NR APLJ
AU Salmona,M.; Morbin,M.; Massignan,T.; Colombo,L.; Mazzoleni,G.; Capobianco,R.; Diomede,L.; Thaler,F.; Mollica,L.; Musco,G.; Kourie,J.J.; Bugiani,O.; Sharma,D.; Inouye,H.; Kirschner,D.A.; Forloni,G.; Tagliavini,F.
TI Structural properties of Gerstmann-Sträussler-Scheinker disease amyloid protein
QU The Journal of Biological Chemistry 2003 Nov 28; 278(48): 48146-53
PT journal article
AB 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.
MH Amino Acid Sequence; Amyloid/*chemistry/metabolism; Animals; Cell Membrane/metabolism; Congo Red/pharmacology; Endopeptidases/pharmacology; Gerstmann-Sträussler-Scheinker Disease/*metabolism; Human; 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; Support, Non-U.S. Gov't; Time Factors; X-Ray Diffraction
AD Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. salmona@marionegri.it
SP englisch
PO USA