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.-Y., Andrade De Lima, M., Rudd, T. R., Guerrini, M., Hung, S.-C., Radford, S. E., & 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
• Electronic ISSN: 1520-5126
• Publisher: American Chemical Society
• Volume: 138
• Issue: 27
• Pages: 8328-8331
• DOI: https://doi.org/10.1021/jacs.6b02816
• Public URL: https://keele-repository.worktribe.com/output/413637
• Publisher URL: https://pubs.acs.org/doi/abs/10.1021/jacs.6b02816