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Abstract:
Prion diseases are associated with misfolding of the natively -helical prion protein into isoforms that are rich in cross -structure. However, both the mechanism by which pathological conformations are produced and their structural properties remain unclear. Using a combination of nuclear magnetic resonance spectroscopy, computation, hydroxyl radical probing combined with mass-spectrometry and site-directed mutagenesis, we showed that prion stop mutants that accumulate in amyloidogenic plaque-forming aggregates fold into a -helix. The polymorphic residue 129 is located in the hydrophobic core of the -helix in line with a critical role of the 129 region in the packing of protein chains into prion particles. Together with electron microscopy our data support a trimeric left-handed -helix model in which the trimer interface is formed by residues L125, Y128 and L130. Different prion types or strains might be related to different aggregate structures or filament assemblies.
