Institut de Biologie du Développement de Marseille Luminy, Centre National de la Recherche Scientifique, Université de la Méditerranée, 13288 Marseille Cedex 09, France.
Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2276-81. doi: 10.1073/pnas.1006964108. Epub 2011 Jan 24.
Hox genes encode transcription factors widely used for diversifying animal body plans in development and evolution. To achieve functional specificity, Hox proteins associate with PBC class proteins, Pre-B cell leukemia homeobox (Pbx) in vertebrates, and Extradenticle (Exd) in Drosophila, and were thought to use a unique hexapeptide-dependent generic mode of interaction. Recent findings, however, revealed the existence of an alternative, UbdA-dependent paralog-specific interaction mode providing diversity in Hox-PBC interactions. In this study, we investigated the basis for the selection of one of these two Hox-PBC interaction modes. Using naturally occurring variations and mutations in the Drosophila Ultrabithorax protein, we found that the linker region, a short domain separating the hexapeptide from the homeodomain, promotes an interaction mediated by the UbdA domain in a context-dependent manner. While using a UbdA-dependent interaction for the repression of the limb-promoting gene Distalless, interaction with Exd during segment-identity specification still relies on the hexapeptide motif. We further show that distinctly assembled Hox-PBC complexes display subtle but distinct repressive activities. These findings identify Hox-PBC interaction as a template for subtle regulation of Hox protein activity that may have played a major role in the diversification of Hox protein function in development and evolution.
Hox 基因编码转录因子，在动物的发育和进化中广泛用于多样化的身体形态。为了实现功能特异性，Hox 蛋白与 PBC 类蛋白（脊椎动物中的 Pre-B 细胞白血病同源盒（Pbx）和果蝇中的 Extradenticle（Exd））结合，并被认为使用独特的六肽依赖性通用相互作用模式。然而，最近的发现揭示了存在替代的、依赖于 UbdA 的、等位基因特异性的相互作用模式，为 Hox-PBC 相互作用提供了多样性。在这项研究中，我们研究了选择这两种 Hox-PBC 相互作用模式之一的基础。我们利用果蝇 Ultrabithorax 蛋白中的自然发生的变异和突变，发现连接区（分隔六肽和同源域的短域）以依赖于 UbdA 域的方式促进上下文依赖的相互作用。虽然使用依赖于 UbdA 的相互作用来抑制肢体促进基因 Distalless，但在节段身份指定期间与 Exd 的相互作用仍然依赖于六肽基序。我们进一步表明，明显组装的 Hox-PBC 复合物显示出细微但明显的抑制活性。这些发现将 Hox-PBC 相互作用确定为 Hox 蛋白活性的细微调节模板，这可能在 Hox 蛋白功能在发育和进化中的多样化中发挥了主要作用。
