Publication Abstract from PubMed
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 due 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 E. coli immunity protein Im7, and stabilized with the Fab 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 (PPII) helix and turn type conformations, enhancing co-operativity 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 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. (c) Proteins 2013;. (c) 2013 Wiley Periodicals, Inc.
Structural studies of the tethered N-terminus of the Alzheimer's disease Abeta peptide.,Nisbet RM, Nuttall SD, Robert R, Caine JM, Dolezal O, Hattarki M, Pearce LA, Davydova N, Masters CL, Varghese JN, Streltsov VA Proteins. 2013 Apr 23. doi: 10.1002/prot.24312. PMID:23609990[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
