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

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DOI

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

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
Volume144
Issue27
Pages (from-to)11949-11954
Number of pages6
ISSN0002-7863
DOIs
Publication statusPublished - Jul 2022

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