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

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Stewart, KL, Hughes, E, Yates, EA ORCID: 0000-0001-9365-5433, Akien, GR, Huang, T-Y, Lima, MA, Rudd, TR ORCID: 0000-0003-4434-0333, Guerrini, M, Hung, S-C, Radford, SE et al (show 1 more authors) and Middleton, DA (2016) Atomic Details of the Interactions of Glycosaminoglycans with Amyloid-beta Fibrils. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 138 (27). pp. 8328-8331.

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Official URL: https://pubs.acs.org/doi/10.1021/jacs.6b02816

Abstract

The amyloid plaques associated with Alzheimer’s disease (AD) comprise fibrillar amyloid-β (Aβ) peptides as well as non-protein factors including glycosaminoglycan (GAG) polysaccharides. GAGs affect the kinetics and pathway of Aβ 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–Aβ fibril interactions from the perspective of the saccharide. Binding analysis indicated that the GAG proxy heparin has a remarkably high affinity for Aβ 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 Aβ40 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.

Item Type:	Article
Uncontrolled Keywords:	nanofibers, peptides and proteins, monomers, nuclear magnetic resonance spectroscopy
Depositing User:	Symplectic Admin
Date Deposited:	05 Oct 2016 15:47
Last Modified:	19 Jan 2023 07:29
DOI:	10.1021/jacs.6b02816
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3003617