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Интеллектуальная Система Тематического Исследования НАукометрических данных |
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NMR evidence for zinc-induced dimerization of beta-amyloid peptide metal binding domain with English mutationтезисы доклада
- Авторы: Zhokhov S.S., Istrate A.N., Kozin S.A., Polshakov V.I.
- Сборник: Book of abstracts of the international conference “Magnetic resonance: fundamental research and pioneering applications"
- Тезисы
- Год издания: 2014
- Место издания: Kazan Federal Universsity Kazan, Russian Federation
- Первая страница: 158
- Последняя страница: 158
- Аннотация: Alzheimer's disease (AD) is caused by abnormal aggregation of the β-amyloid peptide (Aβ) – endogenous product of the proteolytic cleavage of the amyloid precursor protein. The full length Aβ has 40-42 residues and contains both the metal-binding domain (1-16) and hydrophobic tail (17-42). Key pathogenic process of AD is the transition of soluble Aβ monomer into neurotoxic oligomers and then into insoluble fibrillar polymeric aggregates, which form the amyloid plaques. Zinc and copper ions play a critical role in this pathological transition via interaction of metal ions with the Aβ metal binding domain. The various mutations, causing the replacements of the amino acids in Aβ, and their post-translation modifications often increase tendency of the peptide to aggregation. Thus, English familial mutation (H6R) located in the zinc-binding domain of Aβ was recently shown to accelerate amyloid fibril formation leading to earlier development of AD. In order to reveal the molecular mechanism of the accelerated aggregation of AβH6R, we studied interaction of zinc ions with the metal binding domain Aβ(1-16)H6R using the methods of NMR spectroscopy, molecular dynamics and quantum mechanics calculations. It was found that in presence of zinc ions Aβ(1-16)H6R form stable dimeric complex. NMR techniques were used to determine stoichiometry of zinc binding, set of amino acids which form the metal binding site, and the parameters which describe an exchange between monomeric and dimeric forms of the zinc-peptide complex. High resolution spatial structure in solution of the dimeric form of the Aβ(1-16)H6R complex with zinc ion was determined from the NMR data and subsequently refined using the QM/MM calculations. Family of the final 20 NMR conformers was deposited to the Protein Data Bank (PDB id 2MGT).
- Добавил в систему: Польшаков Владимир Иванович