Sheep prion protein synthetic peptide spanning helix 1 and beta-strand 2 (residues 142-166) shows beta-hairpin structure in solution

According to the "protein only" hypothesis, a conformational conversion of the non-pathogenic "cellular" prion isoform. into a pathogenic "scrapie" is oform is the fundamental event in the onset of prion diseases. During this pathogenic conversion, helix H1 and two adjacent surface loops L2 and L3 of the normal prion protein are thought to undergo a conformational transitio n into an extended beta -like structure, which is prompted by interactions with the pre-existing beta -sheet. To get more insight into the interaction between the helix and one of the beta -strands in the partially unfolded p rion protein, the solution structure of a synthetic linear peptide spanning helix HI and beta -strand S2 (residues 142-166 in human numbering) was stu died by circular dichroism. and nuclear magnetic resonance spectroscopies. We found that, in contrast to many prion fragments studied earlier, this pe ptide (i) is highly soluble and does not aggregate up to a millimolar conce ntration range in aqueous medium and (ii) exhibits an intrinsic propensity to a beta -hairpin like conformation at neutral pH. This beta -propensity c an be one of the internal driving forces of the molecular rearrangement res ponsible for the pathogenic conversion of the prion protein.