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Copper, BDNF and its N-terminal domain: Inorganic features and biological perspectives

机译：铜，BDNF及其N末端域：无机特征和生物学观点

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摘要

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that influences development, maintenance, survival, and synaptic plasticity of central and peripheral nervous systems. Altered BDNF signaling is involved in several neurodegenerative disorders including Alzheimer's disease. Metal ions may influence the BDNF activity and it is well known that the alteration of Cu ~(2+) homeostasis is a prominent factor in the development of neurological pathologies. The N-terminal domain of BDNF represents the recognition site of its specific receptor TrkB, and metal ions interaction with this protein domain may influence the protein/receptor interaction. In spite of this, no data inherent the interaction of BDNF with Cu~(2+) ions has been reported up to now. Cu~(2+) complexes of the peptide fragment BDNF(1-12) encompassing the sequence 1-12 of N-terminal domain of human BDNF protein were characterized by means of potentiometry, spectroscopic methods (UV/Vis, CD, EPR), parallel tempering simulations and DFT-geometry optimizations. Coordination features of the acetylated form, Ac-BDNF(1-12), were also characterized to understand the involvement of the terminal amino group. Whereas, an analogous peptide, BDNF(1-12)D3N, in which the aspartate residue was substituted by an asparagine, was synthesized to provide evidence on the possible role of carboxylate group in Cu2+ coordination. The results demonstrated that the amino group is involved in metal binding and the metal coordination environment of the predominant complex species at physiological pH consisted of one amino group, two amide nitrogen atoms, and one carboxylate group. Noteworthy, a strong decrease of the proliferative activity of both BDNF(1-12) and the whole protein on a SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu~(2+). The effect of metal addition is opposite to that observed for the analogous fragment of nerve growth factor (NGF) protein, highlighting the role of specific domains, and suggesting that Cu~(2+) may drive different pathways for the BDNF and NGF in physiological as well as pathological conditions. Key complex: Brain-derived neurotrophic factor (BDNF) N-terminal domain binds copper(II) with the involvement of His-1 α-amino group and Asp-3 carboxylate. The peptide encompassing the sequence 1-12 of the amino-terminal domain (BDNF(1-12)) of human BDNF is able to bind Cu~(2+). The predominant Cu~(2+) complex species, at physiological pH, is the [CuH_(-2)L]~(2-) in which the metal ion is bound to an amino group, two amide nitrogen atoms, and a carboxylate group (NH_2, 2N~-, COO~- Asp) in a planar environment (see figure).
机译：脑源性神经营养因子（BDNF）是一种神经营养蛋白，可影响中枢和周围神经系统的发育，维持，存活以及突触可塑性。改变的BDNF信号传导涉及多种神经退行性疾病，包括阿尔茨海默氏病。金属离子可能影响BDNF的活性，众所周知，Cu〜（2+）稳态的改变是神经病理学发展的重要因素。 BDNF的N末端结构域代表其特异性受体TrkB的识别位点，并且与该蛋白质结构域的金属离子相互作用可能会影响蛋白质/受体相互作用。尽管如此，到目前为止，尚无关于BDNF与Cu〜（2+）离子相互作用的内在数据。通过电位分光光度法，光谱法（UV / Vis，CD，EPR）表征了包含人BDNF蛋白N端结构域序列1-12的肽片段BDNF（1-12）的Cu〜（2+）复合物，平行回火模拟和DFT几何优化。乙酰化形式Ac-BDNF（1-12）的配位特征也可以理解末端氨基的参与。合成了类似的肽BDNF（1-12）D3N，其中天冬氨酸残基被天冬酰胺取代，从而提供了羧酸根在Cu2 +配位中的可能作用的证据。结果表明，氨基参与了金属的结合，在生理pH下主要复合物的金属配位环境由一个氨基，两个酰胺氮原子和一个羧基组成。值得注意的是，在Cu〜（2+）存在下处理后，发现BDNF（1-12）和整个蛋白在SHSY5Y神经母细胞瘤细胞系中的增殖活性都大大降低。金属添加的作用与神经生长因子（NGF）蛋白类似片段所观察到的相反，突出了特定结构域的作用，并暗示Cu〜（2+）可能驱动BDNF和NGF在生理上的不同途径。以及病理状况。关键复合物：脑源性神经营养因子（BDNF）N端结构域在His-1α-氨基和Asp-3羧酸盐的作用下结合铜（II）。包含人BDNF氨基末端结构域的序列1-12（BDNF（1-12））的肽能够结合Cu〜（2+）。在生理pH下，主要的Cu〜（2+）配合物是[CuH _（-2）L]〜（2-），其中金属离子键合至氨基，两个酰胺氮原子和一个羧酸根平面环境中的基团（NH_2、2N〜-，COO〜-Asp）（见图）。

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