title: Conformational switching within individual amyloid fibrils.
abstract: A key structural component of amyloid fibrils is a highly ordered, crystalline-like cross-beta-sheet core. Conformationally different amyloid structures can be formed within the same amino acid sequence. It is generally assumed that individual fibrils consist of conformationally uniform cross-beta-structures. Using mammalian recombinant prion protein (PrP), we showed that, contrary to common perception, amyloid is capable of accommodating a significant conformational switching within individual fibrils. The conformational switch occurred when the amino acid sequence of a PrP variant used as a precursor substrate in a fibrillation reaction was not compatible with the strain-specific conformation of the fibrillar template. Despite the mismatch in amino acid sequences between the substrate and template, individual fibrils recruited the heterologous PrP variant; however, the fibril elongation proceeded through a conformational adaptation, resulting in a change in amyloid strain within individual fibrils. This study illustrates the high adaptation potential of amyloid structures and suggests that conformational switching within individual fibrils may account for adaptation of amyloid strains to a heterologous substrate. This work proposes a new mechanistic explanation for the phenomenon of strain conversion and illustrates the direction in evolution of amyloid structures. This study also provides a direct illustration that catalytic activity of self-replicating amyloid structures is not ultimately coupled with their templating effect.
authors.affiliation: Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201, USA.
authors.forename: Natallia
authors.initials: N
authors.lastname: Makarava
authors.forename: Valeriy G
authors.initials: VG
authors.lastname: Ostapchenko
authors.forename: Regina
authors.initials: R
authors.lastname: Savtchenko
authors.forename: Ilia V
authors.initials: IV
authors.lastname: Baskakov