The C9orf72 gene associated with amyotrophic lateral sclerosis/frontotemporal dementia is translated to five dipeptide repeat proteins, among which poly-proline-arginine (PR) is the most toxic in cell and animal models, contributing to a variety of cellular defects. It has been proposed that polyPR disrupts nucleocytoplasmic transport (NCT) through several mechanisms including accumulation in the nuclear pore complex (NPC), accumulation in the nucleolus, and direct interactions with transport receptors. The NPC, which is the key regulator of transport between the cytoplasm and nucleus, plays a central role in these suggested mechanisms. Exploring polyPR interaction with the NPC provides valuable insight into the molecular details of polyPR-mediated NCT defects. To address this, we use coarse-grained molecular dynamics models of polyPR and the yeast NPC lined with intrinsically disordered FG-nucleoporins (FG-Nups). Our findings indicate no aggregation of polyPR within the NPC or permanent binding to FG-Nups. Instead, polyPR translocates through the NPC, following a trajectory through the central low-density region of the pore. In the case of longer polyPRs, we observe a higher energy barrier for translocation and a narrower translocation channel. Our study shows that polyPR and FG-Nups are mainly engaged in steric interactions inside the NPC with only a small contribution of specific cation-pi, hydrophobic, and electrostatic interactions, allowing polyPR to overcome the entropic barrier of the NPC in a size-dependent manner.

中文翻译：

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C9orf72 polyPR 与核孔复合物的相互作用


与肌萎缩侧索硬化症/额颞叶痴呆相关的 C9orf72 基因被翻译成 5 种二肽重复蛋白，其中聚脯氨酸精氨酸 （PR） 在细胞和动物模型中毒性最强，导致多种细胞缺陷。有人提出，polyPR 通过多种机制破坏核质转运 （NCT），包括在核孔复合体 （NPC） 中的积累、在核仁中的积累以及与转运受体的直接相互作用。鼻咽癌是细胞质和细胞核之间运输的关键调节因子，在这些建议的机制中起着核心作用。探索 polyPR 与 NPC 的相互作用为 polyPR 介导的 NCT 缺陷的分子细节提供了有价值的见解。为了解决这个问题，我们使用 polyPR 和内衬固有无序 FG-核孔蛋白 （FG-Nups） 的酵母 NPC 的粗粒度分子动力学模型。我们的研究结果表明 polyPR 在 NPC 内没有聚集或与 FG-Nups 永久结合。相反，polyPR 通过 NPC 易位，沿着穿过孔中央低密度区域的轨迹。在较长的 polyPR 的情况下，我们观察到更高的易位能量势垒和更窄的易位通道。我们的研究表明，polyPR 和 FG-Nups 主要参与 NPC 内部的空间相互作用，只有很小的特异性阳离子-pi、疏水和静电相互作用的贡献，使 polyPR 能够以大小依赖性方式克服 NPC 的熵壁。