The possible role of 94-125 peptide fragment of histone H2B in nickel-induced carcinogenesis.
The molecular mechanism by which nickel carcinogenicity is exerted is not fully understood. However, it is believed to involve DNA damage and epigenetic effects in chromatin, resulting from metal binding to the cell nucleus. Histone nuclear proteins are the major candidates for metal binding not only due to their abundance but also due to the presence of strong binding sites within their sequence. In order to investigate the binding capacity of histone H2B toward Ni(2+) ions, we synthesized the peptide Ac-IQTAVRLLLPGELAKHAVSEGTKAVTKYTSSK-Am (H2B(94-125)) as a model of the C-terminal tail. Complexation of H2B(94-125) with Ni(2+) starts at pH around 5 with the formation of a distorted octahedral complex. Over pH 8, this species shifts to a square-planar geometry, with the complete consumption of free Ni(2+) ions at pH 10. The formation of the diamagnetic square-planar complex was further studied by means of NMR spectroscopy. On the basis of the NOE connectivities we determined a well-resolved solution structure for the binding site of the H2B(94-125)-Ni(2+) complex, including residues E(12)LAKHAVS(19). Interestingly, nickel binding strongly affects the C-terminal of the peptide, forcing it to approach the coordination plane. If such a structural alteration is able to occur under physiological conditions, it is highly possible that it interferes with the histone's physiological role and particularly with the ubiquitination process, taking place at Lys(120). We believe that these findings will assist in a better understanding of the role of histone H2B in the mechanisms of metal-induced toxicity and carcinogenesis.
Nunes
Ana Mónica
AM
Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece.
Zavitsanos
Kimon
K
Del Conte
Rebecca
R
Malandrinos
Gerasimos
G
Hadjiliadis
Nick
N
D001665:Binding Sites; D002273:Carcinogens / Q000737:chemistry*; D006657:Histones / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008024:Ligands; D008958:Models, Molecular; D009532:Nickel / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry*; D011199:Potentiometry
D002273:Carcinogens; D006657:Histones; D008024:Ligands; D009942:Organometallic Compounds; D010446:Peptide Fragments; D009532:Nickel