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Journal Article

Turn plasticity distinguishes different modes of amyloid-beta aggregation.

MPS-Authors
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Rezaei-Ghaleh,  N.
Research Group of Protein Strcture Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Giller,  K.
Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Becker,  S.
Department of NMR-Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter,  M.
Research Group of Protein Strcture Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

External Ressource
Fulltext (public)

2026427.pdf
(Publisher version), 3MB

Supplementary Material (public)

2026427_Suppl.pdf
(Supplementary material), 2MB

Citation

Rezaei-Ghaleh, N., Amininasab, M., Giller, K., Kumar, S., Stuendl, A., Schneider, A., et al. (2014). Turn plasticity distinguishes different modes of amyloid-beta aggregation. Journal of the American Chemical Society, 136(13), 4913-4919. doi:10.1021/ja411707y.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0019-7739-8
Abstract
Pathogenesis of Alzheimer's disease (AD) is associated with aggregation of the amyloid-beta (A beta) peptide into oligomeric and fibrillar assemblies; however, little is known about the molecular basis of aggregation of A beta into distinct assembly states. Here we demonstrate that phosphorylation at serine 26 (S26) impairs A beta fibrillization while stabilizing its monomers and nontoxic soluble assemblies of nonfibrillar morphology. NMR spectroscopy and replica-exchange molecular dynamics indicate that introduction of a phosphate group or phosphomimetic at position 26 diminishes A beta's propensity to form a beta-hairpin, rigidifies the region around the modification site, and interferes with formation of a fibril-specific salt bridge between aspartic acid 23 and lysine 28. The combined data demonstrate that phosphorylation of S26 prevents a distinct conformational rearrangement that is required for progression of A beta aggregation toward fibrils and provide a basis for a possible role of phosphorylation at serine 26 in AD.