Trigger Factor Slows Co-translational Folding through Kinetic Trapping while Sterically Protecting the Nascent Chain from Aberrant Cytosolic Interactions
Trigger Factor Slows Co-translational Folding through Kinetic Trapping while Sterically Protecting the Nascent Chain from Aberrant Cytosolic Interactions
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DOI：
10.1021/ja302305u
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发表时间：
2012-07-04
影响因子：
15
通讯作者：
Dobson, Christopher M.
中科院分区：
文献类型：
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作者：
O'Brien, Edward P.;Christodoulou, John;Dobson, Christopher M.
当新生多肽链从核糖体出口通道中出现时，大肠杆菌伴侣触发因子 (TF) 直接与它们相互作用。小蛋白质结构域可以在 TF 创建的摇篮下折叠，但较大蛋白质的共翻译折叠会因其存在而减慢。由于实现高空间和时间分辨率方面存在巨大的实验挑战，目前尚不清楚 TF 是否会改变小蛋白质的折叠特性，以及较大蛋白质折叠率的降低是否是动力学或热力学效应的结果。我们通过使用一系列核糖体新生链复合物的粗粒度模型进行分子模拟表明，TF 不会显着改变小蛋白 G 结构域的共翻译折叠过程，但由于其未折叠整体的动力学捕获而延迟了大 β-半乳糖苷酶结构域的共翻译折叠过程。我们证明这种捕获是通过三种不同机制的组合发生的：新生链内结构重排速率的降低、由于摇篮外折叠而导致有效出口隧道长度的增加以及新生链与TF的纠缠。我们提供的证据表明，这种 TF 诱导的捕获代表了促进共翻译折叠和空间保护新生链免受可能导致其聚集或降解的异常胞质相互作用之间的权衡。
The E. coli chaperone trigger factor (TF) interacts directly with nascent polypeptide chains as they emerge from the ribosome exit tunnel. Small protein domains can fold under the cradle created by TF, but the co-translational folding of larger proteins is slowed down by its presence. Because of the great experimental challenges in achieving high spatial and time resolution, it is not yet known whether or not TF alters the folding properties of small proteins and if the reduced rate of folding of larger proteins is the result of kinetic or thermodynamic effects. We show, by molecular simulations employing a coarse-grained model of a series of ribosome nascent-chain complexes, that TF does not alter significantly the co-translational folding process of a small protein G domain but delays that of a large beta-galactosidase domain as a result of kinetic trapping of its unfolded ensemble. We demonstrate that this trapping occurs through a combination of three distinct mechanisms: a decrease in the rate of structural rearrangements within the nascent chain, an increase in the effective exit tunnel length due to folding outside the cradle, and entanglement of the nascent chain with TF. We present evidence that this TF-induced trapping represents a trade-off between promoting co-translational folding and sterically shielding the nascent chain from aberrant cytosolic interactions that could lead to its aggregation or degradation.