Zinc-induced heterodimer formation between metal-binding domains of intact and naturally modified amyloid-beta species: implication to amyloid seeding in Alzheimer's disease?

Zinc ions and modified amyloid-beta peptides (A) play a critical role in the pathological aggregation of endogenous A in Alzheimer's disease (AD). Zinc-induced A oligomerization is mediated by the metal-binding domain (MBD) which includes N-terminal residues 1-16 (A(1-16)). Earlier, it has been shown that A(1-16) 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 A(1-16) forms heterodimers with MBDs of two A species linked to AD: A containing isoAsp7 (isoA) and A containing phosphorylated Ser8 (pS8-A). The heterodimers appear to possess the same interface as the homodimers. Simulation of 200ns molecular dynamic trajectories in two constructed models of dimers ([A(1-16)/Zn/A(1-16)] and [isoA(1-16)/Zn/A(1-16)]), 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 isoA and pS8-A can be involved in the AD pathogenesis by means of their zinc-dependent interactions with endogenous A resulting in the formation of heterodimeric seeds for amyloid aggregation.