Surface-Catalyzed Nucleation of Amyloidogenic Peptides by Peptide-Specific Templates

Abstract

Many soluble proteins self-assemble into fibrillar, β-sheet rich, stable amyloid aggregates, many of which are implicated in diseases. Peptide segments within these proteins form the core amyloidogenic region that drives fibrillation of the protein, and it has been shown that these segments, alone, form fibrillar structures. Amyloid fibers are nucleated via a fiber-dependent pathway in which additional protein adds onto the ends and extends existing fibers. However, it is hypothesized that the walls of existing fibers can also nucleate amyloid fibers in a peptide-specific manner using the solvent-exposed side chains as a template. Using a naturally occurring protein that presents side chains of beta sheet structures but no fiber ends, we have engineered templates specific to amyloidogenic peptides to test this hypothesis. We have found that introduction of these templates drastically alter peptide fiber formation kinetics. These findings suggest that amino acid side chains on the surface of amyloid fibers, and not just fiber ends, play an important role in the formation of amyloid fibers.