title: Structural studies of the tethered N-terminus of the Alzheimer's disease amyloid-β peptide.
abstract: 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.
authors.affiliation: Materials Science and Engineering & Preventative Health Flagship, CSIRO, Parkville, Victoria, 3052, Australia.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Nisbet
authors.forename: Stewart D
authors.initials: SD
authors.lastname: Nuttall
authors.forename: Remy
authors.initials: R
authors.lastname: Robert
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Caine
authors.forename: Olan
authors.initials: O
authors.lastname: Dolezal
authors.forename: Meghan
authors.initials: M
authors.lastname: Hattarki
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Pearce
authors.forename: Natalia
authors.initials: N
authors.lastname: Davydova
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Jose N
authors.initials: JN
authors.lastname: Varghese
authors.forename: Victor A
authors.initials: VA
authors.lastname: Streltsov
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D011993:Recombinant Fusion Proteins
keywords: Alzheimer's disease; Aβ crystal structure; Im7; WO-2 Fab; amyloid-β