Methionine oxidation stabilizes non-toxic oligomers of α-synuclein through strengthening the auto-inhibitory intra-molecular long-range interactions

Wenbo Zhou (1) , Chunmei Long (1) , Stephen H. Reaney (2) , Donato A. Di Monte (2) , Anthony L. Fink (1) , Vladimir N. Uversky (1, 3, 4)

1 Department of Chemistry and Biochemistry
2 The Parkinson's Institute
3 Department of Biochemistry and Molecular Biology
4 Institute for Biological Instrumentation

Oxidative stress and aggregation of the presynaptic protein α-synuclein (α-Syn) are implied in the pathogenesis of Parkinson 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 . 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 (2005) , 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, 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 HO greatly inhibited α-Syn fibrillation , leading to the formation of relatively stable oligomers, which are not toxic to dopaminergic and GABAergic neurons.

Mots clés: Life Sciences

Wenbo Zhou, Chunmei Long, Stephen H. Reaney, Donato A. Di Monte, Anthony L. Fink, et al.. Methionine oxidation stabilizes non-toxic oligomers of α-synuclein through strengthening the auto-inhibitory intra-molecular long-range interactions. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2010, 1802 (3), pp.322. ⟨10.1016/j.bbadis.2009.12.004⟩. ⟨hal-00562951⟩