Historical contingency and its biophysical basis in glucocorticoid receptor evolution.
Historical contingency and its biophysical basis in glucocorticoid receptor evolution.
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DOI：
10.1038/nature13410
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发表时间：
2014-08-14
期刊：
影响因子：
64.8
通讯作者：
Thornton, Joseph W.
中科院分区：
文献类型：
--
作者：
Harms, Michael J.;Thornton, Joseph W.
了解偶然的历史事件如何塑造进化过程是进化生物学的中心目标。对进化偶然性的程度和原因的直接了解仅限于实验系统，因为很难知道遥远的过去发生了什么，也很难描述进化可能遵循的其他路径。在这里，我们结合祖先蛋白质重建、定向进化和生物物理分析，探索新蛋白质功能的古代进化过程中的替代“可能已经”的轨迹。我们之前发现，祖先糖皮质激素受体（GR）中皮质醇特异性的进化取决于允许的取代，这对受体功能没有明显影响，但对于GR耐受导致特异性转变的大效应突变是必要的。在这里，我们表明，在祖先GR可访问的基因型集合中，可能允许历史功能转换替代的替代突变极其罕见。在祖先蛋白质的数千个变体的文库中，我们恢复了历史允许的替换，但没有发现替代的允许的基因型。通过生物物理分析，我们发现允许突变必须满足至少三个物理要求——它们必须稳定蛋白质结构的特定局部元素，维持功能构象之间正确的能量平衡，并与祖先和派生结构兼容——从而揭示了为什么允许突变很少见。这些发现表明，GR 进化强烈依赖于不可能的、不确定的事件，而这种偶然性源于蛋白质的内在生物物理特性。
Understanding how chance historical events shape evolutionary processes is a central goal of evolutionary biology. Direct insights into the extent and causes of evolutionary contingency have been limited to experimental systems, because it is difficult to know what happened in the deep past and to characterize other paths that evolution could have followed. Here we combine ancestral protein reconstruction, directed evolution, and biophysical analysis to explore alternate “might-have-been” trajectories during the ancient evolution of a novel protein function. We previously found that the evolution of cortisol specificity in the ancestral glucocorticoid receptor (GR) was contingent on permissive substitutions, which had no apparent effect on receptor function but were necessary for GR to tolerate the large-effect mutations that caused the shift in specificity. Here we show that alternative mutations that could have permitted the historical function-switching substitutions are extremely rare in the ensemble of genotypes accessible to the ancestral GR. In a library of thousands of variants of the ancestral protein, we recovered historical permissive substitutions, but no alternate permissive genotypes. Using biophysical analysis, we found that permissive mutations must satisfy at least three physical requirements—they must stabilize specific local elements of the protein structure, maintain the correct energetic balance between functional conformations, and be compatible with the ancestral and derived structures—thus revealing why permissive mutations are rare. These findings demonstrate that GR evolution depended strongly on improbable, nondeterministic events, and this contingency arose from intrinsic biophysical properties of the protein.
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