title: Natural and synthetic prion structure from X-ray fiber diffraction.
abstract: A conformational isoform of the mammalian prion protein (PrP(Sc)) is the sole component of the infectious pathogen that causes the prion diseases. We have obtained X-ray fiber diffraction patterns from infectious prions that show cross-beta diffraction: meridional intensity at 4.8 A resolution, indicating the presence of beta strands running approximately at right angles to the filament axis and characteristic of amyloid structure. Some of the patterns also indicated the presence of a repeating unit along the fiber axis, corresponding to four beta-strands. We found that recombinant (rec) PrP amyloid differs substantially from highly infectious brain-derived prions, both in structure as demonstrated by the diffraction data, and in heterogeneity as shown by electron microscopy. In addition to the strong 4.8 A meridional reflection, the recPrP amyloid diffraction is characterized by strong equatorial intensity at approximately 10.5 A, absent from brain-derived prions, and indicating the presence of stacked beta-sheets. Synthetic prions recovered from transgenic mice inoculated with recPrP amyloid displayed structural characteristics and homogeneity similar to those of naturally occurring prions. The relationship between the structural differences and prion infectivity is uncertain, but might be explained by any of several hypotheses: only a minority of recPrP amyloid possesses a replication-competent conformation, the majority of recPrP amyloid has to undergo a conformational maturation to acquire replication competency, or inhibitory forms of recPrP amyloid interfere with replication during the initial transmission.
authors.affiliation: Institute for Neurodegenerative Diseases, Departments of Neurology and Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Wille
authors.forename: Wen
authors.initials: W
authors.lastname: Bian
authors.forename: Michele
authors.initials: M
authors.lastname: McDonald
authors.forename: Amy
authors.initials: A
authors.lastname: Kendall
authors.forename: David W
authors.initials: DW
authors.lastname: Colby
authors.forename: Lillian
authors.initials: L
authors.lastname: Bloch
authors.forename: Julian
authors.initials: J
authors.lastname: Ollesch
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Borovinskiy
authors.forename: Fred E
authors.initials: FE
authors.lastname: Cohen
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.forename: Gerald
authors.initials: G
authors.lastname: Stubbs
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000235:genetics; D000818:Animals; D001923:Brain Chemistry; D006224:Cricetinae; D008647:Mesocricetus; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D000682:Amyloid; D011328:Prions; D011994:Recombinant Proteins