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Zinc-induced dimerization interface of the beta-amyloid metal-binding domain 1-16тезисы доклада
Информация о цитировании статьи получена из
Web of Science
Дата последнего поиска статьи во внешних источниках: 18 марта 2016 г.
- Авторы: Kulikova A.A., Istrate A.N., Kechko O.I., Kozin S.A., Makarov A.A., Polshakov V.I.
- Сборник: FEBS Journal
- Серия: Special Issue: 40th FEBS Congress, The Biochemical Basis of Life
- Том: 282
- Тезисы
- Год издания: 2015
- Первая страница: 344
- Последняя страница: 344
- Аннотация: Oligomerization of beta-amyloid peptide (Ab) plays crucial role in the development of Alzheimer0s disease (AD). Therefore the study of AD-associated mutations and post-translational modifications of the Ab metal-binding domain, Ab(1–16), will help to reveal the mechanism of Zn2+-induced Ab oligomerization. We have characterized interactions of Zn2+ with Ab(1–16)H6R, incorporating the H6R English familial mutation, and with isoAb(1–16), containing isomerized Asp7. We have previously shown that isomerization of Asp7 results in Zn2+-induced dimerization of Ab(1–16). In this study, using ITC and SPR we have shown that the H6R mutation of Ab favors this process as well. NMR experiments have demonstrated that at low concentrations Ab(1–16), Ab(1–16)H6R and isoAb(1–16) form dimers with similar conformation in the presence of Zn2+. At higher concentrations of Ab(1–16) monomeric form is prevalent compared to dimeric (PDB ID 1ZE9). With increasing Ab(1–16)H6R concentration a significant quantity of the dimer complex is formed as a result of the exclusion of His6 from the Zn2+coordination sphere. This allowed us to determine an NMR structure of the Ab(1–16)H6R dimer complexed with Zn2+ (PDB ID 2MGT) and to characterize the dimerization interface, which is common for the analyzed isoforms of Ab(1–16). In the case of isoAb(1– 16) increase of peptide concentration leads to the formation of insoluble aggregates, indicating the existence of additional Zn2+ chelating center. QM/MM calculations showed that this center can be formed by His6 and isoAsp7. Based on these data we propose a mechanism of Zn2+-induced oligomerization of Ab(1–16) H6R and isoAb(1–16).
- Добавил в систему: Польшаков Владимир Иванович