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Peptide Dimer Structure in an Aβ(1-42) Fibril Visualized with Cryo-EM

TitlePeptide Dimer Structure in an Aβ(1-42) Fibril Visualized with Cryo-EM
Publication TypeJournal Article
Year of Publication2015
AuthorsSchmidt, M, Rohou A, Lasker K, Yadav JK, Schiene-Fischer C, Fandrich M, Grigorieff N
Refereed DesignationRefereed
JournalProc Natl Acad Sci U S A
Volume112
Pagination11858-11863
KeywordsCross-β, Frealix, Protein aggregation, Protein Folding
Abstract

Alzheimer’s disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) peptide oligomers and fibrils. These structures may damage the brain and give rise to cerebral amyloid angiopathy (CAA), neuronal dysfunction, and cellular toxicity. Although the connection between Alzheimer’s disease and Aβ fibrillation is extensively documented, much is still unknown about the formation of these Aβ aggregates and their structures at the molecular level. Here, we combined electron cryo-microscopy, three-dimensional reconstruction, and integrative structural modeling methods to determine the molecular architecture of a fibril formed by Aβ(1-42), a particularly pathogenic variant of Aβ peptide. Our model reveals that the individual layers of the Aβ fibril are formed by peptide dimers with face-to-face packing. The two peptides forming the dimer possess identical tilde-shaped conformations and interact with each other by packing of their hydrophobic C-terminal β-strands. The peptide C-termini are located close to the main fibril axis, where they produce a hydrophobic core and are surrounded by the structurally more flexible and charged segments of the peptide N-termini. The observed molecular architecture is compatible with the general chemical properties of Aβ peptide and provides a structural basis for various biological observations that illuminate the molecular underpinnings of AD. Moreover, it provides direct evidence for a steric zipper within a fibril formed by full-length Aβ peptide.

DOI10.1073/pnas.1503455112
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