A key functional event in eukaryotic gene activation is the formation of dynamic protein-protein interaction networks between transcriptional activators and transcriptional coactivators. Seemingly incongruent with the tight regulation of transcription, many biochemical and biophysical studies suggest that activators use nonspecific hydrophobic and/or electrostatic interactions to bind to coactivators, with few if any specific contacts. In contrast, here a mechanistic dissection of a set of representative dynamic activator-coactivator complexes comprised of the ETV/PEA3 family of activators and the coactivator Med25 reveals a different molecular recognition model. The data demonstrate that small sequence variations within an activator family significantly redistribute the conformational ensemble of the complex while not affecting overall affinity, and distal residues within the activator - not often considered as contributing to binding - play a key role in mediating conformational redistribution. The ETV/PEA3-Med25 ensembles are directed by specific contacts between the disordered activator and the Med25 interface, and this specificity is facilitated by structural shifts of the coactivator binding surface. Taken together, this highlights the critical role coactivator plasticity plays in recognition of disordered activators, and indicates that molecular recognition models of disordered proteins must consider the ability of the binding partners to mediate specificity.

中文翻译：

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动态转录蛋白-蛋白质复合物中的意外特异性

真核基因激活中的关键功能事件是转录激活因子和转录共激活因子之间动态蛋白质相互作用的网络的形成。似乎与转录的严格调节不一致，许多生物化学和生物物理研究表明，活化剂利用非特异性的疏水和/或静电相互作用与辅活化剂结合，只有很少的特异性接触。相反，这里由ETV / PEA3活化剂家族和共活化剂Med25组成的一组代表性动态活化剂-协同活化剂复合物的机械解剖揭示了不同的分子识别模型。数据表明，激活剂家族中的小序列变异会显着重新分布复合物的构象整体，而不会影响整体亲和力，活化剂中的远端残基（通常不认为有助于结合）在介导构象重新分布中起关键作用。ETV / PEA3-Med25集成体由无序激活剂和Med25界面之间的特定接触控制，并且通过共激活剂结合表面的结构转移促进了这种特异性。综上所述，这突出了共激活剂可塑性在识别失调激活剂中的关键作用，并表明失调蛋白的分子识别模型必须考虑结合伴侣介导特异性的能力。ETV / PEA3-Med25集成体由无序激活剂和Med25界面之间的特定接触控制，并且通过共激活剂结合表面的结构转移促进了这种特异性。综上所述，这突出了共激活剂可塑性在识别失调激活剂中的关键作用，并表明失调蛋白的分子识别模型必须考虑结合伴侣介导特异性的能力。ETV / PEA3-Med25集成体由无序激活剂和Med25界面之间的特定接触控制，并且通过共激活剂结合表面的结构转移促进了这种特异性。综上所述，这突出了共激活剂可塑性在识别失调激活剂中的关键作用，并表明失调蛋白的分子识别模型必须考虑结合伴侣介导特异性的能力。