Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics

Autores
Verzini, Silvia; Shah, Maliha; Theillet, Francois-Xavier; Belsom, Adam; Bieschke, Jan; Wanker, Erich E.; Rappsilber, Juri; Binolfi, Andrés; Selenko, Philipp
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Heterogeneous aggregates of the human protein α-synuclein (αSyn) are abundantly found in Lewy body inclusions of Parkinson's disease patients. While structural information on classical αSyn amyloid fibrils is available, little is known about the conformational properties of disease-relevant, non-canonical aggregates. Here, we analyze the structural and dynamic properties of megadalton-sized dityrosine adducts of αSyn that form in the presence of reactive oxygen species and cytochrome c, a proapoptotic peroxidase that is released from mitochondria during sustained oxidative stress. In contrast to canonical cross-β amyloids, these aggregates retain high degrees of internal dynamics, which enables their characterization by solution-state NMR spectroscopy. We find that intermolecular dityrosine crosslinks restrict αSyn motions only locally whereas large segments of concatenated molecules remain flexible and disordered. Indistinguishable aggregates form in crowded in vitro solutions and in complex environments of mammalian cell lysates, where relative amounts of free reactive oxygen species, rather than cytochrome c, are rate limiting. We further establish that dityrosine adducts inhibit classical amyloid formation by maintaining αSyn in its monomeric form and that they are non-cytotoxic despite retaining basic membrane-binding properties. Our results suggest that oxidative αSyn aggregation scavenges cytochrome c's activity into the formation of amorphous, high molecular-weight structures that may contribute to the structural diversity of Lewy body deposits.
Fil: Verzini, Silvia. Leibniz Institute Of Molecular Pharmacology; Alemania
Fil: Shah, Maliha. Max Delbrück Center For Molecular Medicine; Alemania
Fil: Theillet, Francois-Xavier. Leibniz Institute Of Molecular Pharmacology; Alemania
Fil: Belsom, Adam. Technische Universität Berlin,; Alemania
Fil: Bieschke, Jan. Max Delbrück Center For Molecular Medicine; Alemania
Fil: Wanker, Erich E.. Max Delbrück Center For Molecular Medicine; Alemania
Fil: Rappsilber, Juri. Technische Universität Berlin,; Alemania
Fil: Binolfi, Andrés. 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: Selenko, Philipp. Weizmann Institute Of Science.; Israel
Materia
AMYLOID PROTEINS
NEURODEGENERATIVE DISEASE
PROTEIN AGGREGATION
PROTEIN DYNAMICS
STRUCTURAL DISORDER
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:11336/181646
Acceder
id CONICETDig_33e246d0696f00a029b77d4156bd6436
oai_identifier_str oai:ri.conicet.gov.ar:11336/181646
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamicsVerzini, SilviaShah, MalihaTheillet, Francois-XavierBelsom, AdamBieschke, JanWanker, Erich E.Rappsilber, JuriBinolfi, AndrésSelenko, PhilippAMYLOID PROTEINSNEURODEGENERATIVE DISEASEPROTEIN AGGREGATIONPROTEIN DYNAMICSSTRUCTURAL DISORDERhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Heterogeneous aggregates of the human protein α-synuclein (αSyn) are abundantly found in Lewy body inclusions of Parkinson's disease patients. While structural information on classical αSyn amyloid fibrils is available, little is known about the conformational properties of disease-relevant, non-canonical aggregates. Here, we analyze the structural and dynamic properties of megadalton-sized dityrosine adducts of αSyn that form in the presence of reactive oxygen species and cytochrome c, a proapoptotic peroxidase that is released from mitochondria during sustained oxidative stress. In contrast to canonical cross-β amyloids, these aggregates retain high degrees of internal dynamics, which enables their characterization by solution-state NMR spectroscopy. We find that intermolecular dityrosine crosslinks restrict αSyn motions only locally whereas large segments of concatenated molecules remain flexible and disordered. Indistinguishable aggregates form in crowded in vitro solutions and in complex environments of mammalian cell lysates, where relative amounts of free reactive oxygen species, rather than cytochrome c, are rate limiting. We further establish that dityrosine adducts inhibit classical amyloid formation by maintaining αSyn in its monomeric form and that they are non-cytotoxic despite retaining basic membrane-binding properties. Our results suggest that oxidative αSyn aggregation scavenges cytochrome c's activity into the formation of amorphous, high molecular-weight structures that may contribute to the structural diversity of Lewy body deposits.Fil: Verzini, Silvia. Leibniz Institute Of Molecular Pharmacology; AlemaniaFil: Shah, Maliha. Max Delbrück Center For Molecular Medicine; AlemaniaFil: Theillet, Francois-Xavier. Leibniz Institute Of Molecular Pharmacology; AlemaniaFil: Belsom, Adam. Technische Universität Berlin,; AlemaniaFil: Bieschke, Jan. Max Delbrück Center For Molecular Medicine; AlemaniaFil: Wanker, Erich E.. Max Delbrück Center For Molecular Medicine; AlemaniaFil: Rappsilber, Juri. Technische Universität Berlin,; AlemaniaFil: Binolfi, Andrés. 