Fibril conformation as the basis of species- and strain-dependent seeding specificity of mammalian prion amyloids.
Spongiform encephalopathies are believed to be transmitted by self-perpetuating conformational conversion of the prion protein. It was shown recently that fundamental aspects of mammalian prion propagation can be reproduced in vitro in a seeded fibrillization of the recombinant prion protein variant Y145Stop (PrP23-144). Here we demonstrate that PrP23-144 amyloids from different species adopt distinct secondary structures and morphologies, and that these structural differences are controlled by one or two residues in a critical region. These sequence-specific structural characteristics correlate strictly with the seeding specificity of amyloid fibrils. However, cross-seeding of PrP23-144 from one species with preformed fibrils from another species may overcome natural sequence-based structural preferences, resulting in a new amyloid strain that inherits the secondary structure and morphology of the template. These data provide direct biophysical evidence that protein conformations are transmitted in PrP amyloid strains, establishing a foundation for a structural basis of mammalian prion transmission barriers.
Jones
Eric M
EM
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Surewicz
Witold K
WK
D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D000818:Animals; D006801:Humans; D018625:Microscopy, Atomic Force; D009154:Mutation / Q000235:genetics*; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D013045:Species Specificity; D017550:Spectroscopy, Fourier Transform Infrared
D000682:Amyloid; D011328:Prions; D011994:Recombinant Proteins