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首页> 外文期刊>Molecular and Cellular Biology >The Significance of Tetramerization in Promoter Recruitment by Stat5
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The Significance of Tetramerization in Promoter Recruitment by Stat5

机译：Stat5促进四聚体在启动子招募中的意义

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Stat5a and Stat5b are rapidly activated by a wide range of cytokines and growth factors, including interleukin-2 (IL-2). We have previously shown that these signal transducers and activators of transcription (STAT proteins) are key regulatory proteins that bind to two tandem gamma interferon-activated site (GAS) motifs within an IL-2 response element (positive regulatory region III [PRRIII]) in the human IL-2Rα promoter. In this study, we demonstrate cooperative binding of Stat5 to PRRIII and explore the molecular basis underlying this cooperativity. We demonstrate that formation of a tetrameric Stat5 complex is essential for the IL-2-inducible activation of PRRIII. Stable tetramer formation of Stat5 is mediated through protein-protein interactions involving a tryptophan residue conserved in all STATs and a lysine residue in the Stat5 N-terminal domain (N domain). The functional importance of tetramer formation is shown by the decreased levels of transcriptional activation associated with mutations in these residues. Moreover, the requirement for STAT protein-protein interactions for gene activation from a promoter with tandemly linked GAS motifs can be relieved by strengthening the avidity of protein-DNA interactions for the individual binding sites. Taken together, these studies demonstrate that a dimeric but tetramerization-deficient Stat5 protein can activate only a subset of target sites. For functional activity on a wider range of potential recognition sites, N-domain-mediated oligomerization is essential.
机译：Stat5a和Stat5b被包括白介素2（IL-2）在内的多种细胞因子和生长因子迅速激活。先前我们已经表明，这些信号转导子和转录激活子（STAT蛋白）是与IL-2反应元件（正调控区III [PRRIII]）内的两个串联γ-干扰素激活位点（GAS）基序结合的关键调控蛋白。在人IL-2Rα启动子中。在这项研究中，我们证明了Stat5与PRRIII的协同结合，并探讨了这种协同作用的分子基础。我们证明四聚体Stat5复合物的形成对于IL-2诱导的PRRIII激活是必不可少的。 Stat5稳定的四聚体形成是通过蛋白质-蛋白质相互作用介导的，其中涉及所有STAT中保守的色氨酸残基和Stat5 N末端结构域（N域）中的赖氨酸残基。与这些残基中的突变相关的转录激活水平降低表明了四聚体形成的功能重要性。此外，通过增强单个结合位点的蛋白质-DNA相互作用的亲合力，可以免除STAT蛋白质-蛋白质相互作用以从具有串联连接的GAS基序的启动子激活基因的需要。综上所述，这些研究表明，二聚体但缺乏四聚体的Stat5蛋白只能激活靶位点的一部分。对于更广泛的潜在识别位点上的功能活性，N域介导的寡聚是必不可少的。

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