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: Selenko, Philipp. Weizmann Institute Of Science.; IsraelAcademic Press Ltd - Elsevier Science Ltd2020-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/181646Verzini, Silvia; Shah, Maliha; Theillet, Francois-Xavier; Belsom, Adam; Bieschke, Jan; et al.; Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics; Academic Press Ltd - Elsevier Science Ltd; Journal of Molecular Biology; 432; 24; 10-2020; 1-450022-2836CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.jmb.2020.10.023info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0022283620305982info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:50:41Zoai:ri.conicet.gov.ar:11336/181646instacron: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:34982025-09-03 09:50:42.04CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics
title Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics
spellingShingle Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics
Verzini, Silvia
AMYLOID PROTEINS
NEURODEGENERATIVE DISEASE
PROTEIN AGGREGATION
PROTEIN DYNAMICS
STRUCTURAL DISORDER
title_short Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics
title_full Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics
title_fullStr Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics
title_full_unstemmed Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics
title_sort Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics
dc.creator.none.fl_str_mv Verzini, Silvia
Shah, Maliha
Theillet, Francois-Xavier
Belsom, Adam
Bieschke, Jan
Wanker, Erich E.
Rappsilber, Juri
Binolfi, Andrés
Selenko, Philipp
author Verzini, Silvia
author_facet Verzini, Silvia
Shah, Maliha
Theillet, Francois-Xavier
Belsom, Adam
Bieschke, Jan
Wanker, Erich E.
Rappsilber, Juri
Binolfi, Andrés
Selenko, Philipp
author_role author
author2 Shah, Maliha
Theillet, Francois-Xavier
Belsom, Adam
Bieschke, Jan
Wanker, Erich E.
Rappsilber, Juri
Binolfi, Andrés
Selenko, Philipp
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AMYLOID PROTEINS
NEURODEGENERATIVE DISEASE
PROTEIN AGGREGATION
PROTEIN DYNAMICS
STRUCTURAL DISORDER
topic AMYLOID PROTEINS
NEURODEGENERATIVE DISEASE
PROTEIN AGGREGATION
PROTEIN DYNAMICS
STRUCTURAL DISORDER
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Heterogeneous aggregates of the human protein α-synuclein (αSyn) are abundantly found in Lewy body inclusions of Parkinson's disease patients. While structural information on classical αSyn amyloid fibrils is available, little is known about the conformational properties of disease-relevant, non-canonical aggregates. Here, we analyze the structural and dynamic properties of megadalton-sized dityrosine adducts of αSyn that form in the presence of reactive oxygen species and cytochrome c, a proapoptotic peroxidase that is released from mitochondria during sustained oxidative stress. In contrast to canonical cross-β amyloids, these aggregates retain high degrees of internal dynamics, which enables their characterization by solution-state NMR spectroscopy. We find that intermolecular dityrosine crosslinks restrict αSyn motions only locally whereas large segments of concatenated molecules remain flexible and disordered. Indistinguishable aggregates form in crowded in vitro solutions and in complex environments of mammalian cell lysates, where relative amounts of free reactive oxygen species, rather than cytochrome c, are rate limiting. We further establish that dityrosine adducts inhibit classical amyloid formation by maintaining αSyn in its monomeric form and that they are non-cytotoxic despite retaining basic membrane-binding properties. Our results suggest that oxidative αSyn aggregation scavenges cytochrome c's activity into the formation of amorphous, high molecular-weight structures that may contribute to the structural diversity of Lewy body deposits.
