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Competing intrachain interactions regulate the formation of ß-sheet fibrils in bovine PrP peptides

¹ Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
² Oxford Centre for Molecular Sciences, Department of Chemistry, University of Oxford, Oxford OX1 3QH, UK
³ Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK

Reprint requests to: William James, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; e-mail: william.james{at}path.ox.ac.uk; fax: 44 (1865) 275501.

At the heart of the pathogenesis of transmissible spongiform encephalopathies (TSEs), such as BSE, scrapie, and Creutzfeldt–Jakob disease, lies a poorly understood structural rearrangement of PrP, an abundant glycoprotein of the nervous and lymphoid systems. The normal form (PrP^C), rich in -helix, converts into an aberrant ß-sheet-dominated form (PrP^Sc), which seems to be at the center of the pathotoxic symptoms observed in TSEs. To understand this process better at a molecular level, we have studied the interactions between different peptides derived from bovine PrP and their structural significance. We show that two unstructured peptides derived from the central region of bovine PrP, residues 115–133 and 140–152, respectively, interact stoichiometrically under physiological conditions to generate ß-sheet-dominated fibrils. However, when both peptides are incubated in the presence of a third peptide derived from an adjoining -helical region (residues 153–169), the formation of ß-sheet-rich fibrils is abolished. These data indicate that native PrP^C helix 1 might inhibit the strong intrinsic ß-sheet-forming propensity of sequences immediately N-terminal to the globular core of PrP^C, by keeping in place intrachain interactions that would prevent these amyloidogenic regions from triggering aggregation. Moreover, these results indicate new ways in which PrP^Sc formation could be prevented.

Keywords: Prions; ß-amyloid; BSE; peptide; fibrillogenesis

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