An epistatic ratchet constrains the direction of glucocorticoid receptor evolution.
An epistatic ratchet constrains the direction of glucocorticoid receptor evolution.
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DOI：
10.1038/nature08249
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发表时间：
2009-09-24
期刊：
影响因子：
64.8
通讯作者：
Thornton JW
中科院分区：
文献类型：
--
作者：
Bridgham JT;Ortlund EA;Thornton JW
进化的可逆性一直吸引着生物学家。大多数以前的工作的可逆性形态和生活史进化一直是不确定的，因为不确定性和偏见的方法来推断祖先的状态，这样的字符。此外，尽管理论工作的因素，可能有助于不可逆性，有很少的经验证据，其原因，因为足够的理解的机制基础，新的或祖先的表型的演变是很少。通过研究蛋白质结构和功能进化变化的可逆性，这些限制可以被克服。在这里，我们表明，使用进化的激素特异性在脊椎动物糖皮质激素受体（GR）作为一个案例研究，GR获得其新的功能的进化路径很快就变得难以逆转的探索。使用祖先基因重建，蛋白质工程和X射线晶体学，我们证明了五个随后的“限制性”突变，优化了GR的新特异性，也破坏了支持祖先构象所需的蛋白质结构元素。除非这些棘轮样上位取代恢复到它们的祖先状态，否则逆转关键的功能转换突变会产生无功能的蛋白质。然而，首先逆转限制性取代并不能增强祖先的功能。我们的研究结果表明，即使对祖先功能进行选择，直接逆转也是极不可能的，这表明历史偶然性在蛋白质进化中起着重要作用。
The extent to which evolution is reversible has long fascinated biologists. Most prior work on the reversibility of morphological and life-history evolution has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters. Further, despite theoretical work on the factors that could contribute to irreversibility, there is scant empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in vertebrate glucocorticoid receptors (GRs) as a case-study, that the evolutionary path by which GR acquired its new function soon became inaccessible to reverse exploration. Using ancestral gene reconstruction, protein engineering, and X-ray crystallography, we demonstrate that five subsequent “restrictive” mutations, which optimized GR’s new specificity, also destabilized elements of the protein’s structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key function-switching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.6
作者：
CRICK, FHC
通讯作者：
CRICK, FHC
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
3.3
作者：
Castric, V;Bonney, F;Bernatchez, L
通讯作者：
Bernatchez, L
影响因子：
3.3
作者：
Goldberg, Emma E.;Igic, Boris
通讯作者：
Igic, Boris