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.