Atomic Details of the Interactions of Glycosaminoglycans with Amyloid-β Fibrils.
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 (13)C-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 (13)C-(15)N 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.
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds , Leeds LS2 9JT, United Kingdom.
Katie L
KL
Stewart
Department of Chemistry, University of Lancaster , Lancaster LA1 4YB, United Kingdom.
Eleri
E
Hughes
Department of Biochemistry, Institute of Integrative Biology, University of Liverpool , Liverpool L69 7ZB, United Kingdom.
Edwin A
EA
Yates
Department of Chemistry, University of Lancaster , Lancaster LA1 4YB, United Kingdom.
Geoffrey R
GR
Akien
Genomics Research Center, Academia Sinica , No. 128, Section 2, Academia Road, Taipei 115, Taiwan.
Teng-Yi
TY
Huang
Department of Biochemistry, Federal University of Sao Paulo , Rua Três de Maio, São Paulo 40440-020, Brazil.
Marcelo A
MA
Lima
National Institute of Biological Standards and Control , South Mimms, Potters Bar, Hertfordshire EN6 3QC, United Kingdom.
Timothy R
TR
Rudd
Ronzoni Institute for Chemical and Biochemical Research , Via G. Colombo 81, Milano 20133 Italy.
Marco
M
Guerrini
Department of Biochemistry, Institute of Integrative Biology, University of Liverpool , Liverpool L69 7ZB, United Kingdom.
Shang-Cheng
SC
Hung
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds , Leeds LS2 9JT, United Kingdom.
Sheena E
SE
Radford
Department of Chemistry, University of Lancaster , Lancaster LA1 4YB, United Kingdom.
David A
DA
Middleton
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D006025:Glycosaminoglycans; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)