Atomic Details of the Interactions of Glycosaminoglycans with Amyloid-beta Fibrils

Stewart, Katie L.; Hughes, Eleri; Yates, Edwin A.; Akien, Geoffrey R.; Huang, Teng-Yi; Andrade De Lima, M; Rudd, Timothy R.; Guerrini, Marco; Hung, Shang-Cheng; Radford, Sheena E.; Middleton, David A.

Abstract

The amyloid plaques associated with Alzheimer’s disease (AD) comprise fibrillar amyloid-ß (Aß) peptides as well as non-protein factors including glycosaminoglycan (GAG) polysaccharides. GAGs affect the kinetics and pathway of Aß self-assembly and can impede fibril clearance; thus, they may be accessory molecules in AD. Here we report the first high-resolution details of GAG–Aß fibril interactions from the perspective of the saccharide. Binding analysis indicated that the GAG proxy heparin has a remarkably high affinity for Aß fibrils with 3-fold cross-sectional symmetry (3Q). Chemical synthesis of a uniformly 13C-labeled octasaccharide heparin analogue enabled magic-angle spinning solid-state NMR of the GAG bound to 3Q fibrils, and measurements of dynamics revealed a tight complex in which all saccharide residues are restrained without undergoing substantial conformational changes. Intramolecular 13C–15N dipolar dephasing is consistent with close (<5 Å) contact between GAG anomeric position(s) and one or more histidine residues in the fibrils. These data provide a detailed model for the interaction between 3Q-seeded Aß40 fibrils and a major non-protein component of AD plaques, and they reveal that GAG–amyloid interactions display a range of affinities that critically depend on the precise details of the fibril architecture.

Citation

Stewart, K. L., Hughes, E., Yates, E. A., Akien, G. R., Huang, T., Andrade De Lima, M., …Middleton, D. A. (2016). Atomic Details of the Interactions of Glycosaminoglycans with Amyloid-beta Fibrils. Journal of the American Chemical Society, 138(27), 8328-8331. https://doi.org/10.1021/jacs.6b02816

• Journal Article Type: Article
• Acceptance Date: Mar 17, 2016
• Publication Date: Jul 13, 2016
• Publicly Available Date: May 26, 2023
• Journal: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• Print ISSN: 0002-7863
• Publisher: American Chemical Society
• Volume: 138
• Issue: 27
• Pages: 8328-8331
• DOI: https://doi.org/10.1021/jacs.6b02816
• Publisher URL: https://pubs.acs.org/doi/abs/10.1021/jacs.6b02816