Evolution of minimal specificity and promiscuity in steroid hormone receptors.
Evolution of minimal specificity and promiscuity in steroid hormone receptors.
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类固醇激素受体的最小特异性和滥交的演变。
DOI：
10.1371/journal.pgen.1003072
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Thornton JW
中科院分区：
文献类型：
--
作者：
Eick GN;Colucci JK;Harms MJ;Ortlund EA;Thornton JW
大多数蛋白质通过与其他分子的物理相互作用来调节;有些是高度特异性的，但其他蛋白质与许多伙伴相互作用。尽管有很多猜测，但我们对天然蛋白质中特异性/混杂性如何以及为什么进化知之甚少。人们普遍认为，特定的蛋白质是从更混杂的古代形式进化而来的，大多数蛋白质的特异性已经通过选择调整到最佳状态。在这里，我们使用祖先的蛋白质重建跟踪配体识别的类固醇激素受体（SR），一个家庭的类固醇调节的动物转录因子的进化历史。我们复活了SR家族中最古老的蛋白质，并表征了它们在配体中区分的结构-活性关系。我们发现，SR进化中最古老的分裂涉及从芳香化雌激素（包括外源性物质）的古老受体到识别非芳香化孕激素和皮质类固醇的衍生受体的离散开关。家族的历史，在其配体的演变，表明SR的演变根据最小特异性的原则：在每一个时间点，受体进化配体识别标准，只是具体到足以解析一组内源性物质，他们被暴露。通过研究复活的SR蛋白的原子结构，我们发现它们的混杂进化是因为祖先的结合腔比主要配体大，并且含有过量的氢键能力，允许具有额外官能团的较大分子的偶然识别。我们的研究结果为现代SR对天然和合成配体（包括内分泌干扰药物和污染物）的敏感性提供了历史解释，并表明历史知识有助于配体预测。他们认为，SR滥交可能反映了真实的生物系统中区分完美和“足够好”的选择能力有限。大多数蛋白质的功能是由它们与其他生物物质（如DNA、营养素、激素或其他蛋白质）的相互作用来定义的。有些蛋白质是高度特异性的，但另一些蛋白质则更加混杂，可以与各种天然物质以及药物和污染物相互作用。了解分子相互作用是药理学和毒理学的一个关键目标，但很少有一般原则来帮助解释或预测蛋白质的特异性。因为每个生物实体都是进化的结果，所以了解蛋白质的历史可能有助于解释为什么它与它敏感的物质相互作用。在本文中，我们使用祖先蛋白质重建来实验性地追踪一组古老的蛋白质，类固醇激素受体（SR），一个调节动物生殖和其他生物过程的蛋白质家族的特异性是如何进化的。我们表明，SR是根据最小特异性的原则进化的：在每个时间点，这些蛋白质进化到足够特异，可以区分它们自然暴露的物质，但不是更多。我们的研究结果为现代SR对天然和人造物质的不同敏感性提供了历史解释;他们表明，历史知识有助于预测现代蛋白质将响应的配体，并表明滥交反映了自然选择区分完美和“足够好”的有限能力。
Most proteins are regulated by physical interactions with other molecules; some are highly specific, but others interact with many partners. Despite much speculation, we know little about how and why specificity/promiscuity evolves in natural proteins. It is widely assumed that specific proteins evolved from more promiscuous ancient forms and that most proteins' specificity has been tuned to an optimal state by selection. Here we use ancestral protein reconstruction to trace the evolutionary history of ligand recognition in the steroid hormone receptors (SRs), a family of hormone-regulated animal transcription factors. We resurrected the deepest ancestral proteins in the SR family and characterized the structure-activity relationships by which they distinguished among ligands. We found that that the most ancient split in SR evolution involved a discrete switch from an ancient receptor for aromatized estrogens—including xenobiotics—to a derived receptor that recognized non-aromatized progestagens and corticosteroids. The family's history, viewed in relation to the evolution of their ligands, suggests that SRs evolved according to a principle of minimal specificity: at each point in time, receptors evolved ligand recognition criteria that were just specific enough to parse the set of endogenous substances to which they were exposed. By studying the atomic structures of resurrected SR proteins, we found that their promiscuity evolved because the ancestral binding cavity was larger than the primary ligand and contained excess hydrogen bonding capacity, allowing adventitious recognition of larger molecules with additional functional groups. Our findings provide an historical explanation for the sensitivity of modern SRs to natural and synthetic ligands—including endocrine-disrupting drugs and pollutants—and show that knowledge of history can contribute to ligand prediction. They suggest that SR promiscuity may reflect the limited power of selection within real biological systems to discriminate between perfect and “good enough.” The functions of most proteins are defined by their interactions with other biological substances, such as DNA, nutrients, hormones, or other proteins. Some proteins are highly specific, but others are more promiscuous and can interact with a variety of natural substances, as well as drugs and pollutants. Understanding molecular interactions is a key goal in pharmacology and toxicology, but there are few general principles to help explain or predict protein specificity. Because every biological entity is the result of evolution, understanding a protein's history might help explain why it interacts with the substances to which it is sensitive. In this paper, we used ancestral protein reconstruction to experimentally trace how specificity evolved in an ancient group of proteins, the steroid hormone receptors (SRs), a family of proteins that regulate reproduction and other biological processes in animals. We show that SRs evolved according to a principle of minimal specificity: at each point in time, these proteins evolved to be specific enough to distinguish among the substances to which they were naturally exposed, but not more so. Our findings provide an historical explanation for modern SRs' diverse sensitivities to natural and man-made substances; they show that knowledge of history can contribute to predicting the ligands to which a modern protein will respond and indicate that promiscuity reflects the limited power of natural selection to discriminate between perfect and “good enough.”
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影响因子：
4.5
作者：
Bridgham, Jamie T.;Brown, Justine E.;Rodriguez-Mari, Adriana;Catchen, Julian M.;Thornton, Joseph W.
通讯作者：
Thornton, Joseph W.
影响因子：
5.6
作者：
Bershtein, Shimon;Goldin, Korina;Tawfik, Dan S.
通讯作者：
Tawfik, Dan S.
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
DOI：
10.1073/pnas.0901522106
发表时间：
2009-06-16
影响因子：
11.1
作者：
Bloom, Jesse D.;Arnold, Frances H.
通讯作者：
Arnold, Frances H.
影响因子：
10.7
作者：
Hanson-Smith V;Kolaczkowski B;Thornton JW
通讯作者：
Thornton JW