National Center for
4WBU: prion peptide
Crystal Structures of Polymorphic Prion Protein beta1 Peptides Reveal Variable Steric Zipper Conformations
Biochemistry (2015) 54 p.3640-3648
The pathogenesis of prion diseases is associated with the conformational conversion of normal, predominantly alpha-helical prion protein (PrP(C)) into a pathogenic form that is enriched with beta-sheets (PrP(Sc)). Several PrP(C) crystal structures have revealed beta1-mediated intermolecular sheets, suggesting that the beta1 strand may contribute to a possible initiation site for beta-sheet-mediated PrP(Sc) propagation. This beta1 strand contains the polymorphic residue 129 that influences disease susceptibility and phenotype. To investigate the effect of the residue 129 polymorphism on the conformation of amyloid-like continuous beta-sheets formed by beta1, crystal structures of beta1 peptides containing each of the polymorphic residues were determined. To probe the conformational influence of the peptide construct design, four different lengths of beta1 peptides were studied. From the 12 peptides studied, 11 yielded crystal structures ranging in resolution from 0.9 to 1.4 A. This ensemble of beta1 crystal structures reveals conformational differences that are influenced by both the nature of the polymorphic residue and the extent of the peptide construct, indicating that comprehensive studies in which peptide constructs vary are a more rigorous approach to surveying conformational possibilities.