Effect of Oxidative Damage on the Stability and Dimerization of Superoxide Dismutase 1.
Effect of Oxidative Damage on the Stability and Dimerization of Superoxide Dismutase 1.
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DOI：
10.1016/j.bpj.2016.02.037
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发表时间：
2016-04-12
影响因子：
3.4
通讯作者：
Zagrovic B
中科院分区：
文献类型：
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作者：
Petrov D;Daura X;Zagrovic B
在其生命周期中，蛋白质受到涉及活性氧的不同修饰。这种对蛋白质的氧化损伤可能导致不溶性聚集体的形成和细胞毒性，并与年龄相关的疾病有关，包括神经退行性疾病、癌症和糖尿病。超氧化物歧化酶1 （SOD1）是人类细胞中的一种关键抗氧化酶，特别容易受到这种修饰的影响。此外，这种同二聚体金属酶与家族性和散发性肌萎缩性侧索硬化症（ALS）直接相关，ALS是一种破坏性的迟发性运动神经元疾病，SOD1基因中有150多个与ALS相关的突变。重要的是，在家族性和散发性疾病中都观察到氧化损伤的SOD1聚集物。然而，氧化应激在sod1诱导的细胞毒性中的分子机制和潜在意义仍然是未知的。在这项研究中，我们研究了氧化修饰对SOD1单体和同型二聚体稳定性的影响，这是与SOD1聚集相关的关键分子性质。我们使用分子动力学模拟结合热力学集成来研究微观水平上二聚体界面氧化“突变”的位点特异性效应，包括赖氨酸、精氨酸、脯氨酸和苏氨酸羰基化以及半胱氨酸氧化。我们的研究结果表明，即使是界面上单个残基的氧化损伤也可能极大地破坏SOD1同型二聚体的稳定性，其中一些修饰表现出与已知的最剧烈的als引起突变相当的效果。此外，我们发现SOD1单体的稳定性在氧化应激下降低，这可能导致局部展开，从而增加聚集倾向。重要的是，这些结果表明氧化应激可能在ALS的发展中发挥关键作用，SOD1基因突变是一个额外的因素。
During their life cycle, proteins are subject to different modifications involving reactive oxygen species. Such oxidative damage to proteins may lead to the formation of insoluble aggregates and cytotoxicity and is associated with age-related disorders including neurodegenerative diseases, cancer, and diabetes. Superoxide dismutase 1 (SOD1), a key antioxidant enzyme in human cells, is particularly susceptible to such modifications. Moreover, this homodimeric metalloenzyme has been directly linked to both familial and sporadic amyotrophic lateral sclerosis (ALS), a devastating, late-onset motor neuronal disease, with more than 150 ALS-related mutations in the SOD1 gene. Importantly, oxidatively damaged SOD1 aggregates have been observed in both familial and sporadic forms of the disease. However, the molecular mechanisms as well as potential implications of oxidative stress in SOD1-induced cytotoxicity remain elusive. In this study, we examine the effects of oxidative modification on SOD1 monomer and homodimer stability, the key molecular properties related to SOD1 aggregation. We use molecular dynamics simulations in combination with thermodynamic integration to study microscopic-level site-specific effects of oxidative “mutations” at the dimer interface, including lysine, arginine, proline and threonine carbonylation, and cysteine oxidation. Our results show that oxidative damage of even single residues at the interface may drastically destabilize the SOD1 homodimer, with several modifications exhibiting a comparable effect to that of the most drastic ALS-causing mutations known. Additionally, we show that the SOD1 monomer stability decreases upon oxidative stress, which may lead to partial local unfolding and consequently to increased aggregation propensity. Importantly, these results suggest that oxidative stress may play a key role in development of ALS, with the mutations in the SOD1 gene being an additional factor.