1. Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization
- Author
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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, and Daniel Erik Otzen
- Subjects
METAL-CATALYZED OXIDATION ,Amyloid ,Amyloid/chemistry ,Biophysics ,Biochemistry and Molecular Biology ,Parkinson Disease ,General Chemistry ,Parkinson Disease/metabolism ,Biochemistry ,Biofysik ,Catalysis ,alpha-Synuclein/chemistry ,Colloid and Surface Chemistry ,OLIGOMERS ,Structural Biology ,BINDING ,alpha-Synuclein ,Humans ,Tyrosine ,FIBRILLATION ,Tyrosine/analogs & derivatives ,COPPER(II) ,Biokemi och molekylärbiologi ,Strukturbiologi - Abstract
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.
- Published
- 2022
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