title: Conformer-specific hydrogen exchange analysis of Aβ(1-42) oligomers by top-down electron capture dissociation mass spectrometry.
abstract: Protein structural studies are particularly challenging under conditions in which several conformational species (e.g., monomers and aggregated forms) coexist in solution. Most spectroscopic techniques provide population-averaged data. Hence, it is usually not possible to obtain detailed structural information on individual protein species in heterogeneous samples. The current work employs an experimental strategy that addresses this issue. Solution-phase hydrogen exchange (HX) is used in combination with tandem mass spectrometry. Electrosprayed intact ions exhibiting specific HX mass shifts are selected in the gas phase, followed by electron capture dissociation. The resulting fragment ion deuteration pattern provides amide hydrogen bonding information in a conformer-specific and spatially resolved fashion. The feasibility of this approach is demonstrated by applying it to neurotoxic Aβ(1-42) oligomers that coexist with disordered monomers in solution. The findings of this study point to similarities between oligomers and mature amyloid fibrils with regard to the Aβ(1-42) backbone organization. Specifically, fibrils and oligomers appear to share a β-loop-β secondary structure motif. The spatial resolution obtained with the "top-down" approach used here exceeds that of earlier proteolysis-based HX data on Aβ.
authors.affiliation: Department of Chemistry, The University of Western Ontario, London, Ontario, N6A 5B7 Canada.
authors.forename: Jingxi
authors.initials: J
authors.lastname: Pan
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Borchers
authors.forename: Lars
authors.initials: L
authors.lastname: Konermann
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D006859:Hydrogen / Q000737:chemistry*; D013058:Mass Spectrometry / Q000379:methods*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D006859:Hydrogen