title: [Effect of mutations and modifications of amino acid residues on zinc-induced interaction of the metal-binding domain of β-amyloid with DNA].
abstract: Interaction of intranuclear β-amyloid with DNA is considered to be a plausible mechanism of Alzheimer's disease pathogenesis. The interaction of single- and double-stranded DNA with synthetic peptides was analyzed using surface plasmon resonance. The peptides represent the metal-binding domain of β-amyloid (amino acids 1-16) and its variants with chemical modifications and point substitutions of amino acid residues which are associated with enhanced neurotoxicity of β-amyloid in cell tests. It has been shown that the presence of zinc ions is necessary for the interaction of the peptides with DNA in solution. H6R substitution has remarkably reduced the ability of domain 1-16 to bind DNA. This is in accordance with the supposition that the coordination of a zinc ion by amino acid residues His6, Glu11, His13, and His14 of the β-amyloid metal-binding domain results in the occurrence of an anion-binding site responsible for the interaction of the domain with DNA. Zinc-induced dimerization and oligomerization of domain 1-16 associated with phosphorylation of Ser8 and the presence of unblocked amino- and carboxy-terminal groups have resulted in a decrease of peptide concentrations required for detection of the peptide-DNA interaction. The presence of multiple anion-binding sites on the dimers and oligomers is responsible for the enhancement of the peptide-DNA interaction. A substitution of the negatively charged residue Asp7 for the neutral residue Asn in close proximity to the anion-binding site of the domain 1-16 of Aβ facilitates the electrostatic interaction between this site and phosphates of a polynucleotide chain, which enhances zinc-induced binding to DNA.
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow, 119121 Russia.
authors.forename: S A
authors.initials: SA
authors.lastname: Khmeleva
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow, 119121 Russia.|Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.
authors.forename: Y V
authors.initials: YV
authors.lastname: Mezentsev
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.
authors.forename: S A
authors.initials: SA
authors.lastname: Kozin
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.
authors.forename: V A
authors.initials: VA
authors.lastname: Mitkevich
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow, 119121 Russia.|Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.
authors.forename: A E
authors.initials: AE
authors.lastname: Medvedev
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow, 119121 Russia.
authors.forename: A S
authors.initials: AS
authors.lastname: Ivanov
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow, 119121 Russia.
authors.forename: N V
authors.initials: NV
authors.lastname: Bodoev
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.
authors.forename: A A
authors.initials: AA
authors.lastname: Makarov
authors.affiliation: Orekhovich Institute of Biomedical Chemistry, Moscow, 119121 Russia.|Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.|radko@ibmc.msk.ru.
authors.forename: S P
authors.initials: SP
authors.lastname: Radko
mesh_terms: D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D001120:Arginine / Q000737:chemistry; D001216:Asparagine / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D015374:Biosensing Techniques; D002413:Cations, Divalent; D056831:Coordination Complexes / Q000737:chemistry*; D004247:DNA / Q000138:chemical synthesis / Q000737:chemistry*; D004277:DNA, Single-Stranded / Q000138:chemical synthesis / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D012694:Serine / Q000737:chemistry; D012996:Solutions; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D018675:Toxicity Tests; D015032:Zinc / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D002413:Cations, Divalent; D056831:Coordination Complexes; D004277:DNA, Single-Stranded; D010446:Peptide Fragments; D012996:Solutions; C433241:amyloid beta-protein (1-16); D001224:Aspartic Acid; D012694:Serine; D006639:Histidine; D001216:Asparagine; D004247:DNA; D001120:Arginine; D015032:Zinc
keywords: Alzheimer's disease; biosensor analysis; zinc; β-amyloid