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NMR solution structure of the English mutant of the β-amyloid peptide metal binding domain Aβ(1-16)H6R and its impact on Aβ oligomerizationтезисы доклада
- Авторы: Istrate 1A, Zhokhov S., Kulikova A., Tsvetkov P., Kozin S., Makarov A., Polshakov V.
- Сборник: The proceedings of international conference EUROMAR-2014
- Тезисы
- Год издания: 2014
- Место издания: ETH Zurich, Switzerland
- Первая страница: 280
- Последняя страница: 280
- Аннотация: The key reason that leads to the development of the pathological disorders during Alzheimer’s disease is the formation of the amyloid plaques in the cerebral tissue of the human brain. It consists of the hyper aggregated β amyloid peptide (Aβ) and dead neuron cells on its periphery. It was reported that zinc ions play the crucial role in the process of the Aβ precipitation. There are numerous mutations in amyloid-β (Aβ) peptide associated with familial Alzheimer’s disease (FAD). Recently, English familial mutation (H6R) located in zinc-binding domain of Aβ was found to accelerate toxic amyloid fibril formation leading to earlier development of Alzheimer’s disease (AD). In an attempt to reveal the mechanism of accelerated fibril formation, with the help of NMR spectroscopy, isothermal titration calorimetry and mass-spectrometry, we investigate zinc binding to H6R mutant of metal-binding domain 1-16 of human Aβ. We found that H6R mutation favors dimerization of Aβ zinc-binding domain. We also demonstrated that dimerization interface of mutant is the same as for its non-modified form and corresponds to the primary zinc recognition site 11EVHH14. Experimental restraints obtained from analyses of the NMR and ITC data were used in structure calculations using an explicit water environment and a simulated annealing MD protocol designed for short peptides followed by QM/MM optimization. These data allow getting insights into the molecular mechanism of FAD associated with English mutation and confirm the role of EVHH(11-14) region as a universal drug target for preventing development and progression of AD. Finally the shift of equilibrium to the dimer formation upon H6R mutation makes this form a good model to probe inhibitors of zinc-induced dimerization of Aβ. Also it was found that the obtained dimer structure may favor antiparallel organization of C-terminal region during oligomerization of Aβ(H6R).
- Добавил в систему: Польшаков Владимир Иванович