Improving the hole picture: towards a consensus on the mechanism of nuclear transport.
Improving the hole picture: towards a consensus on the mechanism of nuclear transport.
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DOI：
10.1042/bst20220494
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发表时间：
2023-04-26
影响因子：
3.9
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中科院分区：
文献类型：
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核孔复合物（NPC）介导核质和细胞质之间的物质交换，在将核酸和蛋白质分离到其所需的隔室中起关键作用。NPC的静态结构通过最近的冷冻-EM和其他研究相对较好地定义。动态组件中的NPC孔，苯丙氨酰-甘氨酰（FG）重复丰富的核孔蛋白的功能作用，是不太清楚，因为我们有限的理解高度动态的蛋白质系统。这些蛋白质形成“受限制的浓缩物”，其与核转运因子（NTR）相互作用并浓缩，以提供货物的促进的核质转运。FG重复序列和NTRs之间非常快速的开启和关闭速率支持极快的易化运输，接近细胞质中大分子扩散的速率，而没有特定相互作用的复合物被熵排除在外，尽管运输机制和FG重复行为的几个方面的细节仍有待解决。然而，正如这里所讨论的，新的技术方法与更先进的建模方法相结合，可能会提供一个改进的动态描述NPC运输，可能在不久的将来在原子水平。这些进展可能对理解NPC在癌症、衰老、病毒性疾病和神经退行性疾病中的作用有重大意义。
Nuclear pore complexes (NPCs) mediate the exchange of materials between the nucleoplasm and cytoplasm, playing a key role in the separation of nucleic acids and proteins into their required compartments. The static structure of the NPC is relatively well defined by recent cryo-EM and other studies. The functional roles of dynamic components in the pore of the NPC, phenylalanyl-glycyl (FG) repeat rich nucleoporins, is less clear because of our limited understanding of highly dynamic protein systems. These proteins form a ‘restrained concentrate’ which interacts with and concentrates nuclear transport factors (NTRs) to provide facilitated nucleocytoplasmic transport of cargoes. Very rapid on- and off-rates among FG repeats and NTRs supports extremely fast facilitated transport, close to the rate of macromolecular diffusion in cytoplasm, while complexes without specific interactions are entropically excluded, though details on several aspects of the transport mechanism and FG repeat behaviors remain to be resolved. However, as discussed here, new technical approaches combined with more advanced modeling methods will likely provide an improved dynamic description of NPC transport, potentially at the atomic level in the near future. Such advances are likely to be of major benefit in comprehending the roles the malfunctioning NPC plays in cancer, ageing, viral diseases, and neurodegeneration.