title: Zinc-Mediated Binding of Nucleic Acids to Amyloid-β Aggregates: Role of Histidine Residues.
abstract: Amyloid-β peptide (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis. Besides extracellular Aβ, intraneuronal Aβ (iAβ) has been suggested to contribute to AD onset and development. Based on reported in vitro Aβ-DNA interactions and nuclear localization of iAβ, the interference of iAβ with the normal DNA expression has recently been proposed as a plausible pathway by which Aβ can exert neurotoxicity. Employing the sedimentation assay, thioflavin T fluorescence, and dynamic light scattering we have studied effects of zinc ions on binding of RNA and single- and double-stranded DNA molecules to Aβ42 aggregates. It has been found that zinc ions significantly enhance the binding of RNA and DNA molecules to pre-formed β-sheet rich Aβ42 aggregates. Another type of Aβ42 aggregates, the zinc-induced amorphous aggregates, was demonstrated to also bind all types of nucleic acids tested. To evaluate the role of the Aβ metal-binding domain's histidine residues in Aβ-nucleic acid interactions mediated by zinc, Aβ16 mutants with substitutions H6R and H6A-H13A and rat Aβ16 lacking histidine residue 13 were used. The zinc-induced interaction of Aβ16 with DNA was shown to critically depend on histidine residues 6 and 13. However, the inclusion of H6R mutation in Aβ42 peptide did not affect DNA binding to Aβ42 aggregates. Since oxidative and/or nitrosative stresses implicated in AD pathogenesis are known to release zinc ions from metallothioneins in cytoplasm and cell nuclei, our findings suggest that intracellular zinc can be an important player in iAβ-nucleic acid interactions.
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.|Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Svetlana A
authors: SA
authors: Khmeleva
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.|Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Sergey P
authors: SP
authors: Radko
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors: Sergey A
authors: SA
authors: Kozin
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Yana Y
authors: YY
authors: Kiseleva
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Yuri V
authors: YV
authors: Mezentsev
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors: Vladimir A
authors: VA
authors: Mitkevich
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Leonid K
authors: LK
authors: Kurbatov
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Alexis S
authors: AS
authors: Ivanov
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors: Alexander A
authors: AA
authors: Makarov
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D056945:Hep G2 Cells; D006639:Histidine / Q000502:physiology*; D006801:Humans; D009696:Nucleic Acids / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D066329:Protein Aggregates / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D009696:Nucleic Acids; D010446:Peptide Fragments; D066329:Protein Aggregates; C433241:amyloid beta-protein (1-16); C075222:amyloid beta-protein (1-42); D006639:Histidine; D015032:Zinc
keywords: Alzheimer’s disease; DNA; RNA; amyloid-β peptide; histidine residues; zinc