Nerve growth factor (NGF) is a protein involved in development and survival of specific neuronal populations [1]. In Alzheimer's Disease (AD), the lack of trophic support guaranteed by NGF has been observed in the same areas involved in learning and memory. Some d-block metal ions have been proposed to play a crucial role in AD and, intriguingly, NGF performs its activity in the same brain areas affected by metal dys-homeostasis in pathological conditions [2]. As N-terminal residues of NGF are crucial for the activity of this protein, the peptide fragment encompassing the sequence 1-14 of the human NGF, named NGF(1-14), was synthesized and its copper(II) and zinc(II) complexes characterized by means of potentiometric and spectroscopic (UV-vis, CD, NMR and EPR) techniques. The predominant Cu2+ complex species in the pH range 5.5-7.4 is the [CuLH-1], in which Cu2+ is bound to an amino, an amide and an imidazole nitrogen atom donors (NH2, N-, NIm) in a highly distorted environment, due to the presence of an apical oxygen atom of the carboxylate and/or Figure 1 an imidazole nitrogen. Otherwise, Zn2+ is bound to two imidazole nitrogen atoms and to the Glu11 carboxylate group in acidic region, whereas Ser1 amino group is involved in the metal coordination above pH 6.5 (Figure 1). Beside to be the first anchoring site for Cu2+ and to be involved in Zn2+ coordination at physiological pH, the free amino group plays a key role which is stressed by biological essays. Indeed, a synergic proliferative effect has been observed after co-treatment with NGF(1-14) and Cu2+ or Zn2+ on SHSY5Y neuroblastoma cell line, but this effect was not observed after co-treatment with metals and the N-acetylated form of the peptide fragment, suggesting an important correlation between biological activity and coordination environment. 1 Chao, M.V. Nat. Rev. Neurosci. 4, 2003, 299 2 A.I. Bush, R.E. Tanzi, Neurotherapeutics, 5, 2008, 421 The N-terminus acetylated form of NGF(1-14) was also investigated to prove the involvement of Ser1 α-amino group in coordination.

Characterization of copper(II) and zinc(II) complexes with the Nterminal domain of Nerve Growth Factor

ARENA, Giuseppe;NICOLETTI, Vincenzo Giuseppe;RIZZARELLI, Enrico
2011

Abstract

Nerve growth factor (NGF) is a protein involved in development and survival of specific neuronal populations [1]. In Alzheimer's Disease (AD), the lack of trophic support guaranteed by NGF has been observed in the same areas involved in learning and memory. Some d-block metal ions have been proposed to play a crucial role in AD and, intriguingly, NGF performs its activity in the same brain areas affected by metal dys-homeostasis in pathological conditions [2]. As N-terminal residues of NGF are crucial for the activity of this protein, the peptide fragment encompassing the sequence 1-14 of the human NGF, named NGF(1-14), was synthesized and its copper(II) and zinc(II) complexes characterized by means of potentiometric and spectroscopic (UV-vis, CD, NMR and EPR) techniques. The predominant Cu2+ complex species in the pH range 5.5-7.4 is the [CuLH-1], in which Cu2+ is bound to an amino, an amide and an imidazole nitrogen atom donors (NH2, N-, NIm) in a highly distorted environment, due to the presence of an apical oxygen atom of the carboxylate and/or Figure 1 an imidazole nitrogen. Otherwise, Zn2+ is bound to two imidazole nitrogen atoms and to the Glu11 carboxylate group in acidic region, whereas Ser1 amino group is involved in the metal coordination above pH 6.5 (Figure 1). Beside to be the first anchoring site for Cu2+ and to be involved in Zn2+ coordination at physiological pH, the free amino group plays a key role which is stressed by biological essays. Indeed, a synergic proliferative effect has been observed after co-treatment with NGF(1-14) and Cu2+ or Zn2+ on SHSY5Y neuroblastoma cell line, but this effect was not observed after co-treatment with metals and the N-acetylated form of the peptide fragment, suggesting an important correlation between biological activity and coordination environment. 1 Chao, M.V. Nat. Rev. Neurosci. 4, 2003, 299 2 A.I. Bush, R.E. Tanzi, Neurotherapeutics, 5, 2008, 421 The N-terminus acetylated form of NGF(1-14) was also investigated to prove the involvement of Ser1 α-amino group in coordination.
NGF, copper, zinc
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/71409
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