Characterization of Intrinsically Disordered Proteins with Electrospray Ionization Mass Spectrometry: Conformational Heterogeneity of α-synuclein

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Conformational heterogeneity of α-synuclein was studied with electrospray ionization mass spectrometry by analyzing protein ion charge state distributions, where the extent of multiple charging reflects compactness of the protein conformations in solution. Although α-synuclein lacks a single well-defined structure under physiological conditions, it was found to sample four distinct conformational states, ranging from a highly structured one to a random coil. The compact highly structured state of α-synuclein is present across the entire range of conditions tested (pH ranging from 2.5 to 10, alcohol content from 0% to 60%), but is particularly abundant in acidic solutions. The only other protein state populated in acidic solutions is a partially folded intermediate state lacking stable tertiary structure. Another, more compact intermediate state is induced by significant amounts of ethanol used as a co-solvent and appears to represent a partially folded conformation with high β-sheet content. Protein dimerization is observed throughout the entire range of conditions tested, although only acidic solutions favor formation of highly structured dimers of α-synuclein. These dimers are likely to present the earliest stages in protein aggregation leading to globular oligomers and, subsequently, protofibrils. Proteins 2010. © 2009 Wiley-Liss, Inc.

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Proteins: Structure, Function, and Bioinformatics, v. 78, issue 3, p. 714-722