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首页> 外文期刊>Journal of Molecular Biology >Cu,Zn-Superoxide Dismutase without Zn Is Folded but Catalytically Inactive
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Cu,Zn-Superoxide Dismutase without Zn Is Folded but Catalytically Inactive

机译：Cu，没有Zn的Zn-超氧化物歧化酶折叠但催化不活性

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摘要

Amyotrophic lateral sclerosis has been linked to the gain of aberrant function of superoxide dismutase, Cu,Zn-SOD1 upon protein misfolding. The mechanism of SOD1 misfolding is thought to involve mutations leading to the loss of Zn, followed by protein unfolding and aggregation. We show that the removal of Zn from SOD1 may not lead to an immediate unfolding but immediately deactivates the enzyme through a combination of subtle structural and electronic effects. Using quantum mechanics/discrete molecular dynamics, we showed that both Zn-less wild-type (WT)-SOD1 and its D124N mutant that does not bind Zn have at least metastable folded states. In those states, the reduction potential of Cu increases, leading to the presence of detectable amounts of Cu(I) instead of Cu(II) in the active site, as confirmed experimentally. The Cu(I) protein cannot participate in the catalytic Cu(I)-Cu(II) cycle. However, even without the full reduction to Cu(I), the Cu site in the Zn-less variants of SOD1 is shown to be catalytically incompetent: unable to bind superoxide in a way comparable to the WT-SOD1. The changes are more radical and different in the D124N Zn-less mutant than in the Zn-less WT-SOD1, suggesting D124N being perhaps not the most adequate model for Zn-less SOD1. Overall, Zn in SOD1 appears to be influencing the Cu site directly by adjusting its reduction potential and geometry. Thus, the role of Zn in SOD1 is not just structural, as was previously thought; it is a vital part of the catalytic machinery. (C) 2014 Elsevier Ltd. All rights reserved.
机译：肌营养的外侧硬化剂与超氧化物歧化酶，Cu，Zn-SOD1对蛋白质错误折叠的增益相关联。 SOD1错误折叠的机制被认为涉及导致Zn丧失的突变，其次是蛋白质展开和聚集。我们表明，从SOD1中去除Zn可能不会导致立即展开，但立即通过微妙的结构和电子效应的组合使酶失活。使用量子力学/离散分子动力学，我们表明，Zn的野生型（WT）-SOD1及其不结合Zn的D124N突变体具有至少稳定的折叠状态。在那些状态中，Cu的降低电位增加，导致在实验证实中存在可检测量的Cu（I）代替Cu（II）的Cu（II）。 Cu（I）蛋白不能参与催化Cu（I）-Cu（II）循环。然而，即使没有完全还原到Cu（I），SOD1的Zn的变体中的Cu位点也被显示为催化不通：不能以与WT-SOD1相当的方式结合超氧化物。该变化在D124N Zn的突变体中比在Zn的WT-SOD1中更加激进和不同，表明D124N可能不是最适合Zn的SOD1模型。总体而言，SOD1中的Zn似乎通过调节其减少电位和几何形状来直接影响Cu位点。因此，Zn在SOD1中的作用不仅仅是结构，如前所述;它是催化机械的重要组成部分。 （c）2014年elestvier有限公司保留所有权利。

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