title: A revised picture of the Cu(II)-α-synuclein complex: the role of N-terminal acetylation.
abstract: 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 Cu(2+) with the physiological acetylated form (Ac-αS). Significantly, N-terminal acetylation abolishes Cu(2+) binding at the high-affinity M1-D2 site present in the nonacetylated protein and maintains Cu(2+) 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.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University , Piscataway, New Jersey 08854, United States.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Moriarty
authors.forename: Conceição A S A
authors.initials: CA
authors.lastname: Minetti
authors.forename: David P
authors.initials: DP
authors.lastname: Remeta
authors.forename: Jean
authors.initials: J
authors.lastname: Baum
mesh_terms: D000107:Acetylation; D000682:Amyloid / Q000096:biosynthesis; D001665:Binding Sites; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008345:Manganese / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein; D008345:Manganese; D003300:Copper