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首页> 外文期刊>Chemistry: A European journal >The inorganic perspective of nerve growth factor: Interactions of Cu ~(2+) and Zn~(2+) with the N-terminus fragment of nerve growth factor encompassing the recognition domain of the TrkA receptor
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The inorganic perspective of nerve growth factor: Interactions of Cu ~(2+) and Zn~(2+) with the N-terminus fragment of nerve growth factor encompassing the recognition domain of the TrkA receptor

机译：神经生长因子的无机视角：Cu〜（2+）和Zn〜（2+）与神经生长因子N端片段（包含TrkA受体的识别域）的相互作用

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摘要

There is a significant overlap between brain areas with Zn~(2+) and Cu~(2+) pathological dys-homeostasis and those in which the nerve growth factor (NGF) performs its biological role. The protein NGF is necessary for the development and maintenance of the sympathetic and sensory nervous systems. Its flexible N-terminal region has been shown to be a critical domain for TrkA receptor binding and activation. Computational analyses show that Zn~(2+) and Cu~(2+) form pentacoordinate complexes involving both the His4 and His8 residues of the N-terminal domain of one monomeric unit and the His84 and Asp105 residues of the other monomeric unit of the NGF active dimer. To date, neither experimental data on the coordination features have been reported, nor has one of the hypotheses according to which Zn~(2+) and Cu~(2+) may have different binding environments or the Ser1 α-amino group could be involved in coordination been supported. The peptide fragment, encompassing the 1-14 sequence of the human NGF amino-terminal domain (NGF(1-14)), blocked at the C terminus, was synthesised and its Cu ~ (2+) and Zn~(2(+) complexes characterized by means of potentiometric and spectroscopic (UV/Vis, CD, NMR, and EPR) techniques. The N-terminus-acetylated form of NGF(1-14) was also investigated to evaluate the involvement of the Ser1 α-amino group in metal-ion coordination. Our results demonstrate that the amino group is the first anchoring site for Cu ~(2+) and is involved in Zn2+ coordination at physiological pH. Finally, a synergic proliferative activity of both NGF(1-14) and the whole protein on SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu~(2+)(. This effect was not observed after treatment with the N-acetylated peptide fragment, demonstrating a functional involvement of the N-terminal amino group in metal binding and peptide activity.
机译：具有Zn〜（2+）和Cu〜（2+）病理性动态平衡的大脑区域与神经生长因子（NGF）发挥其生物学作用的大脑区域之间存在明显的重叠。 NGF蛋白对于交感和感觉神经系统的发育和维持是必需的。它的柔性N端区域已被证明是TrkA受体结合和激活的关键域。计算分析表明，Zn〜（2+）和Cu〜（2+）形成五配位配合物，涉及一个单体单元N端结构域的His4和His8残基，以及另一个单体单元的His84和Asp105残基。 NGF活性二聚体。迄今为止，尚无关于配位特征的实验数据的报道，也没有关于Zn〜（2+）和Cu〜（2+）可能具有不同结合环境或Ser1α-氨基可能为假说的假设之一。支持参与协调。合成了在C端封闭的，包含人NGF氨基末端结构域1-14序列（NGF（1-14））的肽片段，并合成了Cu〜（2+）和Zn〜（2（+ ）的复合物，通过电位和光谱（UV / Vis，CD，NMR和EPR）技术表征，还研究了NGF（1-14）的N末端乙酰化形式，以评估Ser1α-氨基的参与我们的结果表明，氨基是Cu〜（2+）的第一个锚固位点，并在生理pH值下参与Zn2 +的配位，最后两个NGF（1-14）都有协同增生活性。并在Cu〜（2 +）（）存在下处理后发现SHSY5Y神经母细胞瘤细胞全蛋白。用N-乙酰化肽片段处理后未观察到此作用，表明N端氨基金属结合和肽活性中的基团。

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