Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11434-11439. doi: 10.1073/pnas.1705772114. Epub 2017 Oct 10.
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 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.
最近的实验和模拟表明，蛋白质可以在核糖体上折叠。然而，共翻译折叠所导致的适应性效应的程度和普遍性仍然是悬而未决的问题。在这里，我们报告了一项全基因组分析，揭示了进化选择共翻译折叠的证据。我们描述了一种稳健的统计方法来识别基因内的基因座，这些基因座既在翻译速度较慢的密码子中显著富集，又在进化上保守。令人惊讶的是，我们发现结构域边界只能解释这些保守基因座的一小部分。相反，我们提出在翻译速度较慢的密码子中富集的区域与共翻译折叠的中间体相关，这些中间体可能小于单个结构域。我们表明，在共翻译折叠的以天然结构为中心的模型中预测的中间体解释了这些基因座中的大多数，跨越了超过 500 个蛋白质。通过与蛋白质折叠直接联系，这项分析提供了有力的证据，证明许多同义突变已经被选择以优化基因内特定位置的翻译速率。更一般地说，我们的结果表明，动力学，而不仅仅是热力学，可以在生物背景下显著改变自组装的效率。
