Conserved amyloid core structure of stop mutants of the human prion protein |
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Authors: | Markus Zweckstetter |
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Affiliation: | 1.Department for NMR-based Structural Biology; Max Planck Institute for Biophysical Chemistry; Göttingen, Germany;2.German Center for Neurodegenerative Diseases (DZNE); Göttingen, Germany |
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Abstract: | Prion diseases are associated with misfolding of the natively α-helical prion protein into isoforms that are rich in cross β-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 β-helix. The polymorphic residue 129 is located in the hydrophobic core of the β-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 β-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. |
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Keywords: | prion structure amyloid stop mutant trimer |
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