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J Biol Chem. 2013 Feb 1;288(5):2994-3002. doi: 10.1074/jbc.M112.423715. Epub 2012 Dec 3.

Burial of the polymorphic residue 129 in amyloid fibrils of prion stop mutants.

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Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.


Misfolding of the natively α-helical prion protein into a β-sheet rich isoform is related to various human diseases such as Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker 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 hydrogen/deuterium 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.

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