α-Synuclein (αS) is an amyloidogenic intrinsically disordered protein implicated in Parkinson's disease, for which copper-mediated pathways of neurodegeneration have been suggested. We have employed nuclear magnetic resonance, circular dichroism, electrospray ionization mass spectrometry, and thioflavin T fluorescence to characterize interactions of Cu2+ with the physiological acetylated form (Ac-αS). Significantly, N-terminal acetylation abolishes Cu2+ binding at the high-affinity M1-D2 site present in the nonacetylated protein and maintains Cu2+ interactions around H50/D121. Fibrillation enhancement observed at an equimolar Cu 2+ stoichiometry with the nonacetylated model does not occur with Ac-αS. These findings open new avenues of investigation into Cu 2+-mediated neurodegenerative pathology suggested in vivo.
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