Copper Binding and Subsequent Aggregation of α-Synuclein Are Modulated by N-Terminal Acetylation and Ablated by the H50Q Missense Mutation


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.

Keywords: Mass spectrometry,
Academic units: Faculty of Health and Wellbeing (HWB) > Academic Departments > Department of Biosciences
Funder NameGrant NumberFunder ID
Sheffield Hallam UniversityUNSPECIFIED
Royal SocietyRG2010R1
British Mass Spectrometry SocietyUNSPECIFIED
Copyright Holders: Copyright © 2016 American Chemical Society
Publisher of the data: Figshare
Publication date: 12 August 2016
Data last accessed: No data downloaded yet
Embargo expiry date: 13 August 2017
Reason(s) for restriction and conditions for access: Green route paper accessible as open access after one year.
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