Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1802, Issue 3, Pages 322-330Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2009.12.004
Keywords
Alpha-synuclein; Methionine oxidation; Parkinson's disease; Protein aggregation; Amyloid fibril
Funding
- National Institutes of Health [R01 NS39985, R01 LM007688-01A1, GM071714-01A2]
- Russian Academy of Sciences
- IUPUI Signature Centers Initiative
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Oxidative stress and aggregation of the presynaptic protein alpha-synuclein (alpha-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 alpha-Syn fibrillation in vitro. alpha-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 alpha-Syn (residues 30-100) was recently established (Bertoncini et al. (2005) Proc Natl Acad Sci U S A 102,1430-1435). Since alpha-Syn has four methionines, two of which (Met I 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 alpha-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 alpha-Syn. In addition to the hydrophobic interactions between the C-terminal hydrophobic cluster and hydrophobic central region of alpha-Syn, there are some long-range electrostatic interactions in this protein. Both of these interactions likely serve as auto-inhibitors of alpha-Syn fibrillation. Methionine oxidation affects both electrostatic and hydrophobic long-range interactions in alpha-Syn. Finally, oxidation of methionines by H2O2 greatly inhibited alpha-Syn fibrillation in vitro, leading to the formation of relatively stable oligomers, which are not toxic to dopaminergic and GABAergic neurons. (C) 2009 Elsevier B.V. All rights reserved.
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