Protein Evolution by Molecular Tinkering: Diversification of the Nuclear Receptor Superfamily from a Ligand-Dependent Ancestor
Protein Evolution by Molecular Tinkering: Diversification of the Nuclear Receptor Superfamily from a Ligand-Dependent Ancestor
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DOI：
10.1371/journal.pbio.1000497
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发表时间：
2010-10-01
期刊：
影响因子：
9.8
通讯作者：
Thornton, Joseph W.
中科院分区：
文献类型：
--
作者：
Bridgham, Jamie T.;Eick, Geeta N.;Thornton, Joseph W.
了解蛋白质的结构和功能是如何多样化的是分子进化的核心目标。然而，对模式生物中差异很大的蛋白质的调查往往不足以确定祖先蛋白质的特征，也不足以揭示产生现存多样性的进化事件。在这里，我们结合联合收割机的基因组，生化，功能，结构和系统发育分析，以重建核受体（NR），一个不同的转录调节因子的超家族，在动物的发育，生理和生殖的早期进化。通过推断的祖先NR的结构和功能，我们表明，与目前的信念相反，NR进化从一个配体激活的祖先受体附近的后生动物的基础存在，脂肪酸作为可能的祖先配体。对这种祖先结构的进化修补产生了现代受体的非凡多样性：对不同配体的敏感性是由于内部空腔的微妙修改而进化的，而不依赖配体的激活是由于在缺乏配体的情况下稳定活性构象的各种突变而反复进化的。我们的研究结果说明了如何在系统发育背景下的蛋白质进化的机械解剖可以揭示深同源性，显然是“新的”分子功能的一个共同的祖先形式。
Understanding how protein structures and functions have diversified is a central goal in molecular evolution. Surveys of very divergent proteins from model organisms, however, are often insufficient to determine the features of ancestral proteins and to reveal the evolutionary events that yielded extant diversity. Here we combine genomic, biochemical, functional, structural, and phylogenetic analyses to reconstruct the early evolution of nuclear receptors (NRs), a diverse superfamily of transcriptional regulators that play key roles in animal development, physiology, and reproduction. By inferring the structure and functions of the ancestral NR, we show-contrary to current belief-that NRs evolved from a ligand-activated ancestral receptor that existed near the base of the Metazoa, with fatty acids as possible ancestral ligands. Evolutionary tinkering with this ancestral structure generated the extraordinary diversity of modern receptors: sensitivity to different ligands evolved because of subtle modifications of the internal cavity, and ligand-independent activation evolved repeatedly because of various mutations that stabilized the active conformation in the absence of ligand. Our findings illustrate how a mechanistic dissection of protein evolution in a phylogenetic context can reveal the deep homology that links apparently "novel" molecular functions to a common ancestral form.