Structural studies of the tethered N-terminus of the Alzheimer's disease amyloid-β peptide

Proteins. 2013 Oct;81(10):1748-58. doi: 10.1002/prot.24312. Epub 2013 Jul 22.


Alzheimer's disease is the most common form of dementia in humans and is related to the accumulation of the amyloid-β (Aβ) peptide and its interaction with metals (Cu, Fe, and Zn) in the brain. Crystallographic structural information about Aβ peptide deposits and the details of the metal-binding site is limited owing to the heterogeneous nature of aggregation states formed by the peptide. Here, we present a crystal structure of Aβ residues 1-16 fused to the N-terminus of the Escherichia coli immunity protein Im7, and stabilized with the fragment antigen binding fragment of the anti-Aβ N-terminal antibody WO2. The structure demonstrates that Aβ residues 10-16, which are not in complex with the antibody, adopt a mixture of local polyproline II-helix and turn type conformations, enhancing cooperativity between the two adjacent histidine residues His13 and His14. Furthermore, this relatively rigid region of Aβ (residues, 10-16) appear as an almost independent unit available for trapping metal ions and provides a rationale for the His13-metal-His14 coordination in the Aβ1-16 fragment implicated in Aβ metal binding. This novel structure, therefore, has the potential to provide a foundation for investigating the effect of metal ion binding to Aβ and illustrates a potential target for the development of future Alzheimer's disease therapeutics aimed at stabilizing the N-terminal monomer structure, in particular residues His13 and His14, and preventing Aβ metal-binding-induced neurotoxicity.

Keywords: Alzheimer's disease; Aβ crystal structure; Im7; WO-2 Fab; amyloid-β.

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / metabolism
  • Escherichia coli
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / genetics
  • Immunoglobulin Fab Fragments / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Recombinant Fusion Proteins / chemistry*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism


  • Amyloid beta-Peptides
  • Antibodies, Monoclonal
  • Immunoglobulin Fab Fragments
  • Recombinant Fusion Proteins

Associated data

  • PDB/4F37