title: Zinc-induced heterodimer formation between metal-binding domains of intact and naturally modified amyloid-beta species: implication to amyloid seeding in Alzheimer's disease?
abstract: 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 the formation of heterodimeric seeds for amyloid aggregation.
authors.affiliation: a Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow 119991 , Russia.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Mezentsev
authors.affiliation: a Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow 119991 , Russia.
authors.forename: Alexei E
authors.initials: AE
authors.lastname: Medvedev
authors.affiliation: a Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow 119991 , Russia.
authors.forename: Olga I
authors.initials: OI
authors.lastname: Kechko
authors.affiliation: a Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow 119991 , Russia.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Makarov
authors.affiliation: b Institute of Biomedical Chemistry , Moscow 119121 , Russia.
authors.forename: Alexis S
authors.initials: AS
authors.lastname: Ivanov
authors.affiliation: c Faculty of Fundamental Medicine , Lomonosov Moscow State University , Moscow 119991 , Russia.
authors.forename: Alexey B
authors.initials: AB
authors.lastname: Mantsyzov
authors.affiliation: a Engelhardt Institute of Molecular Biology, Russian Academy of Sciences , Moscow 119991 , Russia.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kozin
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D015374:Biosensing Techniques; D006801:Humans; D007477:Ions / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D051381:Rats; D015032:Zinc / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D007477:Ions; D015032:Zinc
keywords: Alzheimer’s disease; amyloid-beta; chemical modifications; molecular dynamics; molecular modeling; oligomerization; surface plasmon resonance; zinc