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

dc.contributor.authorStewart, Katie L.
dc.contributor.authorHughes, Eleri
dc.contributor.authorYates, Edwin A.
dc.contributor.authorAkien, Geoffrey R.
dc.contributor.authorHuang, Teng-Yi
dc.contributor.authorLima, Marcelo A.
dc.contributor.authorRudd, Timothy R.
dc.contributor.authorGuerrini, Marco [UNIFESP]
dc.contributor.authorHung, Shang-Cheng
dc.contributor.authorRadford, Sheena E.
dc.contributor.authorMiddleton, David A.
dc.description.abstractThe amyloid plaques associated with Alzheimer's disease (AD) comprise fibrillar amyloid-beta (A beta) peptides as well as non-protein factors including glycosaminoglycan (GAG) polysaccharides. GAGs affect the kinetics and pathway of A beta self-assembly and can impede fibril clearanceen
dc.description.abstractthus, they may be accessory molecules in AD. Here we report the first high-resolution details of GAG-A beta fibril interactions from the perspective of the saccharide. Binding analysis indicated that the GAG proxy heparin has a remarkably high affinity for A beta fibrils with 3-fold cross-sectional symmetry (3Q). Chemical synthesis of a uniformly C-13-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 C-13-N-15 dipolar dephasing is consistent with close (<5 angstrom) 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 A beta 40 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.en
dc.description.affiliationUniv Leeds, Sch Mol & Cellular Biol, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England
dc.description.affiliationUniv Lancaster, Dept Chem, Lancaster LA1 4YB, England
dc.description.affiliationUniv Liverpool, Dept Biochem, Inst Integrat Biol, Liverpool L69 7ZB, Merseyside, England
dc.description.affiliationAcad Sinica, Genom Res Ctr, 128,Sect 2,Acad Rd, Taipei 115, Taiwan
dc.description.affiliationUniv Fed Sao Paulo, Dept Biochem, Rua Tres Maio, BR-40440020 Sao Paulo, Brazil
dc.description.affiliationNatl Inst Biol Stand & Controls, Potters Bar EN6 3QC, Herts, England
dc.description.affiliationRonzoni Inst Chem & Biochem Res, Via G Colombo 81, I-20133 Milan, Italy
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Biochem, Rua Tres Maio, BR-40440020 Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipBBSRC (UK)
dc.description.sponsorshipAcademia Sinica
dc.description.sponsorshipMinistry of Science and Technology
dc.description.sponsorshipUniversity of Warwick
dc.description.sponsorshipBirmingham Science City Advanced Materials
dc.description.sponsorshipAdvantage West Midlands
dc.description.sponsorshipEuropean Regional Development Fund
dc.description.sponsorshipIDBBSRC (UK): BB/K01451X/1
dc.description.sponsorshipIDBBSRC (UK): BB/K015958/1
dc.description.sponsorshipIDMinistry of Science and Technology: MOST 104-0210-01-09-02
dc.description.sponsorshipIDMinistry of Science and Technology: 104-2628-M-001-001
dc.identifier.citationJournal Of The American Chemical Society. Washington, v. 138, n. 27, p. 8328-8331, 2016.
dc.publisherAmer Chemical Soc
dc.relation.ispartofJournal Of The American Chemical Society
dc.rightsAcesso restrito
dc.titleAtomic Details of the Interactions of Glycosaminoglycans with Amyloid-beta Fibrilsen