JBIC Journal of Biological Inorganic Chemistry ( IF 2.7 ) Pub Date : 2021-09-23 , DOI: 10.1007/s00775-021-01902-7 Camilla Golec 1 , Shaelyn Mortensen 1 , Saba Anwar 2 , Sanela Martic-Milne 1
|
Metal dyshomeostasis plays a critical role in the reactive oxygen species (ROS) formation and protein misfolding and aggregation; hence, contributing to neurodegeneration. Tau protein plays a key role in normal cellular function by maintaining microtubule formation in brain. The role of metal ions on tau protein biochemistry has not been systematically evaluated, but earlier reports indicated that metal ions modulate the complex biochemistry of this protein and its peptides. Herein, we evaluated interactions of biologically-relevant Cu(II) ions with the four repeat peptides of tau protein (R1 through R4) and their role on the formation of ROS, Cu(II) to Cu(I) reduction, and ultimately, peptide aggregation. The role of R peptides on ROS formation was characterized in the absence and presence of biological reducing agent, ascorbate by using UV–Vis and fluorescence spectroscopy. In the presence of the reducing agent, all Cu(II)-peptide complexes reduced hydroxyl radical (OH·), while only Cu(II)-R3 complex depleted the hydrogen peroxide (H2O2). In the absence of a reducing agent, only Cu(II)-R2 and Cu(II)-R3 complexes, which contain Cys and His residues, produced OH· and H2O2. Only R2 and R3 peptides, but not R1 and R4, reduced Cu(II) to Cu(I). The aggregation propensities of R peptides were modulated by Cu(II) and ascorbate, and were imaged by transmission electron microscopy. All metallo-peptides were characterized predominantly as singly charged mononuclear complexes by mass spectrometry. The data indicate that Cu(II)-peptide complexes may act as pro-oxidants or antioxidants and exhibit unique aggregation propensities under specific environmental conditions, with implications in the biological setting.
Graphic abstract
中文翻译：
tau R 肽对 Cu(II)/(I) 介导的活性氧形成的双重作用
金属失调在活性氧 (ROS) 形成和蛋白质错误折叠和聚集中起关键作用；因此，有助于神经退行性变。Tau 蛋白通过维持大脑中的微管形成，在正常细胞功能中起关键作用。金属离子对 tau 蛋白生物化学的作用尚未得到系统评估，但早期的报道表明金属离子调节这种蛋白质及其肽的复杂生物化学。在这里，我们评估了生物学相关的 Cu(II) 离子与 tau 蛋白的四个重复肽（R1 到 R4）的相互作用，以及它们在 ROS 形成、Cu(II) 到 Cu(I) 还原中的作用，最终，肽聚集。R 肽对 ROS 形成的作用以生物还原剂的不存在和存在为特征，使用 UV-Vis 和荧光光谱法检测抗坏血酸。在还原剂存在下，所有的 Cu(II)-肽配合物都还原了羟基自由基 (OH·)，而只有 Cu(II)-R3 配合物消耗了过氧化氢 (H2 O 2 )。在没有还原剂的情况下，只有含有 Cys 和 His 残基的 Cu(II)-R2 和 Cu(II)-R3 配合物产生 OH·和 H 2 O 2。只有 R2 和 R3 肽，而不是 R1 和 R4，将 Cu(II) 还原为 Cu(I)。R 肽的聚集倾向由 Cu(II) 和抗坏血酸调节，并通过透射电子显微镜成像。所有金属肽通过质谱主要表征为单电荷单核复合物。数据表明，Cu(II)-肽复合物可作为促氧化剂或抗氧化剂，并在特定环境条件下表现出独特的聚集倾向，对生物环境具有影响。
京公网安备 11010802027423号