剖析 ALS 突变 S375G 对 TDP-43370-375 片段构象特性和聚集动力学的影响

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zhengdong Xu , Jianxin Zhang , Jiaxing Tang , Yehong Gong , Yu Zou , Qingwen Zhang
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引用次数: 0

摘要

转录反应脱氧核糖核酸(DNA)结合蛋白 43 kDa(TDP-43)聚集成泛素阳性包涵体与肌萎缩侧索硬化症(ALS)、额颞叶变性和慢性创伤性脑病密切相关。TDP-43的370-375片段(370GNNSYS375,TDP-43370-375)是致淀粉样蛋白的六肽,容易形成具有立体拉链特征的致病性淀粉样纤维。之前的实验报告显示,ALS 相关突变(丝氨酸 375 被甘氨酸取代(S375G))与 TDP-43 的早发疾病和蛋白聚集有关。在此基础上,有必要探索其潜在的分子机制。通过总计 102 μs 的全原子分子动力学(MD)模拟,我们研究了 S375G 突变对 TDP-43370-375 多肽构象组合和寡聚动力学的影响。我们的复制交换 MD 模拟结果表明,S375G 突变能促进非结构化构象的形成,诱导多肽形成松散的低聚物,从而抑制 TDP-43370-375 的聚集。进一步分析表明,S375G 突变对 TDP-43370-375 肽间的氢键和接触总数有减少作用。S375G 突变削弱了 TDP-43370-375 肽间的氢键和极性相互作用以及 Y374-Y374 π-π 堆积相互作用。其他微秒级 MD 模拟证明,S375G 突变可阻止构象转化为富含 β 结构的聚集体,并对 TDP-43370-375 的低聚物动力学产生抑制作用。这项研究首次在原子水平上揭示了影响 TDP-43370-375 聚集的 S375G 突变的分子机制,为未来开发特定位点突变疗法开辟了新途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Dissecting the effect of ALS mutation S375G on the conformational properties and aggregation dynamics of TDP-43370-375 fragment

Dissecting the effect of ALS mutation S375G on the conformational properties and aggregation dynamics of TDP-43370-375 fragment

The aggregation of transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43) into ubiquitin-positive inclusions is closely associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and chronic traumatic encephalopathy. The 370–375 fragment of TDP-43 (370GNNSYS375, TDP-43370-375), the amyloidogenic hexapeptides, can be prone to forming pathogenic amyloid fibrils with the characteristic of steric zippers. Previous experiments reported the ALS-associated mutation, serine 375 substituted by glycine (S375G) is linked to early onset disease and protein aggregation of TDP-43. Based on this, it is necessary to explore the underlying molecular mechanisms. By utilizing all-atom molecular dynamics (MD) simulations of 102 μs in total, we investigated the impact of S375G mutation on the conformational ensembles and oligomerization dynamics of TDP-43370-375 peptides. Our replica exchange MD simulations show that S375G mutation could promote the unstructured conformation formation and induce peptides to form a loose packed oligomer, thus inhibiting the aggregation of TDP-43370-375. Further analyses suggest that S375G mutation displays a reduction effect on the number of total hydrogen bonds and contacts among TDP-43370-375 peptides. Hydrogen bonding and polar interactions among TDP-43370-375 peptides, as well as Y374-Y374 π-π stacking interaction, are attenuated by S375G mutation. Additional microsecond MD simulations demonstrate that S375G mutation could prohibit the conformational conversion to β-structure-rich aggregates and possess an inhibitory effect on the oligomerization dynamics of TDP-43370-375. This study offers for the first time of molecular insights into the S375G mutation affecting the aggregation of TDP-43370-375 at the atomic level, and may open new avenues in the development of future site-specific mutation therapeutics.

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来源期刊
Biophysical chemistry
Biophysical chemistry 生物-生化与分子生物学
CiteScore
6.10
自引率
10.50%
发文量
121
审稿时长
20 days
期刊介绍: Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.
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