TY - JOUR
T1 - Structural studies of the tethered N-terminus of the Alzheimer's disease amyloid-beta peptide
AU - Nisbet, Rebecca M
AU - Nuttall, Stewart N
AU - Robert, Remy
AU - Caine, Joanne M
AU - Dolezal, Olan
AU - Hattarki, Meghan
AU - Pearce, Lesley A
AU - Davydova, Natalia
AU - Masters, Colin Louis
AU - Varghese, Jose N
AU - Streltsov, Victor A
PY - 2013
Y1 - 2013
N2 - 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 owing 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 Escherichia coli immunity protein Im7, and stabilized with the fragment antigen binding 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-helix and turn type conformations, enhancing cooperativity 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 the 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.
AB - 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 owing 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 Escherichia coli immunity protein Im7, and stabilized with the fragment antigen binding 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-helix and turn type conformations, enhancing cooperativity 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 the 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.
UR - http://onlinelibrary.wiley.com/doi/10.1002/prot.24312/pdf
U2 - 10.1002/prot.24312
DO - 10.1002/prot.24312
M3 - Article
SN - 0887-3585
VL - 81
SP - 1748
EP - 1758
JO - Proteins: Structure, Function and Bioinformatics
JF - Proteins: Structure, Function and Bioinformatics
IS - 10
ER -