Aneta T. Petkova1, Yoshitaka Ishii1, John J. Balbach1, Oleg N. Antzutkin1, Richard D. Leapman1, Frank Delaglio1, Robert Tycko1
1Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520; Department of Chemistry, Luleå University of Technology, Luleå, Sweden S-97187; and Division of Bioengineering and Physical Science, Office of Research Services, National Institutes of Health, Bethesda, MD 20892-5766
Tóm tắt
We present a structural model for amyloid fibrils formed by the 40-residue β-amyloid peptide associated with Alzheimer's disease (Aβ
1–40
), 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 Aβ
1–40
fibril dimensions and mass-per-length determined from electron microscopy. Approximately the first 10 residues of Aβ
1–40
are 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.
