Molecular Origins of the Compatibility between Glycosaminoglycans and A beta 40 Amyloid Fibrils

Stewart, Katie L, Hughes, Eleri, Yates, Edwin A ORCID: 0000-0001-9365-5433, Middleton, David A and Radford, Sheena E
(2017) Molecular Origins of the Compatibility between Glycosaminoglycans and A beta 40 Amyloid Fibrils. JOURNAL OF MOLECULAR BIOLOGY, 429 (16). 2449 - 2462.

[img] Text
JMB_2017.docx - Accepted Version

Download (3MB)


The Aβpeptide forms extracellular plaques associated with Alzheimer's disease. In addition to protein fibrils,amyloid plaques also contain non-proteinaceous components, including glycosaminoglycans (GAGs). Wehave shown previously that the GAG low-molecular-weight heparin (LMWH) binds to Aβ40 fibrils with athree-fold-symmetric (3Q) morphology with higher affinity than Aβ40 fibrils in alternative structures, Aβ42fibrils, or amyloid fibrils formed from other sequences. Solid-state NMR analysis of the GAG–3Q fibril complexrevealed an interaction site at the corners of the 3Q fibril structure, but the origin of the binding specificityremained obscure. Here, using a library of short heparin polysaccharides modified at specific sites, we showthat theN-sulfate or 6-O-sulfate of glucosamine, but not the 2-O-sulfate of iduronate within heparin is requiredfor 3Q binding, indicating selectivity in the interactions of the GAG with the fibril that extends beyond generalelectrostatic complementarity. By creating 3Q fibrils containing point substitutions in the amino acid sequence,we also show that charged residues at the fibril three-fold apices provide the majority of the binding freeenergy, while charged residues elsewhere are less critical for binding. The results indicate, therefore, thatLMWH binding to 3Q fibrils requires a precise molecular complementarity of the sulfate moieties on the GAGand charged residues displayed on the fibril surface. Differences in GAG binding to fibrils with distinctsequence and/or structure may thus contribute to the diverse etiology and progression of amyloid diseases.© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license(

Item Type: Article
Uncontrolled Keywords: amyloid beta, glycosaminoglycans, Alzheimer's disease, amyloid fibrils, heparin binding
Depositing User: Symplectic Admin
Date Deposited: 14 Jul 2017 09:56
Last Modified: 16 Aug 2022 19:14
DOI: 10.1016/j.jmb.2017.07.003
Related URLs: