Prion Protein (PrP) Synthetic Peptides Induce Cellular PrP to Acquire Properties of the Scrapie Isoform

Conversion of the cellular isoform of prion protein (PrPC) into the scrapie isoform (PrPSc) involves an increase in the β-sheet content, diminished solubility, and resistance to proteolytic digestion. Transgenetic studies argue that PrPCand PrPScform a complex during PrPScformation; thus, synthetic PrP peptides, which mimic the conformational pluralism of PrP, were mixed with PrPCto determine whether its properties were altered. Peptides encompassing two α-helical domains of PrP when mixed with PrPCproduced a complex that displayed many properties of PrPSc. The PrPC-peptide complex formed fibrous aggregates and up to 65% of complexed PrPCsedimented at 100,000 × g for 1 h, whereas PrPCalone did not. These complexes were resistant to proteolytic digestion and displayed a high β-sheet content. Unexpectedly, the peptide in a β-sheet conformation did not form the complex, whereas the random coil did. Addition of 2% Sarkosyl disrupted the complex and rendered PrPCsensitive to protease digestion. While the pathogenic A117V mutation increased the efficacy of complex formation, anti-PrP monoclonal antibody prevented interaction between PrPCand peptides. Our findings in concert with transgenetic investigations argue that PrPCinteracts with PrPScthrough a domain that contains the first two putative α-helices. Whether PrPC-peptide complexes possess prion infectivity as determined by bioassays remains to be established.