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

• DOI: 10.1021/jacs.2c03607
• Publication Date: 2022-06-24T20:44:52Z
• Authors: Cagla Sahin; Eva Christina Øst...; Nicklas Österlund; Joana Costeira-Paulo; Jannik Nedergaard...; Gunna Christiansen; Janni Nielsen; Anne Louise Grønn...; Søren Kirk Amstrup; Manish K. Tiwari; R. Shyama Prasad Rao; Morten Jannik Bje...; Leopold L. Ilag; Michael J. Davies; Erik G. Marklund; Jan Skov Pedersen; Michael Landreh; Ian Max Møller; Thomas J. D. Jørg...; Daniel Erik Otzen
• Keywords: Amyloid (mycology)

α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques 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 chemical physical effects mild oxidation on monomeric its aggregation. Using a combination biophysical methods, small-angle X-ray scattering, native ion mobility mass spectrometry, find leads to formation intramolecular dityrosine cross-linkages compaction monomer by factor √2. Oxidation-induced shown inhibit ordered self-assembly amyloid steric hindrance, suggesting important role preventing formation.