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

• Published in: Proteins, structure, function, and bioinformatics Vol. 81; no. 10; pp. 1748 - 1758
• Main Authors: Nisbet, Rebecca M, Nuttall, Stewart D, Robert, Remy, Caine, Joanne M, Dolezal, Olan, Hattarki, Meghan, Pearce, Lesley A, Davydova, Natalia, Masters, Colin L, Varghese, Jose N, Streltsov, Victor A
• Format: Journal Article
• Language: English
• Published: Hokoben Wiley Subscription Services, Inc 01-10-2013
• Subjects: Escherichia coli
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.24312

Alzheimer's disease is the most common form of dementia in humans and is related to the accumulation of the amyloid-[beta] (A[beta]) peptide and its interaction with metals (Cu, Fe, and Zn) in the brain. Crystallographic structural information about A[beta] 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 A[beta] 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-A[beta] N-terminal antibody WO2. The structure demonstrates that A[beta] 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 A[beta] (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 A[beta]1-16 fragment implicated in A[beta] metal binding. This novel structure, therefore, has the potential to provide a foundation for investigating the effect of metal ion binding to A[beta] 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 A[beta] metal-binding-induced neurotoxicity.Proteins 2013; 81:1748-1758. © 2013 Wiley Periodicals, Inc. [PUBLICATION ABSTRACT]