Crystal Structures of Polymorphic Prion Protein β1
Peptides Reveal Variable Steric Zipper Conformations
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Abstract
The
pathogenesis of prion diseases is associated with the conformational
conversion of normal, predominantly α-helical prion protein
(PrP<sup>C</sup>) into a pathogenic form that is enriched with β-sheets
(PrP<sup>Sc</sup>). Several PrP<sup>C</sup> crystal structures have
revealed β1-mediated intermolecular sheets, suggesting that
the β1 strand may contribute to a possible initiation site for
β-sheet-mediated PrP<sup>Sc</sup> propagation. This β1
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 β-sheets
formed by β1, crystal structures of β1 peptides containing
each of the polymorphic residues were determined. To probe the conformational
influence of the peptide construct design, four different lengths
of β1 peptides were studied. From the 12 peptides studied, 11
yielded crystal structures ranging in resolution from 0.9 to 1.4 Å.
This ensemble of β1 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