Molecular architecture of human prion protein amyloid: A parallel, in-register ß-structure

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-11, Vol.104 (48), p.18946
• Main Authors: Cobb, Nathan J, Sönnichsen, Frank D, Mchaourab, Hassane, Surewicz, Witold K
• Format: Article
• Language: English
• Subjects: Gene expression; Molecular structure; Mutation; Neurological disorders; Protein folding; Proteins
• ISSN: 0027-8424; 1091-6490

Transmissible spongiform encephalopathies (TSEs) represent a group of fatal neurodegenerative diseases that are associated with conformational conversion of the normally monomeric and α-helical prion protein, PrP..., to the β-sheet-rich PrP... This latter conformer is believed to constitute the main component of the infectious TSE agent. In contrast to high-resolution data for the PrP... monomer, structures of the pathogenic PrP... or synthetic PrP...-like aggregates remain elusive. Here we have used site-directed spin labeling and EPR spectroscopy to probe the molecular architecture of the recombinant PrP amyloid, a misfolded form recently reported to induce transmissible disease in mice overexpressing an N-terminally truncated form of PrP... Our data show that, in contrast to earlier, largely theoretical models, the con formational conversion of PrP... involves major refolding of the C-terminal α-helical region. The core of the amyloid maps to C-terminal residues from ... 160-220, and these residues form single-molecule layers that stack on top of one another with parallel, in-register alignment of β-strands. This structural insight has important implications for understanding the molecular basis of prion propagation, as well as hereditary prion diseases, most of which are associated with point mutations in the region found to undergo a refolding to β-structure. (ProQuest: ... denotes formulae/symbols omitted.)