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

ABSTRACT

Alzheimer's disease is the most common form of dementia in humans and is related to the accumulation of the amyloid-ß (Aß) peptide and its interaction with metals (Cu, Fe, and Zn) in the brain. Crystallographic structural information about Aß 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 Aß 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-Aß N-terminal antibody WO2. The structure demonstrates that Aß 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 Aß (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 Aß1-16 fragment implicated in Aß metal binding. This novel structure, therefore, has the potential to provide a foundation for investigating the effect of metal ion binding to Aß 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 Aß metal-binding-induced neurotoxicity.