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dc.contributor.author
Verzini, Silvia
dc.contributor.author
Shah, Maliha
dc.contributor.author
Theillet, Francois-Xavier
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Belsom, Adam
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Bieschke, Jan
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Wanker, Erich E.
dc.contributor.author
Rappsilber, Juri
dc.contributor.author
Binolfi, Andrés
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dc.contributor.author
Selenko, Philipp
dc.date.available
2022-12-16T23:44:56Z
dc.date.issued
2020-10
dc.identifier.citation
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
dc.identifier.issn
0022-2836
dc.identifier.uri
http://hdl.handle.net/11336/181646
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Academic Press Ltd - Elsevier Science Ltd
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
AMYLOID PROTEINS
dc.subject
NEURODEGENERATIVE DISEASE
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PROTEIN AGGREGATION
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PROTEIN DYNAMICS
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STRUCTURAL DISORDER
dc.subject.classification
Biofísica
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dc.subject.classification
Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
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dc.title
Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2021-09-06T21:02:06Z
dc.journal.volume
432
dc.journal.number
24
dc.journal.pagination
1-45
dc.journal.pais
Estados Unidos
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dc.description.fil
Fil: Verzini, Silvia. Leibniz Institute Of Molecular Pharmacology; Alemania
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Fil: Shah, Maliha. Max Delbrück Center For Molecular Medicine; Alemania
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Fil: Theillet, Francois-Xavier. Leibniz Institute Of Molecular Pharmacology; Alemania
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Fil: Belsom, Adam. Technische Universität Berlin,; Alemania
dc.description.fil
Fil: Bieschke, Jan. Max Delbrück Center For Molecular Medicine; Alemania
dc.description.fil
Fil: Wanker, Erich E.. Max Delbrück Center For Molecular Medicine; Alemania
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Fil: Rappsilber, Juri. Technische Universität Berlin,; Alemania
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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
dc.description.fil
Fil: Selenko, Philipp. Weizmann Institute Of Science.; Israel
dc.journal.title
Journal of Molecular Biology
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.jmb.2020.10.023
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0022283620305982
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