title: Structural properties of Gerstmann-Straussler-Scheinker disease amyloid protein.
abstract: Prion protein (PrP) amyloid formation is a central feature of genetic and acquired forms of prion disease such as Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. The major component of GSS amyloid is a PrP fragment spanning residues approximately 82-146. To investigate the determinants of the physicochemical properties of this fragment, we synthesized PrP-(82-146) and variants thereof, including entirely and partially scrambled peptides. PrP-(82-146) readily formed aggregates that were partially resistant to protease digestion. Peptide assemblies consisted of 9.8-nm-diameter fibrils having a parallel cross-beta-structure. Second derivative of infrared spectra indicated that PrP-(82-146) aggregates are primarily composed of beta-sheet (54%) and turn (24%) which is consistent with their amyloid-like properties. The peptide induced a remarkable increase in plasma membrane microviscosity of primary neurons. Modification of the amino acid sequence 106-126 caused a striking increase in aggregation rate, with formation of large amount of protease-resistant amorphous material and relatively few amyloid fibrils. Alteration of the 127-146 region had even more profound effects, with the inability to generate amyloid fibrils. These data indicate that the intrinsic properties of PrP-(82-146) are dependent upon the integrity of the C-terminal region and account for the massive deposition of PrP amyloid in GSS.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. salmona@marionegri.it
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Tania
authors.initials: T
authors.lastname: Massignan
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.forename: Giulia
authors.initials: G
authors.lastname: Mazzoleni
authors.forename: Raffaella
authors.initials: R
authors.lastname: Capobianco
authors.forename: Luisa
authors.initials: L
authors.lastname: Diomede
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.forename: Luca
authors.initials: L
authors.lastname: Mollica
authors.forename: Giovanna
authors.initials: G
authors.lastname: Musco
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Kourie
authors.forename: Orso
authors.initials: O
authors.lastname: Bugiani
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.forename: Hideyo
authors.initials: H
authors.lastname: Inouye
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kirschner
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003224:Congo Red / Q000494:pharmacology; D010450:Endopeptidases / Q000494:pharmacology; D016098:Gerstmann-Straussler-Scheinker Disease / Q000378:metabolism*; D006801:Humans; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011328:Prions / Q000737:chemistry*; D020033:Protein Isoforms; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors; D014961:X-Ray Diffraction
chemical_list: D000682:Amyloid; D010446:Peptide Fragments; D010455:Peptides; D011328:Prions; D020033:Protein Isoforms; C477930:prion protein (82-146); D003224:Congo Red; D010450:Endopeptidases