Megadalton-sized Dityrosine Aggregates of alpha-Synuclein Retain High Degrees of Structural Disorder and Internal Dynamics

Verzini Silvia; Shah Maliha; Theillet Francois-XavierBelsom AdamBieschke JanWanker Erich E.Rappsilber JuriBinolfi AndresSelenko Philipp

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Megadalton-sized Dityrosine Aggregates of alpha-Synuclein Retain High Degrees of Structural Disorder and Internal Dynamics

机译：Megadalton-sized Dityrosine Aggregates of alpha-Synuclein Retain High Degrees of Structural Disorder and Internal Dynamics

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Heterogeneous aggregates of the human protein alpha-synuclein (alpha Syn) are abundantly found in Lewy body inclusions of Parkinson's disease patients. While structural information on classical alpha Syn 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 alpha Syn 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-beta 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 alpha Syn 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 alpha Syn in its monomeric form and that they are non-cytotoxic despite retaining basic membrane-binding properties. Our results suggest that oxidative alpha Syn 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. (C) 2020 The Author(s). Published by Elsevier Ltd.

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《Journal of Molecular Biology》 |2020年第24期|共16页
作者
Verzini Silvia; Shah Maliha; Theillet Francois-XavierBelsom AdamBieschke JanWanker Erich E.Rappsilber JuriBinolfi AndresSelenko Philipp;
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作者单位

Leibniz Inst Mol Pharmacol FMP Berlin, Robert Rossle Str 10, D-13125 Berlin, Germany;

Max Delbruck Ctr Mol Med MDC Berlin, Neuroprote Lab, Robert Rossle Str 10, D-13125 Berlin, Germany;

Univ Edinburgh, Wellcome Ctr Cell Biol, Sch Biol Sci, Edinburgh EH9 3BF, Midlothian, Scotland;

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正文语种英语
中图分类分子生物学;
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amyloid proteins; neurodegenerative disease; protein aggregation; structural disorder; protein dynamics;

Megadalton-sized Dityrosine Aggregates of alpha-Synuclein Retain High Degrees of Structural Disorder and Internal Dynamics

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