J Biol Chem
Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Published: February 2013
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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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561524 | PMC |
http://dx.doi.org/10.1074/jbc.M112.423715 | DOI Listing |
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