An unusual soluble β-turn-rich conformation of prion is involved in fibril formation and toxic to neuronal cells

• Published in: Biochemical and biophysical research communications 2005-03, Vol.328 (1), p.292-305
• Main Authors: Kazlauskaite, Jurate, Young, Anna, Gardner, Catherine E., Macpherson, Julie V., Vénien-Bryan, Catherine, Pinheiro, Teresa J.T.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Survival - drug effects; Cricetinae; Dimerization; Dose-Response Relationship, Drug; Fibrillization; Mesocricetus; Multienzyme Complexes - chemistry; Multienzyme Complexes - pharmacology; Neuroblastoma - pathology; Neurons - drug effects; Neurons - pathology; Neurotoxic molecule; Neurotoxins - chemistry; Neurotoxins - pharmacology; Prion conversion; Prions - chemistry; Prions - pharmacology; Prions - ultrastructure; Protein Conformation; Protein Structure, Secondary; Rafts; Rats; Solubility; Structure-Activity Relationship; Transmissible spongiform encephalopathy
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2004.12.172

A key molecular event in prion diseases is the conversion of the prion protein (PrP) from its normal cellular form (PrP C) to the disease-specific form (PrP Sc). The transition from PrP C to PrP Sc involves a major conformational change, resulting in amorphous protein aggregates and fibrillar amyloid deposits with increased β-sheet structure. Using recombinant PrP refolded into a β-sheet-rich form (β-PrP) we have studied the fibrillization of β-PrP both in solution and in association with raft membranes. In low ionic strength thick dense fibrils form large networks, which coexist with amorphous aggregates. High ionic strength results in less compact fibrils, that assemble in large sheets packed with globular PrP particles, resembling diffuse aggregates found in ex vivo preparations of PrP Sc. Here we report on the finding of a β-turn-rich conformation involved in prion fibrillization that is toxic to neuronal cells in culture. This is the first account of an intermediate in prion fibril formation that is toxic to neuronal cells. We propose that this unusual β-turn-rich form of PrP may be a precursor of PrP Sc and a candidate for the neurotoxic molecule in prion pathogenesis.