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β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides

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  • Andrew C Gill

Abstract

Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109–122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109–122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109–122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106–126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies.

Suggested Citation

  • Andrew C Gill, 2014. "β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-17, January.
  • Handle: RePEc:plo:pone00:0087354
    DOI: 10.1371/journal.pone.0087354
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    1. Dominic M. Walsh & Igor Klyubin & Julia V. Fadeeva & William K. Cullen & Roger Anwyl & Michael S. Wolfe & Michael J. Rowan & Dennis J. Selkoe, 2002. "Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo," Nature, Nature, vol. 416(6880), pages 535-539, April.
    2. Rebecca Nelson & Michael R. Sawaya & Melinda Balbirnie & Anders Ø. Madsen & Christian Riekel & Robert Grothe & David Eisenberg, 2005. "Structure of the cross-β spine of amyloid-like fibrils," Nature, Nature, vol. 435(7043), pages 773-778, June.
    3. Da-Wei Li & Sandipan Mohanty & Anders Irbäck & Shuanghong Huo, 2008. "Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment," PLOS Computational Biology, Public Library of Science, vol. 4(12), pages 1-12, December.
    4. Mookyung Cheon & Iksoo Chang & Sandipan Mohanty & Leila M Luheshi & Christopher M Dobson & Michele Vendruscolo & Giorgio Favrin, 2007. "Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils," PLOS Computational Biology, Public Library of Science, vol. 3(9), pages 1-12, September.
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    1. Lulu Ning & Dabo Pan & Yan Zhang & Shaopeng Wang & Huanxiang Liu & Xiaojun Yao, 2015. "Effects of the Pathogenic Mutation A117V and the Protective Mutation H111S on the Folding and Aggregation of PrP106-126: Insights from Replica Exchange Molecular Dynamics Simulations," PLOS ONE, Public Library of Science, vol. 10(5), pages 1-17, May.

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