Structural properties of Gerstmann-Straussler-Scheinker disease amyloid protein

• Published in: The Journal of biological chemistry Vol. 278; no. 48; pp. 48146 - 48153
• Main Authors: Salmona, Mario, Morbin, Michela, Massignan, Tania, Colombo, Laura, Mazzoleni, Giulia, Capobianco, Raffaella, Diomede, Luisa, Thaler, Florian, Mollica, Luca, Musco, Giovanna, Kourie, Joseph J, Bugiani, Orso, Sharma, Deepak, Inouye, Hideyo, Kirschner, Daniel A, Forloni, Gianluigi, Tagliavini, Fabrizio
• Format: Journal Article
• Language: English
• Published: United States 28-11-2003
• Subjects: Amino Acid Sequence; Amyloid - chemistry; Amyloid - metabolism; Animals; Cell Membrane - metabolism; Congo Red - pharmacology; Endopeptidases - pharmacology; Gerstmann-Straussler-Scheinker Disease - metabolism; Humans; Microscopy, Electron; Molecular Sequence Data; Neurons - metabolism; Peptide Fragments - chemistry; Peptides - chemistry; Prions - chemistry; Protein Isoforms; Protein Structure, Secondary; Protein Structure, Tertiary; Rats; Spectroscopy, Fourier Transform Infrared; Time Factors; X-Ray Diffraction
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M307295200

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.