Selenoprotein P and selenoprotein M block Zn2+-mediated Aβ42 aggregation and toxicity
Selenoprotein P and selenoprotein M block Zn2+-mediated Aβ42 aggregation and toxicity
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DOI：
10.1039/c3mt20282h
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发表时间：
2013-01-01
期刊：
影响因子：
3.4
通讯作者：
Ni, Jiazuan
中科院分区：
文献类型：
--
作者：
Du, Xiubo;Li, Haiping;Ni, Jiazuan
研究表明，神经元细胞中淀粉样蛋白 (Aβ) 肽与过渡金属离子的聚集和细胞毒性与阿尔茨海默病 (AD) 的进展有关。对抗这种不治之症的治疗策略是设计针对金属 A β 物质的化学制剂。硒蛋白是一组特殊蛋白质，其序列中含有第 21 个氨基酸 Sec。由于Sec的存在，对这组蛋白质的研究基本上集中在它们调节氧化还原电位和清除活性氧的作用上。在这里，我们报道了硒蛋白 P (SelP-H) 的富含 His 结构域和 Sec-to-Cys 突变体硒蛋白 M (SelM') 能够结合过渡金属离子并调节 Zn2+ 介导的 Aβ 聚集、ROS 产生和神经毒性。 SelM' (U48C) 和 SelP-H 分别以微摩尔和亚微摩尔亲和力配位 0.5 和 2 摩尔当量的 Zn2+/Cd2+。根据圆二色光谱，金属结合诱导了 SelP-H 和 SelM' 的结构变化。 Zn2+ 与 A beta(42) 结合几乎完全抑制了 A beta(42) 原纤维化，通过硫黄素 T (ThT) 荧光和透射电子显微镜 (TEM) 观察到，SelP-H 和 SelM' 可以显着恢复 A beta(42) 原纤维化。有趣的是，SelP-H 和 SelM' 均抑制 Zn2+-A beta(42) 诱导的神经毒性和活细胞中细胞内 ROS 的产生。这些研究表明 SelP 和 SelM 可能在调节氧化还原平衡以及金属稳态方面发挥一定作用。
Aggregation and cytotoxicity of the amyloid-beta (A beta) peptide with transition metal ions in neuronal cells have been suggested to be involved in the progression of Alzheimer's disease (AD). A therapeutic strategy to combat this incurable disease is to design chemical agents to target metal-A beta species. Selenoproteins are a group of special proteins that contain the 21st amino acid Sec in their sequence. Due to the presence of Sec, studies of this group of proteins are basically focused on their roles in regulating redox potential and scavenging reactive oxygen species. Here, we reported that the His-rich domain of selenoprotein P (SelP-H) and the Sec-to-Cys mutant selenoprotein M (SelM') are capable of binding transition metal ions and modulating the Zn2+-mediated A beta aggregation, ROS production and neurotoxicity. SelM' (U48C) and SelP-H were found to coordinate 0.5 and 2 molar equivalents of Zn2+/Cd2+ with micromolar and submicromolar affinities, respectively. Metal binding induced the structural changes in SelP-H and SelM' according to the circular dichorism spectra. Zn2+ binding to A beta(42) almost completely suppressed A beta(42) fibrillization, which could be significantly restored by SelP-H and SelM', as observed by thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM). Interestingly, both SelP-H and SelM' inhibited Zn2+-A beta(42)-induced neurotoxicity and the intracellular ROS production in living cells. These studies suggest that SelP and SelM may play certain roles in regulating redox balance as well as metal homeostasis.