Biophysical mechanisms for large-effect mutations in the evolution of steroid hormone receptors
Biophysical mechanisms for large-effect mutations in the evolution of steroid hormone receptors
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DOI：
10.1073/pnas.1303930110
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发表时间：
2013-07-09
影响因子：
11.1
通讯作者：
Thornton, Joseph W.
中科院分区：
文献类型：
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作者：
Harms, Michael J.;Eick, Geeta N.;Thornton, Joseph W.
新蛋白质功能进化的遗传和生物物理机制是进化生物学、生物化学和生物物理学的中心问题。特别令人感兴趣的是蛋白质功能的主要变化是否是由几个大的影响突变引起的，如果是，介导这些变化的机制。在这里，我们结合联合收割机祖先的蛋白质重建与遗传操作和明确的蛋白质结构和动力学的研究，解剖一个古老的和离散的转变，在配体特异性的类固醇受体，一个家庭的生物学上必不可少的转录控制因子。我们以前发现，整个类固醇受体家族的祖先是高度特异性的雌激素，但其直接的系统发育后代只对雄激素，孕激素和皮质类固醇敏感。在这里，我们表明这种功能的转变主要是由两个历史氨基酸变化驱动的，这导致了祖先蛋白质特异性的70，000倍变化。这些取代微妙地改变了两个氨基酸的化学性质，但它们通过将过量的相互作用伴侣引入受体/雌激素复合物中，诱导了雌激素特有的次优氢键网络的受挫集合，从而大大降低了雌激素的敏感性。这项工作展示了蛋白质的结构和动力学如何塑造其进化，将一些生化上的细微突变放大为蛋白质能量和功能的重大转变。
The genetic and biophysical mechanisms by which new protein functions evolve is a central question in evolutionary biology, biochemistry, and biophysics. Of particular interest is whether major shifts in protein function are caused by a few mutations of large effect and, if they are, the mechanisms that mediate these changes. Here we combine ancestral protein reconstruction with genetic manipulation and explicit studies of protein structure and dynamics to dissect an ancient and discrete shift in ligand specificity in the steroid receptors, a family of biologically essential hormone-controlled transcription factors. We previously found that the ancestor of the entire steroid receptor family was highly specific for estrogens, but its immediate phylogenetic descendant was sensitive only to androgens, progestogens, and corticosteroids. Here we show that this shift in function was driven primarily by two historical amino acid changes, which caused a similar to 70,000-fold change in the ancestral protein's specificity. These replacements subtly changed the chemistry of two amino acids, but they dramatically reduced estrogen sensitivity by introducing an excess of interaction partners into the receptor/estrogen complex, inducing a frustrated ensemble of suboptimal hydrogen bond networks unique to estrogens. This work shows how the protein's architecture and dynamics shaped its evolution, amplifying a few biochemically subtle mutations into major shifts in the energetics and function of the protein.