Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification.
Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification.
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DOI：
10.1016/j.str.2008.06.013
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发表时间：
2008-09-10
期刊：
影响因子：
--
通讯作者：
Marmorstein R
中科院分区：
文献类型：
--
作者：
Brent MM;Anand R;Marmorstein R
FoxO 转录因子调节控制新陈代谢、细胞增殖、应激耐受性和可能的寿命的基因的转录。叉头 DNA 结合域内的许多翻译后修饰调节 FoxO 介导的转录。我们报告了 FoxO1 与三种不同 DNA 元件结合的晶体结构，并测量了 FoxO1-DNA 亲和力随乙酰化和磷酸化的变化。这些结构揭示了最高亲和力 DNA 位点的额外接触和增加的 DNA 扭曲。在结构中未观察到叉头结构域的柔性翼 2 区域，但它对于 DNA 结合是必需的，并且我们表明翼 2 中的 p300 乙酰化会降低 DNA 亲和力。我们还表明 FoxO1 的 MST1 磷酸化可阻止高亲和力 DNA 结合。 FoxO-DNA 亲和力在反应元件之间和翻译后修饰之间变化的观察结果表明，FoxO-DNA 亲和力的调节是 FoxO 健康调节和疾病失调的重要组成部分。
FoxO transcription factors regulate the transcription of genes that control metabolism, cellular proliferation, stress tolerance and possibly lifespan. A number of post-translational modifications within the forkhead DNA binding domain regulate FoxO mediated transcription. We report the crystal structures of FoxO1 bound to three different DNA elements and measure the change in FoxO1-DNA affinity with acetylation and phosphorylation. The structures reveal additional contacts and increased DNA distortion for the highest affinity DNA site. The flexible wing 2 region of the forkhead domain was not observed in the structures but is necessary for DNA-binding, and we show that p300 acetylation in wing 2 reduces DNA affinity. We also show that MST1 phosphorylation of FoxO1 prevents high affinity DNA binding. The observation that FoxO-DNA affinity varies between response elements and with post-translational modifications suggests that modulation of FoxO-DNA affinity is an important component of FoxO regulation in health and misregulation in disease.
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影响因子：
64.5
作者：
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通讯作者：
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DOI：
10.1107/s0907444904019158
发表时间：
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