5how Citations

X-ray Crystallographic Structures of a Trimer, Dodecamer, and Annular Pore Formed by an Aβ17-36 β-Hairpin.

OpenAccess logo J Am Chem Soc 138 4634-42 (2016)
Related entries: 5hox, 5hoy

Cited: 39 times
EuropePMC logo PMID: 26967810

Abstract

High-resolution structures of oligomers formed by the β-amyloid peptide Aβ are needed to understand the molecular basis of Alzheimer's disease and develop therapies. This paper presents the X-ray crystallographic structures of oligomers formed by a 20-residue peptide segment derived from Aβ. The development of a peptide in which Aβ17-36 is stabilized as a β-hairpin is described, and the X-ray crystallographic structures of oligomers it forms are reported. Two covalent constraints act in tandem to stabilize the Aβ17-36 peptide in a hairpin conformation: a δ-linked ornithine turn connecting positions 17 and 36 to create a macrocycle and an intramolecular disulfide linkage between positions 24 and 29. An N-methyl group at position 33 blocks uncontrolled aggregation. The peptide readily crystallizes as a folded β-hairpin, which assembles hierarchically in the crystal lattice. Three β-hairpin monomers assemble to form a triangular trimer, four trimers assemble in a tetrahedral arrangement to form a dodecamer, and five dodecamers pack together to form an annular pore. This hierarchical assembly provides a model, in which full-length Aβ transitions from an unfolded monomer to a folded β-hairpin, which assembles to form oligomers that further pack to form an annular pore. This model may provide a better understanding of the molecular basis of Alzheimer's disease at atomic resolution.

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  2. The biogenesis and biology of amyloid β oligomers in the brain. Ashe KH. Alzheimers Dement 16 1561-1567 (2020)
  3. Elucidating the Structures of Amyloid Oligomers with Macrocyclic β-Hairpin Peptides: Insights into Alzheimer's Disease and Other Amyloid Diseases. Kreutzer AG, Nowick JS. Acc. Chem. Res. 51 706-718 (2018)
  4. Rosetta Stone for Amyloid Fibrils: The Key Role of Ring-Like Oligomers in Amyloidogenesis. Galzitskaya OV, Selivanova OM. J. Alzheimers Dis. 59 785-795 (2017)
  5. Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer's Disease Development. Urban AS, Pavlov KV, Kamynina AV, Okhrimenko IS, Arseniev AS, Bocharov EV. Molecules 26 2897 (2021)
  6. Exploring amyloid oligomers with peptide model systems. Samdin TD, Kreutzer AG, Nowick JS. Curr Opin Chem Biol 64 106-115 (2021)
  7. High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways. Watanabe-Nakayama T, Sahoo BR, Ramamoorthy A, Ono K. Int J Mol Sci 21 (2020)

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