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

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

alpha-Synuclein (alpha-Syn) is an intrinsically disordered protein which self-assembles into highly organized beta-sheet structures that accumulate in plaques in brains of Parkinson's disease patients. Oxidative stress influences alpha-Syn structure and selfassembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric alpha-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 alpha-Syn monomer by a factor of root 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
Issue number27
Pages (from-to)11949-11954
Number of pages6
Publication statusPublished - 2022

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