Ando David, Gopinathan Ajay
Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United States of America.
Joint BioEnergy Institute, Emeryville, CA, United States of America.
PLoS One. 2017 Jan 9;12(1):e0169455. doi: 10.1371/journal.pone.0169455. eCollection 2017.
Nucleocytoplasmic transport is highly selective, efficient, and is regulated by a poorly understood mechanism involving hundreds of disordered FG nucleoporin proteins (FG nups) lining the inside wall of the nuclear pore complex (NPC). Previous research has concluded that FG nups in Baker's yeast (S. cerevisiae) are present in a bimodal distribution, with the "Forest Model" classifying FG nups as either di-block polymer like "trees" or single-block polymer like "shrubs". Using a combination of coarse-grained modeling and polymer brush modeling, the function of the di-block FG nups has previously been hypothesized in the Di-block Copolymer Brush Gate (DCBG) model to form a higher-order polymer brush architecture which can open and close to regulate transport across the NPC. In this manuscript we work to extend the original DCBG model by first performing coarse grained simulations of the single-block FG nups which confirm that they have a single block polymer structure rather than the di-block structure of tree nups. Our molecular simulations also demonstrate that these single-block FG nups are likely cohesive, compact, collapsed coil polymers, implying that these FG nups are generally localized to their grafting location within the NPC. We find that adding a layer of single-block FG nups to the DCBG model increases the range of cargo sizes which are able to translocate the pore through a cooperative effect involving single-block and di-block FG nups. This effect can explain the puzzling connection between single-block FG nup deletion mutants in S. cerevisiae and the resulting failure of certain large cargo transport through the NPC. Facilitation of large cargo transport via single-block and di-block FG nup cooperativity in the nuclear pore could provide a model mechanism for designing future biomimetic pores of greater applicability.
核质运输具有高度选择性、高效性，其调控机制尚不清楚，涉及数百种位于核孔复合体（NPC）内壁的无序FG核孔蛋白（FG nups）。先前的研究得出结论，面包酵母（酿酒酵母）中的FG nups呈双峰分布，“森林模型”将FG nups分类为类似“树”的双嵌段聚合物或类似“灌木”的单嵌段聚合物。通过粗粒度建模和聚合物刷建模相结合的方法，双嵌段FG nups的功能先前在双嵌段共聚物刷门（DCBG）模型中被假设为形成一种高阶聚合物刷结构，该结构可以打开和关闭以调节跨NPC的运输。在本论文中，我们致力于扩展原始的DCBG模型，首先对单嵌段FG nups进行粗粒度模拟，证实它们具有单嵌段聚合物结构而非树状nups的双嵌段结构。我们的分子模拟还表明，这些单嵌段FG nups可能是有粘性的、紧凑的、塌陷的卷曲聚合物，这意味着这些FG nups通常定位于NPC内它们的嫁接位置。我们发现，在DCBG模型中添加一层单嵌段FG nups会增加能够通过单嵌段和双嵌段FG nups协同作用穿过孔的货物大小范围。这种效应可以解释酿酒酵母中单嵌段FG nup缺失突变体与某些大货物通过NPC运输失败之间令人困惑的联系。通过核孔中单一嵌段和双嵌段FG nup协同作用促进大货物运输，可以为设计未来适用性更强的仿生孔提供一种模型机制。
