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

Rebecca M Nisbet, Stewart N Nuttall, Remy Robert, Joanne M Caine, Olan Dolezal, Meghan Hattarki, Lesley A Pearce, Natalia Davydova, Colin Louis Masters, Jose N Varghese, Victor A Streltsov

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    21 Citations (Scopus)

    Abstract

    Alzheimer s disease is the most common form of dementia in humans and is related to the accumulation of the amyloid-beta (Abeta) peptide and its interaction with metals (Cu, Fe, and Zn) in the brain. Crystallographic structural information about Abeta 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 Abeta 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-Abeta N-terminal antibody WO2. The structure demonstrates that Abeta 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 Abeta (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 Abeta1-16 fragment implicated in Abeta metal binding. This novel structure, therefore, has the potential to provide a foundation for investigating the effect of metal ion binding to Abeta 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 Abeta metal-binding-induced neurotoxicity.
    Original languageEnglish
    Pages (from-to)1748 - 1758
    Number of pages11
    JournalProteins: Structure, Function and Bioinformatics
    Volume81
    Issue number10
    DOIs
    Publication statusPublished - 2013

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