The Y145Stop prion protein mutant (PrP23–144), which has been linked to a heritable amyloid disease in humans, is a valuable in vitro model for investigating the phenomena of amyloid strains and cross-seeding barriers. We have previously used multidimensional MAS solid-state NMR methods to show that human PrP23-144 fibrils consist of a compact ~30-residue β-rich amyloid core region located near the C-terminus and a flexible and unstructured N-terminal domain, and that the β-sheet core adopts a parallel in-register intermolecular alignment. I will describe our progress toward providing the structural basis of amyloid strains and seeding specificities of PrP23-144 amyloids. Our most recent studies indicate that mouse and Syrian hamster PrP23-144 fibrils also contain a compact C-terminal amyloid β-core. The conformation of this core region for the hamster amyloid differs from that for the human and mouse proteins, which resemble each other, and these data are consistent with the observed cross-seeding barriers between the species. We also show that specific mutations of single amino acid residues in the human protein sequence that are characteristic of the mouse and hamster proteins are sufficient to alter the human amyloid core conformation into that of the corresponding species, and that these mutations appear to be responsible for the onset of polymorphism for the mouse and hamster amyloids. A preliminary structural model for human PrP23–144 amyloid provides initial insights into these observations and will also be presented.

Structural studies of Y145Stop prion protein amyloids

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.