Zinc-induced heterodimer formation between metal-binding domains of intact and naturally modified amyloid-beta species: implication to amyloid seeding in Alzheimer’s disease?статья
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 18 марта 2016 г.
Аннотация:Zinc ions and modified amyloid-beta peptides (Aβ) play a critical role in the pathological
aggregation of endogenous Aβ in Alzheimer’s disease (AD). Zinc-induced Aβ oligomerization is
mediated by the metal-binding domain (MBD) which includes N-terminal residues 1-16 (Aβ1-16).
Earlier, it has been shown that Aβ1-16 as well as some of its naturally occurring variants
undergoes zinc-induced homodimerization via the interface in which zinc ion is coordinated by
Glu11 and His14 of the interacting subunits. In this study using surface plasmon resonance
technique we have found that in the presence of zinc ions Aβ1-16 forms heterodimers with MBDs
of two Aβ species linked to AD: Aβ containing isoAsp7 (isoAβ) and Aβ containing
phosphorylated Ser8 (pS8-Aβ). The heterodimers appear to possess the same interface as the
homodimers. Simulation of 200 ns molecular dynamic trajectories in two constructed models of
dimers ([Aβ1-16/Zn/Aβ1-16] and [isoAβ1-16/Zn/Aβ1-16], has shown that conformational flexibility of the N-terminal fragments of the dimer subunits is controlled by the structure of corresponding
sites 6-8. The data suggest that isoAβ and pS8-Aβ can be involved in the AD pathogenesis by
means of their zinc-dependent interactions with endogenous Aβ resulting in formation of
heterodimeric seeds for amyloid aggregation.