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 ps-metric and spectroscopic (UV/vis, CD, NMR) study of the Ni(II) binding to CH3CO-Thr-Glu-Ser-His-His-Lys-NH2 (AcTESHHKam), a bl ocked hexapeptide modeling a part of the C-terminal sequence of the ma jor variant of histone H2A (residues 120-125), revealed the formation of a pseudo-octahedral NiHL complex in weakly acidic and neutral solut ions. Ni(II) is bound to the peptide through imidazole nitrogens on bo th of its histidine residues and the carboxylate of the side chain of glutamic acid. At higher pH, a series of square-planar complexes are f ormed. This process is accompanied by hydrolytic degradation of the pe ptide. 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 produ ct detected by CD, MALDI-TOF MS, and HPLC. Quantitative analysis of co mplex stabilities indicates that the -TESHHK- motif is a very likely b inding site for carcinogenic Ni(II) ions in the cell nucleus. The Ni(I I)-assisted hydrolysis of the C-terminal chain of histone H2A may prov ide a novel mechanism of genotoxicity combining the damage to the nucl eosome with the generation of further toxic Ni(II) species.