title: Burial of the polymorphic residue 129 in amyloid fibrils of prion stop mutants.
abstract: 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.
authors.affiliation: Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Skora
authors.forename: Luis
authors.initials: L
authors.lastname: Fonseca-Ornelas
authors.forename: Romina V
authors.initials: RV
authors.lastname: Hofele
authors.forename: Dietmar
authors.initials: D
authors.lastname: Riedel
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.forename: Jens
authors.initials: J
authors.lastname: Watzlawik
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Schulz-Schaeffer
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics*; D002498:Centrifugation; D018388:Codon, Terminator / Q000235:genetics*; D006801:Humans; D008715:Methionine / Q000235:genetics; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic; D011328:Prions / Q000737:chemistry / Q000235:genetics*; D020836:Protein Structure, Quaternary; D012997:Solvents
chemical_list: D000682:Amyloid; D018388:Codon, Terminator; D050505:Mutant Proteins; D011328:Prions; D012997:Solvents; D008715:Methionine