title: Solvent exposure of Tyr10 as a probe of structural differences between monomeric and aggregated forms of the amyloid-β peptide.
abstract: Aggregation of amyloid-β (Aβ) peptides is a characteristic pathological feature of Alzheimer's disease. We have exploited the relationship between solvent exposure and intrinsic fluorescence of a single tyrosine residue, Tyr10, in the Aβ sequence to probe structural features of the monomeric, oligomeric and fibrillar forms of the 42-residue Aβ1-42. By monitoring the quenching of Tyr10 fluorescence upon addition of water-soluble acrylamide, we show that in Aβ1-42 oligomers this residue is solvent-exposed to a similar extent to that found in the unfolded monomer. By contrast, Tyr10 is significantly shielded from acrylamide quenching in Aβ1-42 fibrils, consistent with its proximity to the fibrillar cross-β core. Furthermore, circular dichroism measurements reveal that Aβ1-42 oligomers have a considerably lower β-sheet content than the Aβ1-42 fibrils, indicative of a less ordered molecular arrangement in the former. Taken together these findings suggest significant differences in the structural assembly of oligomers and fibrils that are consistent with differences in their biological effects.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Pablo
authors.initials: P
authors.lastname: Aran Terol
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Kumita
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Hook
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK; Department of Biology and Biological Engineering, Division of Chemical Biology, Chalmers University of Technology, Kemivägen 10, 412 96 Gothenburg, Sweden. Electronic address: eline@chalmers.se.
authors.forename: Elin K
authors.initials: EK
authors.lastname: Esbjörner
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure*; D019281:Dimerization; D015336:Molecular Probe Techniques; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000648:ultrastructure; D010446:Peptide Fragments / Q000737:chemistry* / Q000648:ultrastructure*; D011487:Protein Conformation; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; D010446:Peptide Fragments; D012997:Solvents; C075222:amyloid beta-protein (1-42); D014443:Tyrosine
keywords: Acrylamide quenching; Amyloid fibril; Amyloid-β; Aβ oligomer; tyrosine fluorescence