TY - JOUR
T1 - Structural Basis for Dityrosine-Mediated Inhibition of alpha-Synuclein Fibrillization
AU - Sahin, Cagla
AU - Osterlund, Eva Christina
AU - Osterlund, Nicklas
AU - Costeira-Paulo, Joana
AU - Pedersen, Jannik Nedergaard
AU - Christiansen, Gunna
AU - Nielsen, Janni
AU - Grønnemose, Anne Louise
AU - Amstrup, Søren Kirk
AU - Tiwari, Manish K.
AU - Rao, R. Shyama Prasad
AU - Bjerrum, Morten Jannik
AU - Ilag, Leopold L.
AU - Davies, Michael J.
AU - Marklund, Erik G.
AU - Pedersen, Jan Skov
AU - Landreh, Michael
AU - Moller, Ian Max
AU - Jorgensen, Thomas J. D.
AU - Otzen, Daniel Erik
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - METAL-CATALYZED OXIDATION
KW - FIBRILLATION
KW - COPPER(II)
KW - OLIGOMERS
KW - BINDING
U2 - 10.1021/jacs.2c03607
DO - 10.1021/jacs.2c03607
M3 - Journal article
C2 - 35749730
VL - 144
SP - 11949
EP - 11954
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 27
ER -