Evidence of evolutionary selection for cotranslational folding.
Evidence of evolutionary selection for cotranslational folding.
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DOI：
10.1073/pnas.1705772114
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发表时间：
2017-10-24
影响因子：
11.1
通讯作者：
Shakhnovich EI
中科院分区：
文献类型：
--
作者：
Jacobs WM;Shakhnovich EI
影响蛋白质产生的机制至关重要，但尚未完全了解。特别是，多肽链合成的速度可以影响它是否折叠到其天然状态。我们建议，翻译的最佳速率取决于一个新生链，因为它正在合成的采样的稳定构象的序列。使用最佳和罕见的同义密码子作为翻译速度的代理，我们发现，合成中的短暂停顿与共翻译折叠过程中出现的特定中间构象有关，并且这种行为在数百个基因和多个原核基因组中是保守的。这些结果提供了惊人的证据，进化选择有效的蛋白质折叠在体内。最近的实验和模拟表明，蛋白质可以在核糖体上折叠。然而，从共翻译折叠的健身效果的程度和一般性仍然是一个悬而未决的问题。在这里，我们报告了一个全基因组的分析，揭示了共翻译折叠的进化选择的证据。我们描述了一个强大的统计方法，以确定基因内的位点，都显着丰富的缓慢翻译的密码子和进化保守。令人惊讶的是，我们发现，域边界只能解释这些保守的基因座的一小部分。相反，我们提出，在缓慢翻译的密码子丰富的区域与共翻译折叠中间体，这可能是小于一个单一的结构域。我们表明，预测的中间体的一个本地为中心的模型的共翻译折叠占大多数这些位点在超过500大肠杆菌蛋白质。通过与蛋白质折叠的直接联系，该分析提供了强有力的证据，证明许多同义取代已被选择用于优化基因内特定位置的翻译速率。更一般地说，我们的研究结果表明，动力学，而不仅仅是热力学，可以显着改变生物背景下的自组装效率。
The mechanisms that affect protein production are crucially important but incompletely understood. In particular, the speed at which a polypeptide chain is synthesized can affect whether it folds to its native state. We propose that the optimal rate of translation depends on the sequence of stable conformations that are sampled by a nascent chain as it is being synthesized. Using optimal and rare synonymous codons as a proxy for translation speed, we find that transient pauses in synthesis are associated with specific intermediate conformations that appear during cotranslational folding and that this behavior is conserved across hundreds of genes and multiple prokaryotic genomes. These results provide striking evidence of evolutionary selection for efficient protein folding in vivo. Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from cotranslational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for cotranslational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci. Instead, we propose that regions enriched in slowly translated codons are associated with cotranslational folding intermediates, which may be smaller than a single domain. We show that the intermediates predicted by a native-centric model of cotranslational folding account for the majority of these loci across more than 500 Escherichia coli proteins. By making a direct connection to protein folding, this analysis provides strong evidence that many synonymous substitutions have been selected to optimize translation rates at specific locations within genes. More generally, our results indicate that kinetics, and not just thermodynamics, can significantly alter the efficiency of self-assembly in a biological context.
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