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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dynamical Roles Of Metal Ions And The Disulfide Bond In Cu, Zn Superoxide Dismutase Folding And Aggregation
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Dynamical Roles Of Metal Ions And The Disulfide Bond In Cu, Zn Superoxide Dismutase Folding And Aggregation

机译：金属离子和二硫键在铜，锌超氧化物歧化酶折叠和聚集中的动力学作用

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摘要

Misfolding and aggregation of Cu, Zn superoxide dismutase (SOD1) is implicated in neuronal death in amyotrophic lateral sclerosis. Each SOD1 monomer binds to 1 copper and 1 zinc ion and maintains its disulfide bond (Cys-57-Cys-146) in the reducing cytoplasm of cell. Mounting experimental evidence suggests that metal loss and/or disulfide reduction are important for initiating misfolding and aggregation of SOD1. To uncover the role of metals and the disulfide bond in the SOD1 folding, we systemically study the folding thermodynamics and structural dynamics of SOD1 monomer and dimer with and without metal binding and under disulfide-intact or disulfide-reduced environments in computational simulations. We use all-atom discrete molecular dynamics for sampling. Our simulation results provide dynamical evidence to the stabilizing role of metal ions in both dimer and monomer SOD1. The disulfide bond anchors a loop (Glu-49 to Asn-53) that contributes to the dimer interface. The reduction of the disulfide bond in SOD1 with metal ions depleted results in a flexible Glu-49-Asn-53 loop, which, in turn, disrupts dimer formation. Interestingly, the disulfide bond reduction does not affect the thermostability of monomer SOD1 as significantly as the metal ions do. We further study the structural dynamics of metal-free SOD1 monomers, the precursor for aggregation, in simulations and find inhomogeneous local unfolding of β-strands. The strands protected by the metal-binding and electrostatic loops are found to unfold first after metal loss, leading to a partially unfolded β-sheet prone to aggregation. Our simulation study sheds light on the critical role of metals and disulfide bond in SOD1 folding and aggregation.
机译：铜，锌超氧化物歧化酶（SOD1）的错误折叠和聚集与肌萎缩性侧索硬化症的神经元死亡有关。每个SOD1单体与1个铜和1个锌离子结合，并在还原性细胞质中维持其二硫键（Cys-57-Cys-146）。越来越多的实验证据表明，金属损失和/或二硫化物还原对于启动SOD1的错误折叠和聚集很重要。为了揭示金属和二硫键在SOD1折叠中的作用，我们在计算模拟中系统地研究了有和没有金属结合以及在二硫键完整或二硫键还原的环境下，SOD1单体和二聚体的折叠热力学和结构动力学。我们使用全原子离散分子动力学进行采样。我们的模拟结果为二聚体和单体SOD1中金属离子的稳定作用提供了动力学证据。二硫键可锚定有助于二聚体界面的环（Glu-49至Asn-53）。金属离子消耗后，SOD1中的二硫键还原导致了柔性的Glu-49-Asn-53环，进而破坏了二聚体的形成。有趣的是，二硫键的还原不会像金属离子那样显着影响单体SOD1的热稳定性。我们在模拟中进一步研究了无金属的SOD1单体（聚集体的前体）的结构动力学，并发现了β链的不均匀局部展开。发现受金属结合和静电环保护的链在金属损失后首先解开，导致部分解折叠的β-折叠易于聚集。我们的模拟研究揭示了金属和二硫键在SOD1折叠和聚集中的关键作用。

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