Copper binding to the N-terminally acetylated, naturally occurring form of alpha-synuclein induces local helical folding.
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.
Marco C
MC
Miotto
Ariel A
AA
Valiente-Gabioud
§Computational Biophysics, German Research School for Simulation Sciences and Computational Biomedicine, Institute for Advanced Simulations IAS-5, Forschungszentrum Jülich, D-52425 Jülich, Germany.
Giulia
G
Rossetti
∥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.
Markus
M
Zweckstetter
§Computational Biophysics, German Research School for Simulation Sciences and Computational Biomedicine, Institute for Advanced Simulations IAS-5, Forschungszentrum Jülich, D-52425 Jülich, Germany.
Paolo
P
Carloni
∇Department of NMR-assisted Structural Biology, In-cell NMR, Leibniz Institute of Molecular Pharmacology, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
Philipp
P
Selenko
∥Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Göttingen, Germany.
Christian
C
Griesinger
∇Department of NMR-assisted Structural Biology, In-cell NMR, Leibniz Institute of Molecular Pharmacology, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
Andres
A
Binolfi
Claudio O
CO
Fernández
D000107:Acetylation; D001665:Binding Sites; D003300:Copper / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D017510:Protein Folding; D051844:alpha-Synuclein / Q000737:chemistry*
D009942:Organometallic Compounds; D051844:alpha-Synuclein; D003300:Copper