Fil: Verzini, Silvia. Leibniz Institute Of Molecular Pharmacology; Alemania
Fil: Shah, Maliha. Max Delbrück Center For Molecular Medicine; Alemania
Fil: Theillet, Francois-Xavier. Leibniz Institute Of Molecular Pharmacology; Alemania
Fil: Belsom, Adam. Technische Universität Berlin,; Alemania
Fil: Bieschke, Jan. Max Delbrück Center For Molecular Medicine; Alemania
Fil: Wanker, Erich E.. Max Delbrück Center For Molecular Medicine; Alemania
Fil: Rappsilber, Juri. Technische Universität Berlin,; Alemania
Fil: Binolfi, Andrés. 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: Selenko, Philipp. Weizmann Institute Of Science.; Israel
description Heterogeneous aggregates of the human protein α-synuclein (αSyn) are abundantly found in Lewy body inclusions of Parkinson's disease patients. While structural information on classical αSyn amyloid fibrils is available, little is known about the conformational properties of disease-relevant, non-canonical aggregates. Here, we analyze the structural and dynamic properties of megadalton-sized dityrosine adducts of αSyn that form in the presence of reactive oxygen species and cytochrome c, a proapoptotic peroxidase that is released from mitochondria during sustained oxidative stress. In contrast to canonical cross-β amyloids, these aggregates retain high degrees of internal dynamics, which enables their characterization by solution-state NMR spectroscopy. We find that intermolecular dityrosine crosslinks restrict αSyn motions only locally whereas large segments of concatenated molecules remain flexible and disordered. Indistinguishable aggregates form in crowded in vitro solutions and in complex environments of mammalian cell lysates, where relative amounts of free reactive oxygen species, rather than cytochrome c, are rate limiting. We further establish that dityrosine adducts inhibit classical amyloid formation by maintaining αSyn in its monomeric form and that they are non-cytotoxic despite retaining basic membrane-binding properties. Our results suggest that oxidative αSyn aggregation scavenges cytochrome c's activity into the formation of amorphous, high molecular-weight structures that may contribute to the structural diversity of Lewy body deposits.
publishDate 2020
dc.date.none.fl_str_mv 2020-10
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/11336/181646
Verzini, Silvia; Shah, Maliha; Theillet, Francois-Xavier; Belsom, Adam; Bieschke, Jan; et al.; Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics; Academic Press Ltd - Elsevier Science Ltd; Journal of Molecular Biology; 432; 24; 10-2020; 1-45
0022-2836
CONICET Digital
CONICET
url http://hdl.handle.net/11336/181646
identifier_str_mv Verzini, Silvia; Shah, Maliha; Theillet, Francois-Xavier; Belsom, Adam; Bieschke, Jan; et al.; Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics; Academic Press Ltd - Elsevier Science Ltd; Journal of Molecular Biology; 432; 24; 10-2020; 1-45
0022-2836
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jmb.2020.10.023
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0022283620305982
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
dc.publisher.none.fl_str_mv Academic Press Ltd - Elsevier Science Ltd
publisher.none.fl_str_mv Academic Press Ltd - Elsevier Science Ltd
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 13.13397

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