Competing intrachain interactions regulate the formation of beta-sheet fibrils in bovine PrP peptides.
At the heart of the pathogenesis of transmissible spongiform encephalopathies (TSEs), such as BSE, scrapie, and Creutzfeldt-Jakob disease, lies a poorly understood structural rearrangement of PrP, an abundant glycoprotein of the nervous and lymphoid systems. The normal form (PrP(C)), rich in alpha-helix, converts into an aberrant beta-sheet-dominated form (PrP(Sc)), which seems to be at the center of the pathotoxic symptoms observed in TSEs. To understand this process better at a molecular level, we have studied the interactions between different peptides derived from bovine PrP and their structural significance. We show that two unstructured peptides derived from the central region of bovine PrP, residues 115-133 and 140-152, respectively, interact stoichiometrically under physiological conditions to generate beta-sheet-dominated fibrils. However, when both peptides are incubated in the presence of a third peptide derived from an adjoining alpha-helical region (residues 153-169), the formation of beta-sheet-rich fibrils is abolished. These data indicate that native PrP(C) helix 1 might inhibit the strong intrinsic beta-sheet-forming propensity of sequences immediately N-terminal to the globular core of PrP(C), by keeping in place intrachain interactions that would prevent these amyloidogenic regions from triggering aggregation. Moreover, these results indicate new ways in which PrP(Sc) formation could be prevented.
Tahiri-Alaoui
Abdessamad
A
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Bouchard
Mario
M
Zurdo
Jesús
J
James
William
W
D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D006224:Cricetinae; D006801:Humans; D008854:Microscopy, Electron; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D018622:PrP 27-30 Protein / Q000096:biosynthesis*; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D013055:Spectrophotometry, Infrared
D010446:Peptide Fragments; D018621:PrPC Proteins; D018622:PrP 27-30 Protein