Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c03607
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Funding
- Danish Council for Independent Research-Technology and Production Sciences [DFF|FTP 4005-00082]
- NNF [NNF19OC0055700]
- European Commission
- Swedish Research Council [2020-04825, 2015-00559]
- Novo Nordisk Foundation [NNF13OC0004294]
- Lundbeck Foundation [R276-2018-671]
- Marie Sklodowska Curie International Career Grant
- Swedish Research Council [2015-00559, 2020-04825] Funding Source: Swedish Research Council
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Oxidation leads to the formation of intramolecular dityrosine cross-linkages and compaction of alpha-Syn monomer, inhibiting ordered self-assembly and amyloid formation by steric hindrance.
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.
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