Structural Rearrangement upon Fragmentation of the Stability Core of the ALS-Linked Protein TDP-43.
Structural Rearrangement upon Fragmentation of the Stability Core of the ALS-Linked Protein TDP-43.
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DOI：
10.1016/j.bpj.2017.06.049
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发表时间：
2017-08
影响因子：
3.4
通讯作者：
Brittany R. Morgan;J. Zitzewitz;F. Massi
中科院分区：
文献类型：
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作者：
Brittany R. Morgan;J. Zitzewitz;F. Massi
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是最常见的成人退行性运动神经元疾病。实验证据表明，反式反应DNA结合蛋白43（TDP-43）在ALS和其他神经退行性疾病的病理学中的直接作用。TDP-43已被确定为散发性ALS患者细胞质内含物的主要成分;然而，疾病机制的分子基础尚未完全了解。在患者组织中观察到TDP-43的第二RNA识别基序（RRM 2）内的片段化，可能在疾病中形成聚集体中发挥作用。为了确定由可能导致聚集和毒性的截短引起的结构和动力学变化，我们对全长RRM 2结构域（TDP-43的稳定性核心）和截短变体（其中残基189-207被删除以模拟ALS患者中发现的RRM 2内的切割位点）进行了分子动力学模拟。我们的模拟表明，异构结构重组和稳定性降低的截断RRM 2域相比，全长域，与以前的实验结果一致。截短RRM 2的稳定性降低和结构重组通过改变静电表面电荷和增加疏水残基（包括核输出序列）的可及性导致蛋白质-蛋白质相互作用的可能性更高，这为在散发性ALS患者中观察到的RRM 2片段的细胞质聚集增加提供了依据。
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.