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

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. and Streltsov, Victor A. (2013) Structural studies of the tethered N-terminus of the Alzheimer's disease amyloid-beta peptide. Proteins, 81 10: 1748-1758. doi:10.1002/prot.24312


Author 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.
Title Structural studies of the tethered N-terminus of the Alzheimer's disease amyloid-beta peptide
Formatted title
Structural studies of the tethered N-terminus of the Alzheimer's disease amyloid-β peptide
Journal name Proteins   Check publisher's open access policy
ISSN 0887-3585
1097-0134
Publication date 2013-10-01
Sub-type Article (original research)
DOI 10.1002/prot.24312
Volume 81
Issue 10
Start page 1748
End page 1758
Total pages 11
Place of publication Hoboken, NJ, United States
Publisher Jossey Bass, Ed. & Pub.
Collection year 2014
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Queensland Brain Institute Publications
 
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Created: Thu, 06 Mar 2014, 23:44:31 EST by Rebecca Nisbet on behalf of Clem Jones Centre for Ageing Dementia Research