3D structure of Alzheimer's amyloid-beta(1-42) fibrils

Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7. doi: 10.1073/pnas.0506723102. Epub 2005 Nov 17.


Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (Abeta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Abeta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a beta-strand-turn-beta-strand motif that contains two intermolecular, parallel, in-register beta-sheets that are formed by residues 18-26 (beta1) and 31-42 (beta2). At least two molecules of Abeta(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand beta1 of the nth molecule and the even-numbered residues of strand beta2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Abeta fibril growth. It also provides a structural basis for fibrillization inhibitors.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amino Acid Sequence
  • Amyloid / chemistry*
  • Amyloid / genetics
  • Deuterium
  • Humans
  • Hydrogen
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutagenesis
  • Nitrogen Isotopes
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation


  • Amyloid
  • Nitrogen Isotopes
  • Hydrogen
  • Deuterium

Associated data

  • PDB/2BEG