A Structural Model for Alzheimer's β-Amyloid Fibrils Based on Experimental Constraints from Solid State NMR

We present a structural model for amyloid fibrils formed by the 40-residue β-amyloid peptide associated with Alzheimer's disease (Aβ1-40), based on a set of experimental constraints from solid state NMR spectroscopy. The model additionally incorporates the cross-β structural motif established b...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-12, Vol.99 (26), p.16742-16747
Main Authors: Petkova, Aneta T., Ishii, Yoshitaka, Balbach, John J., Antzutkin, Oleg N., Leapman, Richard D., Delaglio, Frank, Tycko, Robert
Format: Article
Language:English
Subjects:
Alzheimer's disease
Alzheimers disease
Amino Acid Sequence
Amyloid beta-Peptides - chemistry
Amyloids
Biochemistry
Biological Sciences
Biophysics
Chemical equilibrium
Chemistry of Interfaces
Disease models
Electrostatics
Gränsytors kemi
Humans
Models, Molecular
Molecular Sequence Data
Molecular structure
NMR
Nuclear magnetic resonance
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments - chemistry
Peptides
Protein Structure, Secondary
Salts
Solar fibrils
Spectral correlation
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Summary:We present a structural model for amyloid fibrils formed by the 40-residue β-amyloid peptide associated with Alzheimer's disease (Aβ1-40), based on a set of experimental constraints from solid state NMR spectroscopy. The model additionally incorporates the cross-β structural motif established by x-ray fiber diffraction and satisfies constraints on Aβ1-40fibril dimensions and mass-per-length determined from electron microscopy. Approximately the first 10 residues of Aβ1-40are structurally disordered in the fibrils. Residues 12-24 and 30-40 adopt β-strand conformations and form parallel β-sheets through intermolecular hydrogen bonding. Residues 25-29 contain a bend of the peptide backbone that brings the two β-sheets in contact through sidechain-sidechain interactions. A single cross-β unit is then a double-layered β-sheet structure with a hydrophobic core and one hydrophobic face. The only charged sidechains in the core are those of D23 and K28, which form salt bridges. Fibrils with minimum mass-per-length and diameter consist of two cross-β units with their hydrophobic faces juxtaposed.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.262663499