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キーワード:
Prions, amyloid, NMR, mass spectrometry, aggregation
要旨:
Misfolding of the natively alpha-helical prion protein into a beta-sheet rich isoform is related to various human diseases such as Creutzfeldt-Jakob disease and Gerstmann-Straeussler-Scheinker-like syndrome. In humans the disease phenotype is modified by a methionine/valine polymorphism at codon 129 of the prion protein gene. Using a combination of H/D exchange coupled to NMR spectroscopy, hydroxyl radical probing detected by mass spectrometry and site-directed mutagenesis we demonstrate that stop mutants of the human prion protein have a conserved amyloid core. The 129 residue is deeply buried in the amyloid core structure and its mutation strongly impacts aggregation. Taken together the data support a critical role of the polymorphic residue 129 of the human prion protein in aggregation and disease.
