Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization

Cagla Sahin*, Eva Christina Østerlund, Nicklas Österlund, Joana Costeira-Paulo, Jannik Nedergaard Pedersen, Gunna Christiansen, Janni Nielsen, Anne Louise Grønnemose, Søren Kirk Amstrup, Manish K. Tiwari, R. Shyama Prasad Rao, Morten Jannik Bjerrum, Leopold L. Ilag, Michael J. Davies, Erik G. Marklund, Jan Skov Pedersen, Michael Landreh, Ian Max Møller, Thomas J. D. Jørgensen*, Daniel Erik Otzen*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques in brains of Parkinson's disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the α-Syn monomer by a factor of √2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation.

Original languageEnglish
JournalJournal of the American Chemical Society
Pages (from-to)11949-11954
Number of pages6
Publication statusPublished - Jul 2022


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