Structural studies about abeta by Masters et al, in Proteins Apr.23, 2013
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 due 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 E. coli immunity protein Im7, and stabilized with the Fab 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 (PPII) helix and turn type conformations, enhancing co-operativity 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 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
I believe this novel structure offers a model system for studying the metal binding site of Abeta. How does the metal binding lead to oligomer formation? How does the metal binding lead to structural changes which favor dimer formation and so on. These can be investigated with a good model.
And of course, what drug molecules make the monomer more stable, and therefore favor its formation, preventing toxicity. It's interesting that only one stereo-isomer (i forget, left or right) is toxic. Altering the conformation, blocking key binding sites in the oligomers - all questions that can be studied with a good model.
Of course, this model is a crystal structure, which is a solid. That's not how Abeta is present in the cell, or rather in vivo. Solvent effects could make the model more or less relevant. But in any event, this structure provides a great way to gain insight into Abeta toxicity at a very low level. Atom to atom interactions.
In the YouTube video, he explains how frustrating it has been to characterize this little 40 something residue
protein. Tough little nut to crack I guess, figures.
Does this mean they have now identified the structure of domains13,14 &15 he spoke about at the 13min mark of the YouTube clip "Laureate Professor Colin L Masters on Alzheimer's disease"
That is the same lecture where he says with what they have learned from the AIBL study, to prove an amyloid removal drug with a 10% effect, they only need 23 patients and to prove a 20% effect, only 7 patients.
That is at the 43 min mark in that youtube clip.
Interesting abstract showing the nature of the basic research they are still doing. As I read it, inference is that they may have demonstrated a potential vaccine target(s) to inhibit metal binding at the vulnerable AB sites. Thanks.