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.
Edwin A. Yates
Geoffrey R. Akien
Marcelo Andrade De Lima firstname.lastname@example.org
Timothy R. Rudd
Sheena E. Radford
David A. Middleton
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
|Mar 17, 2016
|Jul 13, 2016
|Publicly Available Date
|May 26, 2023
|JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
|American Chemical Society
M Lima - Atomic details of the interactions of glycisaminoglycans with amyloid-beta fibrils.pdf
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