Translational tuning optimizes nascent protein folding in cells
Translational tuning optimizes nascent protein folding in cells
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DOI：
10.1126/science.aaa3974
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发表时间：
2015-04-24
期刊：
影响因子：
56.9
通讯作者：
Skach, William R.
中科院分区：
文献类型：
--
作者：
Kim, Soo Jung;Yoon, Jae Seok;Skach, William R.
在细胞中，生物合成机制协调蛋白质合成和折叠，以优化效率并最大限度地减少非途径结果。然而，它一直难以实验描绘的机制负责。利用荧光共振能量转移技术，我们研究了囊性纤维化跨膜传导调节因子第一个核苷酸结合域的共翻译折叠。在合成过程中，折叠通过N-末端、α-螺旋和α/β-核心亚结构域的顺序压缩而离散地发生。此外，这些事件的时机是至关重要的;过早的α-亚结构域折叠阻止了随后的核心形成。通过以三种不同的方式调节内在折叠倾向来促进该过程：延迟α-亚结构域压缩，促进b-链嵌入，以及通过密码子使用优化翻译动力学。因此，从头折叠是由一个综合的细胞反应，形状的共翻译折叠景观在合成的关键阶段的微调。
In cells, biosynthetic machinery coordinates protein synthesis and folding to optimize efficiency and minimize off-pathway outcomes. However, it has been difficult to delineate experimentally the mechanisms responsible. Using fluorescence resonance energy transfer, we studied cotranslational folding of the first nucleotide-binding domain from the cystic fibrosis transmembrane conductance regulator. During synthesis, folding occurred discretely via sequential compaction of N-terminal, alpha-helical, and alpha/beta-core subdomains. Moreover, the timing of these events was critical; premature alpha-subdomain folding prevented subsequent core formation. This process was facilitated by modulating intrinsic folding propensity in three distinct ways: delaying alpha-subdomain compaction, facilitating b-strand intercalation, and optimizing translation kinetics via codon usage. Thus, de novo folding is translationally tuned by an integrated cellular response that shapes the cotranslational folding landscape at critical stages of synthesis.