Evolution of a derived protein-protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation
Evolution of a derived protein-protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation
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DOI：
10.1073/pnas.1100990108
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发表时间：
2011-08-09
影响因子：
11.1
通讯作者：
Wagner, Guenter P.
中科院分区：
文献类型：
--
作者：
Brayer, Kathryn J.;Lynch, Vincent J.;Wagner, Guenter P.
目前的发育进化模型表明，基因调控的变化是形态进化的基础。尽管事实上，蛋白质复合物调节基因的表达，调控蛋白质复合物的进化很少被研究。在这里，我们研究了同源框A11（HoxA 11）和叉头框01 A（Foxo 1a）之间的蛋白质-蛋白质相互作用（PPI）的演变。使用现存的和“复活”的祖先蛋白质，我们表明，HoxA 11和Foxo 1a之间的物理相互作用起源于哺乳动物的干细胞谱系。异源蛋白对的功能分歧测试和免疫共沉淀表明，相互作用的演变是由于HoxA 11的变化，和删除的研究表明，相互作用的界面位于HoxA 11的同源结构域区域。然而，在这段时间内同源结构域区域的氨基酸序列没有变化，表明衍生PPI的起源可归因于结合界面外的变化。我们推断HoxA 11中的氨基酸取代改变了Foxo 1a进入HoxA 11同源结构域保守结合界面的途径。我们还发现哺乳动物谱系物种基因组中成对的Hox/Fox结合位点数量增加，表明该复合物具有生物学功能。我们的数据表明，HoxA 11和Foxo 1a之间的物理相互作用通过促进PPI的非界面变化，从而防止不适当的相互作用，而不是通过一个新的结合界面的演变。我们推测，与相互作用结构域本身的变化相比，分子内调控的进化变化具有有限的多效性效应。
Current models of developmental evolution suggest changes in gene regulation underlie the evolution of morphology. Despite the fact that protein complexes regulate gene expression, the evolution of regulatory protein complexes is rarely studied. Here, we investigate the evolution of a protein-protein interaction (PPI) between Homeobox A11 (HoxA11) and Forkhead box 01A (Foxo1a). Using extant and "resurrected" ancestral proteins, we show that the physical interaction between HoxA11 and Foxo1a originated in the mammalian stem lineage. Functional divergence tests and coimmunoprecipitation with heterologous protein pairs indicate that the evolution of interaction was attributable to changes in HoxA11, and deletion studies demonstrate that the interaction interface is located in the homeodomain region of HoxA11. However, there are no changes in amino acid sequence in the homeodomain region during this time period, indicating that the origin of the derived PPI was attributable to changes outside the binding interface. We infer that the amino acid substitutions in HoxA11 altered Foxo1a's access to the conserved binding interface at the HoxA11 homeodomain. We also found an expansion in the number of paired Hox/Fox binding sites in the genomes of mammalian lineage species suggesting the complex has a biological function. Our data indicate that the physical interaction between HoxA11 and Foxo1a evolved through noninterface changes that facilitate the PPI, which prevents inappropriate interactions, rather than through the evolution of a novel binding interface. We speculate that evolutionary changes of intramolecular regulation have limited pleiotropic effects compared with changes to interaction domains themselves.