Methionine oxidation stabilizes non-toxic oligomers of α-synuclein through strengthening the auto-inhibitory intra-molecular long-range interactions
| Autor: | Wenbo Zhou, Vladimir N. Uversky, Donato A. Di Monte, Anthony L. Fink, Chunmei Long, Stephen H. Reaney |
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| Přispěvatelé: | Department of Chemistry and Biochemistry, University of California [Santa Cruz] (UCSC), University of California-University of California, The Parkinson's Institute, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indiana University System-Indiana University System, Institute for Biological Instrumentation, Russian Academy of Sciences [Moscow] (RAS) |
| Rok vydání: | 2010 |
| Předmět: |
Circular dichroism
Parkinson's disease animal diseases Kinetics Protein aggregation Article Hydrophobic effect 03 medical and health sciences chemistry.chemical_compound Methionine 0302 clinical medicine Nitration Humans heterocyclic compounds Molecular Biology Chromatography High Pressure Liquid 030304 developmental biology Alpha-synuclein 0303 health sciences Chemistry Circular Dichroism Life Sciences Methionine oxidation Hydrogen Peroxide Oxidants In vitro nervous system diseases Amino Acid Substitution nervous system Biochemistry Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Mutation Mutagenesis Site-Directed alpha-Synuclein Biophysics Molecular Medicine Amyloid fibril Oxidation-Reduction 030217 neurology & neurosurgery |
| Zdroj: | Biochimica et Biophysica Acta-Molecular Basis of Disease Biochimica et Biophysica Acta-Molecular Basis of Disease, Elsevier, 2010, 1802 (3), pp.322. ⟨10.1016/j.bbadis.2009.12.004⟩ |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2009.12.004 |
| Popis: | 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 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 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. |
| Databáze: | OpenAIRE |
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