Crystallographic studies of prion protein (PrP) segments suggest how structural changes encoded by polymorphism at residue 129 modulate susceptibility to human prion disease.
Publication Type:
Journal ArticleSource:
J Biol Chem, Volume 285, Issue 39, p.29671-5 (2010)Keywords:
Amino Acid Substitution, Crystallography, X-Ray, Genetic Predisposition to Disease, Humans, Mutation, Missense, Polymorphism, Single Nucleotide, Prion Diseases, Prions, Protein Structure, Secondary, Structure-Activity RelationshipAbstract:
<p>A single nucleotide polymorphism (SNP) in codon 129 of the human prion gene, leading to a change from methionine to valine at residue 129 of prion protein (PrP), has been shown to be a determinant in the susceptibility to prion disease. However, the molecular basis of this effect remains unexplained. In the current study, we determined crystal structures of prion segments having either Met or Val at residue 129. These 6-residue segments of PrP centered on residue 129 are "steric zippers," pairs of interacting β-sheets. Both structures of these "homozygous steric zippers" reveal direct intermolecular interactions between Met or Val in one sheet and the identical residue in the mating sheet. These two structures, plus a structure-based model of the heterozygous Met-Val steric zipper, suggest an explanation for the previously observed effects of this locus on prion disease susceptibility and progression.</p>