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  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., et al. (2014). Site-specific copper-catalyzed oxidation of alpha-synuclein: Tightening the link between metal binding and protein oxidative damage in Parkinson's disease. Inorganic Chemistry, 53(9), 4350-4358. doi:10.1021/ic4031377.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-B6EC-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CCB3-5
Genre: Journal Article

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 Creators:
Miotto, M. C., Author
Rodriguez, E. E., Author
Valiente-Gabioud, A. A., Author
Torres-Monserrat, V., Author
Binolfi, A., Author
Quintanar, L., Author
Zweckstetter, M.1, Author              
Griesinger, C.2, Author              
Fernandez, C. O., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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 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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Language(s): eng - English
 Dates: 2014-04-112014-05-05
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/ic4031377
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Title: Inorganic Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 53 (9) Sequence Number: - Start / End Page: 4350 - 4358 Identifier: -