Crystal Structures of Polymorphic Prion Protein 尾1 Peptides Reveal Variable Steric Zipper Conformations

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• 作者：Lu Yu ; Seung-Joo Lee ; Vivien C. Yee
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：June 16, 2015
• 年：2015
• 卷：54
• 期：23
• 页码：3640-3648
• 全文大小：423K
• ISSN：1520-4995

文摘

The pathogenesis of prion diseases is associated with the conformational conversion of normal, predominantly 伪-helical prion protein (PrP^C) into a pathogenic form that is enriched with 尾-sheets (PrP^Sc). Several PrP^C crystal structures have revealed 尾1-mediated intermolecular sheets, suggesting that the 尾1 strand may contribute to a possible initiation site for 尾-sheet-mediated PrP^Sc propagation. This 尾1 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 尾-sheets formed by 尾1, crystal structures of 尾1 peptides containing each of the polymorphic residues were determined. To probe the conformational influence of the peptide construct design, four different lengths of 尾1 peptides were studied. From the 12 peptides studied, 11 yielded crystal structures ranging in resolution from 0.9 to 1.4 脜. This ensemble of 尾1 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.