In the light of directed evolution: Pathways of adaptive protein evolution
In the light of directed evolution: Pathways of adaptive protein evolution
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DOI：
10.1073/pnas.0901522106
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发表时间：
2009-06-16
影响因子：
11.1
通讯作者：
Arnold, Frances H.
中科院分区：
文献类型：
--
作者：
Bloom, Jesse D.;Arnold, Frances H.
定向进化是一种广泛使用的工程策略，通过反复的突变和选择来提高蛋白质的稳定性或生化功能。这些实验提供了关于蛋白质在面对明确定义的实验室选择压力时如何进化的经验教训。定向进化表明，单个氨基酸突变可以增强催化活性或稳定性等特性，并且适应通常可以通过由顺序有益突变组成的途径发生。当没有单一的突变可以改善某一特定蛋白质的特性时，实验总是会发现大量的突变在实验室定义的适应度测量中是中性的。这些中性突变可以通过至少两种不同的机制开启新的适应途径。功能中性突变可以增强蛋白质的稳定性，从而增加其对随后功能有益但不稳定突变的耐受性。它们也可能导致“混杂”功能的变化，这些功能目前没有选择压力，但随后可能成为新功能适应性进化的起点。这些关于实验室中适应性蛋白和中性蛋白进化之间耦合的经验教训，提供了对自然界中蛋白质进化的洞察。
Directed evolution is a widely-used engineering strategy for improving the stabilities or biochemical functions of proteins by repeated rounds of mutation and selection. These experiments offer empirical lessons about how proteins evolve in the face of clearly-defined laboratory selection pressures. Directed evolution has revealed that single amino acid mutations can enhance properties such as catalytic activity or stability and that adaptation can often occur through pathways consisting of sequential beneficial mutations. When there are no single mutations that improve a particular protein property experiments always find a wealth of mutations that are neutral with respect to the laboratory-defined measure of fitness. These neutral mutations can open new adaptive pathways by at least 2 different mechanisms. Functionally-neutral mutations can enhance a protein's stability, thereby increasing its tolerance for subsequent functionally beneficial but destabilizing mutations. They can also lead to changes in "promiscuous'' functions that are not currently under selective pressure, but can subsequently become the starting points for the adaptive evolution of new functions. These lessons about the coupling between adaptive and neutral protein evolution in the laboratory offer insight into the evolution of proteins in nature.