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首页> 外文期刊>Biophysical Journal >Structural Rearrangement upon Fragmentation of the Stability Core of the ALS-Linked Protein TDP-43
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Structural Rearrangement upon Fragmentation of the Stability Core of the ALS-Linked Protein TDP-43

机译：在ALS连接蛋白TDP-43的稳定性核心碎片后结构重排

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摘要

Amyotrophic lateral sclerosis (ALS) is the most common adult degenerative motor neuron disease. Experimental evidence indicates a direct role of transactive-response DNA-binding protein 43 (TDP-43) in the pathology of ALS and other neurodegenerative diseases. TDP-43 has been identified as a major component of cytoplasmic inclusions in patients with sporadic ALS; however, the molecular basis of the disease mechanism is not yet fully understood. Fragmentation within the second RNA recognition motif (RRM2) of TDP-43 has been observed in patient tissues and may play a role in the formation of aggregates in disease. To determine the structural and dynamical changes resulting from the truncation that could lead to aggregation and toxicity, we performed molecular dynamics simulations of the full-length RRM2 domain (the stability core of TDP-43) and of a truncated variant (where residues 189-207 are deleted to mimic a site of cleavage within RRM2 found in ALS patients). Our simulations show heterogeneous structural reorganization and decreased stability of the truncated RRM2 domain compared to the full-length domain, consistent with previous experimental results. The decreased stability and structural reorganization in the truncated RRM2 result in a higher probability of protein-protein interactions through altered electrostatic surface charges and increased accessibility of hydrophobic residues (including the nuclear export sequence), providing a rationale for the increased cytoplasmic aggregation of RRM2 fragments seen in sporadic ALS patients.
机译：肌营养的外侧硬化症（ALS）是最常见的成人退行性运动神经元疾病。实验证据表明过敏 - 反应DNA结合蛋白43（TDP-43）在ALS和其他神经变性疾病的病理中直接作用。 TDP-43已被鉴定为孢子患者患者细胞质夹杂物的主要成分;然而，疾病机制的分子基础尚未完全理解。在患者组织中观察到TDP-43的第二RNA识别基序（RRM2）内的碎片化，并且可能在疾病中形成聚集体的作用。为了确定可能导致聚集和毒性的截断产生的结构和动态变化，我们对全长RRM2结构域（TDP-43的稳定性核心）进行了分子动力学模拟和截短的变体（其中残留物189-删除207以模仿ALS患者的RRM2内的裂解部位）。与全长域相比，我们的模拟显示出异构结构重组，并降低截短的RRM2结构域的稳定性，与先前的实验结果一致。截短的RRM2中的稳定性和结构重组降低导致通过改变的静电表面电荷和疏水残留物（包括核导出序列）的可及性增加的蛋白质 - 蛋白质相互作用的较高概率，为RRM2碎片的增加的细胞质聚集提供了基本原理在零星艾尔斯患者中看到。

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