11336/94278
Miotto, Marco César; Binolfi, Andrés; Zweckstetter, Markus; Griesinger, Christian; Fernandez, Claudio Oscar; Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions; Elsevier Science Inc; Journal of Inorganic Biochemistry; 141; 12-2014; 208-211
0162-0134
CONICET Digital
CONICET
url http://hdl.handle.net/11336/94278
identifier_str_mv Miotto, Marco César; Binolfi, Andrés; Zweckstetter, Markus; Griesinger, Christian; Fernandez, Claudio Oscar; Bioinorganic chemistry of synucleinopathies: Deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions; Elsevier Science Inc; Journal of Inorganic Biochemistry; 141; 12-2014; 208-211
0162-0134
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://www.sciencedirect.com/science/article/pii/S0162013414002323
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jinorgbio.2014.08.012
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 Elsevier Science Inc
publisher.none.fl_str_mv Elsevier Science Inc
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 13.22299

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