Interactions of Ni(ii) and Cu(ii) ions with the hydrolysis products of the C-terminal -ESHH- motif of histone H2A model peptides. Association of the stability of the complexes formed with the cleavage of the -E–S- bond

Abstract

We studied the interactions of Ni(II) and Cu(II) ions with the synthetic tetrapeptides SHHK- and SAHK-, which were blocked by amidation making them more realistic models of the hydrolysis peptidic products of the hexapeptides models of H2A histone. A combination of potentiometric and spectroscopic techniques (UV/Vis, CD, NMR and EPR) suggested that at pH > 7 both tetrapeptides coordinated equatorially through the imidazole ring of His in position 3, the N-terminal amino group and the two amide nitrogens existing between these groups {NH2, 2N-, NIm} forming 4N square-planar complexes. While in the case of the CuH(-1)L complex with SHHK- a possible axial coordination of the imidazole ring of His in position 2 was suggested, in the case of the analogous NiH(-1)L complex a completely different interaction of the same ring with metal ions was observed. As expected these complexes have the same structures with the hydrolysis products produced from the Ni(II)- or Cu(II)-assisted hydrolysis of previously studied hexapeptide models of the C-terminal of histone H2A, due to their predominance at pH > 7.4. In addition, the competition plots presented herein showed that the synthetic tetrapeptides SHHK- and SAHK- have higher affinity towards Ni(II) and Cu(II) ions than the previously studied hexapeptides, suggesting that metal ions remain bound to the peptidic products during the hydrolysis cleavage. Thus, it can be concluded that the stability of Ni(II) or Cu(II) complexes with the synthetic tetrapeptides and consequently with the real hydrolysis peptidic products is the driving force of the hydrolysis reaction of H2A histone blocked hexapeptide models, presented in previous studies.

Copper effective binding with 32–62 and 94–125 peptide fragments of histone H2B

“…In all cases, no new product formation was observed, suggesting a strong resistance in copper induced hydrolysis of the H2B 32-62 and H2B 94-125 fragments. This is in accordance with our previous findings [42] requesting a Ser or Thr residue to be present near the metal coordination site, to result in peptide hydrolysis.…”

Nickel Toxicity and Carcinogenesis

“…Importantly, Ni(II) coordinated in -CAIH-, RTHGQSHYR-, and -SHHKAKGK complexes was capable of mediating oxidative damage to other molecules (see Section 2.3.2). The latter complex is derived from the original Ni(II)-TESH-HKAKGK complex of histone H2A owing to a novel effect: nickel-facilitated hydrolysis of the E-S bond [176,177]. Since the C-terminal tail of H2A is involved in maintaining chromatin structure [178], its hydrolytic truncation in nickelexposed cells may affect chromatin by disturbing orderly gene expression.…”

Nickel Ion Complexes of Amino Acids and Peptides

“…2, 63-108 (2007) Ala did not affect the hydrolysis reaction, substitution of the His-5 or Ser residues inhibited the reaction, supporting the important role of the last two residues in peptide bond hydrolysis [139,140]. Above pH 7 SHHK and SAHK (hydrolysis products) coordinate to Ni(II) equatorially through the imidazole of His-3, the N-terminal amino group, and the two amide nitrogens located between Ser-1 and His-3, {NH 2 , 2N Ϫ , N im }, forming 4N albumin-like square planar complexes [141]. Spectroscopic evidence and theoretical predictions suggest that the positioning of the free imidazole ring, in the Ni-SHHK complex, above the coordination plane, induces the extra stability of the complex [142].…”