Evolutionary trend toward kinetic stability in the folding trajectory of RNases H
Evolutionary trend toward kinetic stability in the folding trajectory of RNases H
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DOI：
10.1073/pnas.1611781113
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发表时间：
2016-11-15
影响因子：
11.1
通讯作者：
Marqusee, Susan
中科院分区：
文献类型：
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作者：
Lim, Shion A.;Hart, Kathryn M.;Marqusee, Susan
蛋白质的正确折叠对于生产细胞功能所必需的生物机械至关重要。蛋白质折叠过程的速率和能量由其能量状况描述，编码在氨基酸序列中。在进化过程中，必须保持这种格局，使蛋白质在生物学上相关的时间尺度上折叠并保持折叠。蛋白质的能量格局在整个进化过程中究竟是如何维持或改变的，目前尚不清楚。为了研究蛋白质的能量格局是如何随着时间的变化而变化的，我们通过祖先序列重构来表征核糖核酸酶H(RNaseH)家族祖先蛋白质的折叠轨迹，以了解嗜中性菌和嗜热菌RNase H之间的进化历史。我们发现，尽管有很大的序列分歧，但整个折叠途径在数十亿年的进化过程中是保守的。蛋白质折叠和展开的速度有很强的趋势；现代的两种核糖核酸酶H都比它们最近的共同祖先进化得更稳定。最后，我们的研究展示了部分折叠的中间体如何通过允许动力学和热力学的独立调整来提供易于适应的折叠环境。
Proper folding of proteins is critical to producing the biological machinery essential for cellular function. The rates and energetics of a protein's folding process, which is described by its energy landscape, are encoded in the amino acid sequence. Over the course of evolution, this landscape must be maintained such that the protein folds and remains folded over a biologically relevant time scale. How exactly a protein's energy landscape is maintained or altered throughout evolution is unclear. To study how a protein's energy landscape changed over time, we characterized the folding trajectories of ancestral proteins of the ribonuclease H (RNase H) family using ancestral sequence reconstruction to access the evolutionary history between RNases H from mesophilic and thermophilic bacteria. We found that despite large sequence divergence, the overall folding pathway is conserved over billions of years of evolution. There are robust trends in the rates of protein folding and unfolding; both modern RNases H evolved to be more kinetically stable than their most recent common ancestor. Finally, our study demonstrates how a partially folded intermediate provides a readily adaptable folding landscape by allowing the independent tuning of kinetics and thermodynamics.