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

• 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
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.262663499

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.