Interactions of Nickel(II) with histones: interactions of Nickel(II) with CH3CO-Thr-Glu-Ser-His-His-Lys-NH2, a peptide modeling the potential metal binding site in the "C-Tail" region of histone H2A.
A combined pH-metric and spectroscopic (UV/vis, CD, NMR) study of the Ni(II) binding to CH3CO-Thr-Glu-Ser-His-His-Lys-NH2 (AcTESHHKam), a blocked hexapeptide modeling a part of the C-terminal sequence of the major variant of histone H2A (residues 120-125), revealed the formation of a pseudo-octahedral NiHL complex in weakly acidic and neutral solutions. Ni(II) is bound to the peptide through imidazole nitrogens on both of its histidine residues and the carboxylate of the side chain of glutamic acid. At higher pH, a series of square-planar complexes are formed. This process is accompanied by hydrolytic degradation of the peptide. At pH 7.4, the peptide hydrolyzes in a Ni(II)-assisted fashion, yielding the square-planar Ni(II) complex of SHHKam as the sole product detected by CD, MALDI-TOF MS, and HPLC. Quantitative analysis of complex stabilities indicates that the -TESHHK- motif is a very likely binding site for carcinogenic Ni(II) ions in the cell nucleus. The Ni(II)-assisted hydrolysis of the C-terminal chain of histone H2A may provide a novel mechanism of genotoxicity combining the damage to the nucleosome with the generation of further toxic Ni(II) species.
Laboratory of Comparative Carcinogenesis, National Cancer Institute, FCRDC, Frederick, Maryland 21702, Maryland 20852.
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Lukszo
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Bialkowski
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Kasprzak
D001665:Binding Sites; D002384:Catalysis; D002413:Cations, Divalent; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002942:Circular Dichroism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D009532:Nickel / Q000737:chemistry / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet
D002413:Cations, Divalent; D006657:Histones; D009842:Oligopeptides; D012996:Solutions; D009532:Nickel