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: Mario Salmona, Michela Morbin, Tania Massignan, Laura Colombo, Giulia Mazzoleni, Raffaella Capobianco, Luisa Diomede, Florian Thaler, Luca Mollica, Giovanna Musco, Joseph J Kourie, Orso Bugiani, Deepak Sharma, Hideyo Inouye, Daniel A Kirschner, Gianluigi Forloni, Fabrizio Tagliavini
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 48 Pg. 48146-53 (Nov 28 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12970341 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid
• Peptide Fragments
• Peptides
• Prions
• Protein Isoforms
• prion protein (82-146)
• Congo Red
• Endopeptidases

Topics

• Amino Acid Sequence
• Amyloid (chemistry, 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