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首页> 美国卫生研究院文献>Research >Highly Dynamic Polynuclear Metal Cluster Revealed in a Single Metallothionein Molecule
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Highly Dynamic Polynuclear Metal Cluster Revealed in a Single Metallothionein Molecule

机译：高度动态的多核金属簇在单一的金属硫蛋白分子中显示出来

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Human metallothionein (MT) is a small-size yet efficient metal-binding protein, playing an essential role in metal homeostasis and heavy metal detoxification. MT contains two domains, each forming a polynuclear metal cluster with an exquisite hexatomic ring structure. The apoprotein is intrinsically disordered, which may strongly influence the clusters and the metal-thiolate (M-S) bonds, leading to a highly dynamic structure. However, these features are challenging to identify due to the transient nature of these species. The individual signal from dynamic conformations with different states of the cluster and M-S bond will be averaged and blurred in classic ensemble measurement. To circumvent these problems, we combined a single-molecule approach and multiscale molecular simulations to investigate the rupture mechanism and chemical stability of the metal cluster by a single MT molecule, focusing on the Zn4S11 cluster in the α domain upon unfolding. Unusual multiple unfolding pathways and intermediates are observed for both domains, corresponding to different combinations of M-S bond rupture. None of the pathways is clearly preferred suggesting that unfolding proceeds from the distribution of protein conformational substates with similar M-S bond strengths. Simulations indicate that the metal cluster may rearrange, forming and breaking metal-thiolate bonds even when MT is folded independently of large protein backbone reconfiguration. Thus, a highly dynamic polynuclear metal cluster with multiple conformational states is revealed in MT, responsible for the binding promiscuity and diverse cellular functions of this metal-carrier protein.
机译：人金属硫蛋白（MT）是一种小尺寸但有效的金属结合蛋白，在金属稳态和重金属排毒中发挥着重要作用。 MT含有两个结构域，每个结构域具有具有精致的六己族环结构的多核金属簇。甲壳素是本质上的混乱，这可能强烈影响簇和金属硫醇酸酯（M-S）键，导致高度动态的结构。然而，由于这些物种的瞬态性质，这些特征是挑战。来自集群和M-S键的不同状态的动态构象的各个信号将平均并在经典集合测量中模糊。为了规避这些问题，我们组合了单分子方法和多尺度分子模拟，以研究单个Mt分子的金属簇的破裂机制和化学稳定性，聚焦在展开时α结构域中的Zn4S11集群。对于两个结构域，观察到不寻常的多展开途径和中间体，对应于M-S债券破裂的不同组合。没有一种途径明确地表明，展开从具有相似M-S粘合强度的蛋白质构象变电站的分布进行。即使在大型蛋白质骨架重构的大蛋白质骨架重构的折叠时，模拟表明金属簇也可以重新排列，形成和破坏金属硫醇酯键。因此，在MT中揭示了具有多种构象状态的高度动态的多核金属簇，其负责该金属载体蛋白的结合滥交和不同的细胞功能。

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