Seminars Archive

Structural differences between brain-derived prions and recombinant prion protein amyloid as seen by X-ray fiber diffraction, electron microscopy, and bioassays

Abstract
A conformational variant of the mammalian prion protein (PrPSc) is the sole component of the infectious pathogen causing the prion diseases that include Creutzfeldt-Jakob disease (CJD) of humans and mad cow disease (BSE). The insolubility of PrPSc and of its N-terminal truncation product, PrP 27-30, has hampered all attempts to determine its atomic structure by X-ray crystallography or NMR spectroscopy. We used electron microscopy, molecular modelling, and X-ray fiber diffraction to investigate the structures of PrPSc and of PrP 27-30. Recent data, obtained by X-ray fiber diffraction, revealed substantial, structural differences between brain-derived prion amyloids and recombinant (rec) PrP amyloid. Fiber diffraction of synthetic prions, initially formed from recPrP by polymerization into amyloid but passaged in transgenic (Tg) mice, displayed structural characteristics similar to those of naturally occurring prions. Our findings indicate that recPrP amyloids contain multiple conformers, only a minority of which may be able to initiate a prion infection.