Atomic details of the interactions of Glycosaminoglycans with amyloid-β fibrils

Stewart, Katie and Hughes, Eleri and Yates, Edwin and Akien, Geoffrey Richard and Huang, Teng-Yi and Lima, Marcelo and Rudd, Timothy and Guerrini, Marco and Hung, Shang-Cheng and Radford, Sheena and Middleton, David Andrew (2016) Atomic details of the interactions of Glycosaminoglycans with amyloid-β fibrils. Journal of the American Chemical Society, 138 (27). pp. 8328-8331. ISSN 0002-7863

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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:
Journal Article
Journal or Publication Title:
Journal of the American Chemical Society
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1500/1503
Subjects:
ID Code:
80023
Deposited By:
Deposited On:
15 Nov 2016 09:18
Refereed?:
Yes
Published?:
Published
Last Modified:
06 May 2020 04:22