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- W1993476629 abstract "Understanding the structural transitions that amyloid proteins undergo during amyloidogenesis would greatly enhance our understanding of this process. However, our knowledge has been currently largely limited to global conformational changes, with high-resolution structural information only available for the monomeric proteins and for a few structures of the final amyloid product. In particular, high-resolution structures of intermediate states have been notoriously absent with few exceptions. We show here that high-resolution structures of intermediates can be obtained by using SOFAST-HMQC, CPMG, NOESY, magic-angle-spinning, and other experiments in real-time to track the aggregation pathway at atomic-level detail and at a time-resolution of minutes. As examples, we show the aggregation pathways of Aβ and IAPP, two initially unstructured peptides implicated in Alzheimer's and type II Diabetes, respectively.While previous studies commonly show the Aβ1-40 is largely unstructured in solution before the formation of β-sheet oligomers, we show that Aβ1-40 gradually adopts a compact, partially folded helical structure over a period of several days. In this structure, the central hydrophobic region of the peptide forms a 310 helix from H13 to D23 and the N- and C-termini collapse against the helix due to the clustering of hydrophobic residues (pdb:2LFM). The formation of the helical intermediate is concentration dependent and can be partially reversed by dilution of the peptide. Helical intermediates have been predicted to be crucial on-pathway intermediates in amyloid fibrillogenesis, and the structure presented here presents a new target for structure-based intervention, shown here by the interaction of the helical intermediate with polyphenols. By contrast, the more amyloidogenic IAPP peptide shows only a gradual transition to the fiber form after an initial pH dependent formation of a micelle-like aggregate, with distinct β-sheet small oligomers forming only a small fraction of the observable population." @default.
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- W1993476629 date "2012-01-01" @default.
- W1993476629 modified "2023-09-29" @default.
- W1993476629 title "Tracking Conformational Changes during Amyloidogenesis in Real-Time at Atomic-Resolution by NMR" @default.
- W1993476629 doi "https://doi.org/10.1016/j.bpj.2011.11.1334" @default.
- W1993476629 hasPublicationYear "2012" @default.
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