Katie L. Stewart
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.
Authors
Eleri Hughes
Edwin A. Yates
Geoffrey R. Akien
Teng-Yi Huang
Marcelo Andrade De Lima m.andrade.de.lima@keele.ac.uk
Timothy R. Rudd
Marco Guerrini
Shang-Cheng Hung
Sheena E. Radford
David A. Middleton
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.
Journal Article Type | Article |
---|---|
Acceptance Date | Mar 17, 2016 |
Publication Date | Jul 13, 2016 |
Publicly Available Date | Mar 29, 2024 |
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 |
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