4F37

Structure of the tethered N-terminus of Alzheimer's disease A peptide

Summary for 4F37

• Entry DOI: 10.2210/pdb4f37/pdb
• Related: 1AYI 3BKJ
• Descriptor: Colicin-E7 immunity protein, Im7 immunity protein, Fab WO2 anti-amyloid-beta antibody Fab fragment, ... (4 entities in total)
• Functional Keywords: amyloid-beta, alzheimer's disease, immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 6
• Total formula weight: 126379.85

Authors

Nisbet, R.M.,Nuttall, S.D.,Caine, J.M.,Rober, R.,Hittaki, M.,Pearce, L.A.,Davydova, N.,Masters, C.L.,Varghese, J.N.,Streltsov, V.A. (deposition date: 2012-05-09, release date: 2013-05-15, Last modification date: 2024-11-13)

Primary citation

Nisbet, R.M.,Nuttall, S.D.,Robert, R.,Caine, J.M.,Dolezal, O.,Hattarki, M.,Pearce, L.A.,Davydova, N.,Masters, C.L.,Varghese, J.N.,Streltsov, V.A.
Structural studies of the tethered N-terminus of the Alzheimer's disease amyloid-beta peptide.
Proteins, 81:1748-1758, 2013

PubMed 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.

PubMed: 23609990
DOI: 10.1002/prot.24312

Experimental method

X-RAY DIFFRACTION (2.57 Å)