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Molecular mechanisms underlying the impact of mutations in SOD1 on its conformational properties associated with amyotrophic lateral sclerosis as revealed with molecular modelling.
BMC Structural Biology Pub Date : 2018-02-05 , DOI: 10.1186/s12900-018-0080-9
Nikolay A Alemasov 1 , Nikita V Ivanisenko 1, 2 , Srinivasan Ramachandran 3, 4 , Vladimir A Ivanisenko 1
Affiliation  

BACKGROUND So far, little is known about the molecular mechanisms of amyotrophic lateral sclerosis onset and progression caused by SOD1 mutations. One of the hypotheses is based on SOD1 misfolding resulting from mutations and subsequent deposition of its cytotoxic aggregates. This hypothesis is complicated by the fact that known SOD1 mutations of similar clinical effect could be distributed over the whole protein structure. RESULTS In this work, a measure of hydrogen bond stability in conformational states was studied with elastic network analysis of 35 SOD1 mutants. Twenty-eight hydrogen bonds were detected in nine of 35 mutants with their stability being significantly different from that with the wild-type. These hydrogen bonds were formed by the amino acid residues known from the literature to be located in contact between SOD1 aggregates. Additionally, residues disposed between copper binding sites of both protein subunits were found from the models to form a stiff core, which can be involved in mechanical impulse transduction between these active centres. CONCLUSIONS The modelling highlights that both stability of the copper binding site and stability of the dimer can play an important role in ALS progression.

中文翻译:

分子建模揭示了SOD1突变对其构象特性与肌萎缩性侧索硬化相关的影响的分子机制。

背景技术到目前为止,关于由SOD1突变引起的肌萎缩性侧索硬化发作和进展的分子机制知之甚少。假设之一是基于SOD1折叠错误,该错误折叠是由突变和其细胞毒性聚集物的后续沉积引起的。该假设由于以下事实而变得复杂:已知的具有类似临床作用的SOD1突变可以分布在整个蛋白质结构上。结果在这项工作中,通过35个SOD1突变体的弹性网络分析研究了在构象状态下氢键稳定性的方法。在35个突变体中的9个中检测到28个氢键,其稳定性与野生型显着不同。这些氢键由文献中已知的位于SOD1聚集体之间接触的氨基酸残基形成。此外,从模型中发现了两个蛋白质亚基的铜结合位点之间的残基,形成了一个刚性核,该核可参与这些活性中心之间的机械冲动传导。结论该模型强调了铜结合位点的稳定性和二聚体的稳定性均可在ALS进展中发挥重要作用。
更新日期:2018-02-05
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