Institute of Crystallography, CNR, Via Gaifami 18, 95126 Catania, Italy.
Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
Int J Mol Sci. 2021 May 11;22(10):5085. doi: 10.3390/ijms22105085.
Nerve growth factor (NGF) is a protein essential to neurons survival, which interacts with its receptor as a non-covalent dimer. Peptides belonging to NGF N-terminal domain are able to mimic the activity of the whole protein. Such activity is affected by the presence of copper ions. The metal is released in the synaptic cleft where proteins, not yet identified, may bind and transfer to human copper transporter 1 (hCtr1), for copper uptake in neurons. The measurements of the stability constants of copper complexes formed by amyloid beta and hCtr1 peptide fragments suggest that beta-amyloid (Aβ) can perform this task. In this work, the stability constant values of copper complex species formed with the dimeric form of N-terminal domain, sequence 1-15 of the protein, were determined by means of potentiometric measurements. At physiological pH, NGF peptides bind one equivalent of copper ion with higher affinity of Aβ and lower than hCtr1 peptide fragments. Therefore, in the synaptic cleft, NGF may act as a potential copper chelating molecule, ionophore or chaperone for hCtr1 for metal uptake. Copper dyshomeostasis and mild acidic environment may modify the balance between metal, NGF, and Aβ, with consequences on the metal cellular uptake and therefore be among causes of the Alzheimer's disease onset.
神经生长因子（NGF）是神经元生存所必需的一种蛋白质，它与受体相互作用形成非共价二聚体。属于 NGF N 端结构域的肽能够模拟整个蛋白质的活性。这种活性受铜离子的存在影响。金属在突触间隙中释放，在那里尚未确定的蛋白质可能结合并转移到人类铜转运蛋白 1（hCtr1），以便在神经元中摄取铜。通过测定淀粉样β蛋白和 hCtr1 肽片段形成的铜配合物的稳定常数值，表明β-淀粉样蛋白（Aβ）可以完成此任务。在这项工作中，通过电位测定法确定了与蛋白质的 N 端结构域 1-15 序列的二聚形式形成的铜配合物物种的稳定常数值。在生理 pH 值下，NGF 肽与铜离子结合一个当量，其亲和力高于 Aβ，低于 hCtr1 肽片段。因此，在突触间隙中，NGF 可能作为一种潜在的铜螯合分子、离子载体或 hCtr1 的伴侣，用于金属摄取。铜代谢失调和轻微的酸性环境可能会改变金属、NGF 和 Aβ 之间的平衡，从而影响金属的细胞摄取，因此可能是阿尔茨海默病发病的原因之一。
