College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China.
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China.
J Inorg Biochem. 2019 Jul;196:110693. doi: 10.1016/j.jinorgbio.2019.110693. Epub 2019 Apr 13.
Aberrant interactions of metal ions with amyloid-β peptide (Aβ) can potentiate Alzheimer's disease (AD) by participating in the aggregation process of Aβ and in the generation of reactive oxygen species (ROS). Metallothionein-3 (MT3), which is aberrantly expressed in AD brains, is believed to play an important role in the AD progression due to its ability of maintaining metal homeostasis and scavenging ROS. However, the related molecular mechanism is not clear. In this work, the metal-dependent interactions of MT3 β-domain (βMT3) with amyloid-β peptide (Aβ) were systematically studied. The results showed that Zn-βMT3 has a higher affinity to Aβ (K: ~0.7 μM) than Cu-βMT3 (K: ~22 μM). In Zn-βMT3, both Pro and Pro face outwards with their five-member rings in parallel, favoring their binding with aromatic residues via CH/π interactions. Two aromatic residues (Phe and Tyr) in Aβ were identified as the specific binding sites for βMT3. Based on these, we posit a characteristic in-situ protection role of Zn-MT3 in inhibiting the Cu-induced Aβ neurotoxicity, in which stable Zn-MT3/Aβ complex forms via the Zn-βMT3/Aβ interaction and effectively prevents the formation of Cu-Aβ in high viscosity physiological fluids. Our results provide the mechanistic pathway and the specific roles of βMT3 in its protective bioactivity against AD progression, which means significant for elucidating the function of MT3 in AD neuropathology and for designing a MT3-related therapeutic strategy for AD.
金属离子与淀粉样β肽（Aβ）的异常相互作用可以通过参与 Aβ的聚集过程和生成活性氧物种（ROS）来增强阿尔茨海默病（AD）。金属硫蛋白-3（MT3）在 AD 大脑中异常表达，由于其维持金属内稳态和清除 ROS 的能力，被认为在 AD 进展中发挥重要作用。然而，相关的分子机制尚不清楚。在这项工作中，系统研究了 MT3 β-结构域（βMT3）与淀粉样β肽（Aβ）的金属依赖性相互作用。结果表明，Zn-βMT3 与 Aβ的亲和力（K：0.7μM）高于 Cu-βMT3（K：22μM）。在 Zn-βMT3 中，Pro 和 Pro 面均向外，其五元环平行，有利于通过 CH/π 相互作用与芳香族残基结合。Aβ 中的两个芳香族残基（Phe 和 Tyr）被确定为βMT3 的特定结合位点。基于这些，我们提出了 Zn-MT3 在抑制 Cu 诱导的 Aβ神经毒性中的特征原位保护作用，其中稳定的 Zn-MT3/Aβ 复合物通过 Zn-βMT3/Aβ 相互作用形成，并有效地防止高粘度生理流体中 Cu-Aβ 的形成。我们的研究结果为βMT3 在其对 AD 进展的保护生物活性中的作用提供了机制途径和具体作用，这对阐明 MT3 在 AD 神经病理学中的功能和设计 AD 相关的 MT3 治疗策略具有重要意义。
