title: Molecular architecture of human prion protein amyloid: a parallel, in-register beta-structure.
abstract: Transmissible spongiform encephalopathies (TSEs) represent a group of fatal neurodegenerative diseases that are associated with conformational conversion of the normally monomeric and alpha-helical prion protein, PrP(C), to the beta-sheet-rich PrP(Sc). This latter conformer is believed to constitute the main component of the infectious TSE agent. In contrast to high-resolution data for the PrP(C) monomer, structures of the pathogenic PrP(Sc) or synthetic PrP(Sc)-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(C). Our data show that, in contrast to earlier, largely theoretical models, the con formational conversion of PrP(C) involves major refolding of the C-terminal alpha-helical region. The core of the amyloid maps to C-terminal residues from approximately 160-220, and these residues form single-molecule layers that stack on top of one another with parallel, in-register alignment of beta-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 beta-structure.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cobb
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sönnichsen
authors.forename: Hassane
authors.initials: H
authors.lastname: McHaourab
authors.forename: Witold K
authors.initials: WK
authors.lastname: Surewicz
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D003545:Cysteine / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D018625:Microscopy, Atomic Force; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D018621:PrPC Proteins / Q000737:chemistry*; D018620:PrPSc Proteins / Q000737:chemistry*; D011328:Prions / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry
chemical_list: D000682:Amyloid; D010446:Peptide Fragments; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D011993:Recombinant Fusion Proteins; C507417:prion protein (90-231); D003545:Cysteine