Nickel Binding Sites in Histone Proteins: Spectroscopic and Structural Characterization

Nickel compounds influence carcinogenesis by interfering with a variety of cellular targets. It has been found that nickel is a potent inhibitor in vivo of histone H4 acetylation, in both yeast and mammalian cells. It has preference to specific lysine residues in the H4 N-terminal - S(1)GRGK(5)GGK(8)GLGK(12)GGAK(16)RH(18)RKVL(22) tail, in which the sites of acetylation are clustered. About the nature of the structural changes induced by histone acetylation on H4, it has been recently demonstrated that acetylation promotes an increase in a-helical conformation of the acetylated N-terminal tail of H4. This causes a shortening of the tail and such an effect may have an important structural and functional implication as a mechanism of transcriptional regulation. Here we report a study on the conformational changes induced by carcinogenic nickel compounds on the histone H4 protein. From a circular dichroism study we found that nickel is able to induce a secondary structure in the protein. In particular, nickel has the same effect as acetylation: it induces an increase in a-helical conformation of the non-acetylated histone H4. The a-helical increase occurring upon nickel interaction with histone H4 should decrease the ability of histone acetyl transferase to recognize and bind the histone tail, thus affecting the ability of the enzyme to further modify the lysine residues. The shortening of the distance between adjacent amino acids, caused by the translation from an extended to a helical conformation, could disrupt the histone recognition motif; this may eventually compromise the entire "histone code"