title: Conformational Effects of the A21G Flemish Mutation on the Aggregation of Amyloid β Peptide.
abstract: Among the various hereditary mutants of amyloid β (Aβ) in familial Alzheimer's disease (AD), the A21G Flemish-type mutant has unique properties showing a low aggregation propensity but progressive deposition in vascular walls. Moreover, in contrast to other familial AD cases that show extensive Aβ1-42 deposition in the brain, patients with Flemish AD predominantly exhibit the deposition of the Aβ1-40 isoform. Here we report the structural characterization of the Flemish-type mutant (A21G) in comparison with the wild-type Aβ1-40 peptide to examine the possible effects of the A21G mutation on the conformation of the Aβ1-40 isoform. The kinetic analysis of the aggregation of the peptides monitored by thioflavin T fluorescence measurement indicates that the mutation precludes the initial nucleation process of amyloid fibril formation by Aβ1-40. Spectroscopic data indicate that the Flemish-type mutant bound to aqueous micelles composed of lyso-GM1, in which the mobile N-terminal segment is tethered through the C-terminal helical segment, has reduced α-helical structure compared to the wild-type peptide. Our findings suggest that the mutational perturbation to the membrane binding properties is coupled with the changes in nucleation behavior of Aβ during its fibril formation.
authors.affiliation: Department of Chemistry, University of Cambridge.
authors.forename: Maho
authors.initials: M
authors.lastname: Yagi-Utsumi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics*; D005677:G(M1) Ganglioside / Q000031:analogs & derivatives / Q000737:chemistry; D008823:Micelles; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides; D008823:Micelles; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C029465:lysoGM1 ganglioside; D005677:G(M1) Ganglioside