Solid-state NMR studies of the secondary structure of a mutant prion protein fragment of 55 residues that induces neurodegeneration

The secondary structure of a 55-residue fragment of the mouse prion protein, MoPrP(89-143), was studied in randomly aggregated (dried from water) and fibrillar (precipitated from water/ acetonitrile) forms by ¹³C solid-state NMR. Recent studies have shown that the fibrillar form of the P101L mutant of MoPrP(89-143) is capable of inducing prion disease in transgenic mice, whereas unaggregated or randomly aggregated samples do not provoke disease. Through analysis of 13C chemical shifts, we have determined that both wild-type and mutant sequence MoPrP(89-143) form a mixture of β-sheet and α-helical conformations in the randomly aggregated state although the β-sheet content in MoPrP(89-143, P101L) is significantly higher than in the wild-type peptide. In a fibrillar state, MoPrP(89-143, P101L) is completely converted into β-sheet, suggesting that the formation of a specific β-sheet structure may be required for the peptide to induce disease. Studies of an analogous peptide from Syrian hamster PrP verify that sequence alterations in residues 101-117 affect the conformation of aggregated forms of the peptides.