title: Copper Binding and Subsequent Aggregation of α-Synuclein Are Modulated by N-Terminal Acetylation and Ablated by the H50Q Missense Mutation.
abstract: The Parkinson's disease-associated protein α-synuclein exhibits significant conformational heterogeneity. Bacterially expressed α-synuclein is known to bind to copper, resulting in the formation of aggregation-prone compact conformations. However, in vivo, α-synuclein undergoes acetylation at its N-terminus. Here the effect of this modification and the pathological H50Q mutation on copper binding and subsequent conformational transitions were investigated by electrospray ionization-ion mobility spectrometry-mass spectrometry. We demonstrate that acetylation perturbs the ability of α-synuclein to bind copper and that the H50Q missense mutation in the presence of N-terminal acetylation prevents copper binding. These modifications and mutations prevent the formation of the most compact conformations and inhibit copper-induced aggregation.
authors: Biomolecular Sciences Research Centre, Sheffield Hallam University , Sheffield S1 1WB, U.K.
authors: Rebecca J
authors: RJ
authors: Mason
authors: Biomolecular Sciences Research Centre, Sheffield Hallam University , Sheffield S1 1WB, U.K.
authors: Aimee R
authors: AR
authors: Paskins
authors: Biomolecular Sciences Research Centre, Sheffield Hallam University , Sheffield S1 1WB, U.K.
authors: Caroline F
authors: CF
authors: Dalton
authors: Biomolecular Sciences Research Centre, Sheffield Hallam University , Sheffield S1 1WB, U.K.
authors: David P
authors: DP
authors: Smith
mesh_terms: D000107:Acetylation; D003300:Copper / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D066329:Protein Aggregates / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D066329:Protein Aggregates; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein; D003300:Copper