title: Mutagenic exploration of the cross-seeding and fibrillation propensity of Alzheimer's beta-amyloid peptide variants.
abstract: Amyloid formation is a nucleation-dependent process that is accelerated dramatically in vivo and in vitro upon addition of appropriate fibril seeds. A potent species barrier can be effective in this reaction if donor and recipient come from different biological species. This species barrier is thought to reflect differences in the amino acid sequence between seed and target polypeptide. Here we present an in vitro mutagenic cross-seeding analysis of Alzheimer's Abeta(1-40) peptide in which we mapped out the effect of systematically varied amino acid replacements on the propensity of seed-dependent amyloid fibril formation. We find that the susceptibility of different peptides toward cross-seeding relates to the intrinsic aggregation propensity of the respective polypeptide chain and, therefore, to properties such as beta-sheet propensity and hydrophobicity. These data imply that the seed-dependent formation of amyloid-like fibrils is affected by the intrinsic properties of the polypeptide chain in a manner that is similar to what has been described previously for aggregation reactions in general. Hence, the nucleus acts in this case as a catalyst that promotes the fibrillation of different polypeptide chains according to their intrinsic structural predilection.
authors.affiliation: Leibniz-Institut für Altersforschung, Jena, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Peim
authors.forename: Peter
authors.initials: P
authors.lastname: Hortschansky
authors.forename: Tony
authors.initials: T
authors.lastname: Christopeit
authors.forename: Volker
authors.initials: V
authors.lastname: Schroeckh
authors.forename: Walter
authors.initials: W
authors.lastname: Richter
authors.forename: Marcus
authors.initials: M
authors.lastname: Fändrich
mesh_terms: D000682:Amyloid / Q000096:biosynthesis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides