Methionine Oxidation Stabilizes Non-toxic Oligomers of α-synuclein Through Strengthening The Auto-inhibitory Intra-molecular Long-range Interactions
Document Type
Article
Publication Date
2010
Keywords
Alpha-synuclein, Methionine Oxidation, Parkinson's Disease, Protein Aggregation, Amyloid Fibril
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.bbadis.2009.12.004
Abstract
Oxidative stress and aggregation of the presynaptic protein α-synuclein (α-Syn) are implied in the pathogenesis of Parkinson's disease and several other neurodegenerative diseases. Various posttranslational modifications, such as oxidation, nitration and truncation, have significant effects on the kinetics of α-Syn fibrillation in vitro. α-Syn is a typical natively unfolded protein, which possesses some residual structure. The existence of long-range intra-molecular interactions between the C-terminal tail (residues 120–140) and the central part of α-Syn (residues 30–100) was recently established (Bertoncini et al. (2005) Proc Natl Acad Sci U S A 102, 1430–1435). Since α-Syn has four methionines, two of which (Met 1 and 5) are at the N-terminus and the other two (Met 116 and 127) are in the hydrophobic cluster at the C-terminus of protein, the perturbation of these residues via their oxidation represents a good model for studying the effect of long-range interaction on α-Syn fibril formation. In this paper we show that Met 1, 116, and 127 are more protected from the oxidation than Met 5 likely due to the residual structure in the natively unfolded α-Syn. In addition to the hydrophobic interactions between the C-terminal hydrophobic cluster and hydrophobic central region of α-Syn, there are some long-range electrostatic interactions in this protein. Both of these interactions likely serve as auto-inhibitors of α-Syn fibrillation. Methionine oxidation affects both electrostatic and hydrophobic long-range interactions in α-Syn. Finally, oxidation of methionines by H2O2 greatly inhibited α-Syn fibrillation in vitro, leading to the formation of relatively stable oligomers, which are not toxic to dopaminergic and GABAergic neurons.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, v. 1802, issue 3, p. 322-330
Scholar Commons Citation
Zhou, Wenbo; Long, Chunmei; Reaney, Stephen H.; Do Monte, Donato A.; Fink, Anthony L.; and Uversky, Vladimir N., "Methionine Oxidation Stabilizes Non-toxic Oligomers of α-synuclein Through Strengthening The Auto-inhibitory Intra-molecular Long-range Interactions" (2010). Molecular Medicine Faculty Publications. 545.
https://digitalcommons.usf.edu/mme_facpub/545
