FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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References
Site-Specific Copper-Catalyzed Oxidation of alpha-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson's Disease
Miotto(*), M. C., Rodriguez(*), E. E., Valiente-Gabioud(*), A. A., Torres-Monserrat(*), V., Binolfi, A., Quintanar(*), L., Zweckstetter(*), M., Griesinger(*), C.; Fernandez(*), C. O.
Inorg Chem, 53:4350-4358
(2014)

Tags: In-Cell NMR (Selenko)

Abstract: Amyloid aggregation of a-synuclein (AS) has been linked to the pathological effects associated with Parkinson's disease (PD). Cu-II binds specifically at the N-terminus of AS and triggers its aggregation. Site-specific Cu-I-catalyzed oxidation of AS has been proposed as a plausible mechanism for metal-enhanced AS amyloid formation. In this study, Cu-I binding to AS was probed by NMR spectroscopy, in combination with synthetic peptide models, site-directed mutagenesis, and C-terminal-truncated protein variants. Our results demonstrate that both Met residues in the motif (MDVFM5)-M-1 constitute key structural determinants for the high-affinity binding of Cu-I to the N-terminal region of AS. The replacement of one Met residue by Ile causes a dramatic decrease in the binding affinity for Cu-I, whereas the removal of both Met residues results in a complete lack of binding. Moreover, these Met residues can be oxidized rapidly after air exposure of the AS-Cu-I complex, whereas Met-116 and Met-127 in the C-terminal region remain unaffected. Met-1 displays higher susceptibility to oxidative damage compared to Met-5 because it is directly involved in both Cu-II and Cu-I coordination, resulting in closer exposure to the reactive oxygen species that may be generated by the redox cycling of copper. Our findings support a mechanism where the interaction of AS with copper ions leads to site-specific metal-catalyzed oxidation in the protein under physiologically relevant conditions. In light of recent biological findings, these results support a role for AS-copper interactions in neurodegeneration in PD.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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