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.
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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)
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Chemical References |
- Amyloid
- Peptide Fragments
- Peptides
- Prions
- Protein Isoforms
- prion protein (82-146)
- Congo Red
- Endopeptidases
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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
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