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J Am Chem Soc. 2015 May 27;137(20):6444-7. doi: 10.1021/jacs.5b01911. Epub 2015 May 15.

Copper binding to the N-terminally acetylated, naturally occurring form of alpha-synuclein induces local helical folding.

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§Computational Biophysics, German Research School for Simulation Sciences and Computational Biomedicine, Institute for Advanced Simulations IAS-5, Forschungszentrum Jülich, D-52425 Jülich, Germany.
∥Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Göttingen, Germany.
⊥Deutsches Zentrum für Neurodegenerative Erkrankungen, 37077 Göttingen, Germany.
#Center for the Molecular Physiology of the Brain, University Medical Center, 37077 Göttingen, Germany.
∇Department of NMR-assisted Structural Biology, In-cell NMR, Leibniz Institute of Molecular Pharmacology, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.


Growing evidence supports a link between brain copper homeostasis, the formation of alpha-synuclein (AS)-copper complexes, and the development of Parkinson disease (PD). Recently it was demonstrated that the physiological form of AS is N-terminally acetylated (AcAS). Here we used NMR spectroscopy to structurally characterize the interaction between Cu(I) and AcAS. We found that the formation of an AcAS-Cu(I) complex at the N-terminal region stabilizes local conformations with α-helical secondary structure and restricted motility. Our work provides new evidence into the metallo-biology of PD and opens new lines of research as the formation of AcAS-Cu(I) complex might impact on AcAS membrane binding and aggregation.

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