Intramolecular cohesion of coils mediated by phenylalanine--glycine motifs in the natively unfolded domain of a nucleoporin.
Intramolecular cohesion of coils mediated by phenylalanine--glycine motifs in the natively unfolded domain of a nucleoporin.
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DOI：
10.1371/journal.pcbi.1000145
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发表时间：
2008-08-08
影响因子：
4.3
通讯作者：
Rexach MF
中科院分区：
文献类型：
--
作者：
Krishnan VV;Lau EY;Yamada J;Denning DP;Patel SS;Colvin ME;Rexach MF
核孔复合体（NPC）为细胞核和细胞质之间的大分子交换提供了唯一的水通道。它的扩散导管包含由NPC蛋白家族形成的大小选择性门，该NPC蛋白家族具有大的天然未折叠结构域，具有苯丙氨酸-甘氨酸重复序列（FG结构域）。核孔蛋白的这些结构域在建立NPC渗透屏障中起着关键作用，但对其动态结构知之甚少。在这里，我们使用分子建模和生物物理技术来表征的动态合奏的结构的一个代表FG域从酵母核孔蛋白Nup 116。结果表明，它的FG基序的功能作为分子内的凝聚力元素，赋予秩序的FG域和紧凑的整体结构到本地premelt球状配置。在NPC中，核孔蛋白的FG基序可以在分子间和分子内发挥这种内聚效应，以形成由高度柔性的多肽链组成的可延展但内聚的四级结构。分子内和分子间FG基序相互作用之间的平衡或竞争的动态变化可以促进NPC导管处的快速和可逆的结构转变，所述NPC导管需要容纳通过的各种形状和大小的核转运蛋白-货物复合物，同时保持针对蛋白质扩散的大小选择性门。核孔复合物是一种分子过滤器，它控制细胞质和核质之间的大分子交换。它在其中心包含一个大小选择性扩散屏障，由名为FG核孔蛋白的蛋白质组成。这些核孔蛋白具有大的、结构无序的结构域，其高度修饰有苯丙氨酸-甘氨酸（FG）序列基序。这些无序FG域的动态结构将它们从经典的结构生物学分析（如X射线晶体学）中排除;因此，需要新的方法来表征它们的形状。在这里，计算和生物物理的方法被用来阐明合奏的FG结构域的核孔蛋白所采用的结构。分析表明，FG基序的功能作为分子内的凝聚力元素，紧凑的FG域的形状，迫使它采取松散的球形结构，不断重新配置。在核孔复合物内，数十个这些核孔蛋白FG结构域可以堆叠为松散编织的小球，形成通过尺寸排阻门控分子扩散的多孔筛。
The nuclear pore complex (NPC) provides the sole aqueous conduit for macromolecular exchange between the nucleus and the cytoplasm of cells. Its diffusion conduit contains a size-selective gate formed by a family of NPC proteins that feature large, natively unfolded domains with phenylalanine–glycine repeats (FG domains). These domains of nucleoporins play key roles in establishing the NPC permeability barrier, but little is known about their dynamic structure. Here we used molecular modeling and biophysical techniques to characterize the dynamic ensemble of structures of a representative FG domain from the yeast nucleoporin Nup116. The results showed that its FG motifs function as intramolecular cohesion elements that impart order to the FG domain and compact its ensemble of structures into native premolten globular configurations. At the NPC, the FG motifs of nucleoporins may exert this cohesive effect intermolecularly as well as intramolecularly to form a malleable yet cohesive quaternary structure composed of highly flexible polypeptide chains. Dynamic shifts in the equilibrium or competition between intra- and intermolecular FG motif interactions could facilitate the rapid and reversible structural transitions at the NPC conduit needed to accommodate passing karyopherin–cargo complexes of various shapes and sizes while simultaneously maintaining a size-selective gate against protein diffusion. The nuclear pore complex is a molecular filter that gates macromolecular exchange between the cytoplasm and the nucleoplasm of cells. It contains a size-selective diffusion barrier at its center composed of proteins named FG nucleoporins. These nucleoporins feature large, structurally disordered domains that are highly decorated with phenylalanine–glycine (FG) sequence motifs. The dynamic structure of these disordered FG domains excludes them from classical structural biology analyses such as X-ray crystallography; thus, new approaches are needed to characterize their shape. Here computational and biophysical approaches were used to elucidate the ensemble of structures adopted by the FG domain of a nucleoporin. The analyses showed that the FG motifs function as intramolecular cohesion elements that compact the shape of the FG domain, forcing it to adopt loosely knit globular configurations that are constantly reconfiguring. Within the nuclear pore complex, dozens of these nucleoporin FG domains may stack as loosely knit globules forming a porous sieve that gates molecular diffusion by size exclusion.
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影响因子：
16.8
作者：
Dhe-Sirano, D;Werner, ED;Shoelson, SE
通讯作者：
Shoelson, SE
影响因子：
2.8
作者：
Krishnan, VV;Thornton, KH;Cosman, M
通讯作者：
Cosman, M
影响因子：
56.9
作者：
Frey, Steffen;Richter, Ralf P.;Goerlich, Dirk
通讯作者：
Goerlich, Dirk
DOI：
10.1073/pnas.0506202102
发表时间：
2005-11-22
影响因子：
11.1
作者：
Bernadó, P;Blanchard, L;Blackledge, M
通讯作者：
Blackledge, M
影响因子：
7
作者：
Denning, Daniel P.;Rexach, Michael F.
通讯作者：
Rexach, Michael F.