Intricate coupling between the transactivation and basic-leucine zipper domains governs phosphorylation of transcription factor ATF4 by casein kinase 2.
Intricate coupling between the transactivation and basic-leucine zipper domains governs phosphorylation of transcription factor ATF4 by casein kinase 2.
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DOI：
10.1016/j.jbc.2022.101633
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Roche J
中科院分区：
文献类型：
--
作者：
Siang S;Underbakke ES;Roche J
大多数转录因子都具有至少一个长的内在无序的反式激活结构域，该结构域与多种共激活因子和共阻遏因子结合，在调节转录活性中起关键作用。尽管这些结构域至关重要，反式激活的结构和功能基础仍然知之甚少。在这里，我们专注于激活转录因子4（ATF4）/cAMP反应元件结合蛋白-2，细胞应激适应的一个重要转录因子。对ATF4反式激活结构域序列的生物信息学序列分析显示，前125个氨基酸的结构紊乱倾向明显低于结构域的其余部分。使用溶液核磁共振光谱补充了一系列的生物物理方法，我们发现，孤立的反式激活结构域是占主导地位，但没有完全无序的解决方案。我们还观察到，在N-末端的反式激活结构域的短基序具有高螺旋倾向。重要的是，我们发现，N-末端区域的反式激活结构域参与了短暂的长程相互作用与碱性亮氨酸拉链结构域参与DNA结合。最后，酪蛋白激酶2的体外磷酸化试验表明，碱性亮氨酸拉链结构域的存在是反式激活结构域磷酸化所必需的。这项研究揭示了ATF4的反式激活和碱性亮氨酸拉链结构域之间存在的复杂耦合，突出了其潜在的调控意义。
Most transcription factors possess at least one long intrinsically disordered transactivation domain that binds to a variety of coactivators and corepressors and plays a key role in modulating the transcriptional activity. Despite the crucial importance of these domains, the structural and functional basis of transactivation remains poorly understood. Here, we focused on activating transcription factor 4 (ATF4)/cAMP response element-binding protein-2, an essential transcription factor for cellular stress adaptation. Bioinformatic sequence analysis of the ATF4 transactivation domain sequence revealed that the first 125 amino acids have noticeably less propensity for structural disorder than the rest of the domain. Using solution nuclear magnetic resonance spectroscopy complemented by a range of biophysical methods, we found that the isolated transactivation domain is predominantly yet not fully disordered in solution. We also observed that a short motif at the N-terminus of the transactivation domain has a high helical propensity. Importantly, we found that the N-terminal region of the transactivation domain is involved in transient long-range interactions with the basic-leucine zipper domain involved in DNA binding. Finally, in vitro phosphorylation assays with the casein kinase 2 show that the presence of the basic-leucine zipper domain is required for phosphorylation of the transactivation domain. This study uncovers the intricate coupling existing between the transactivation and basic-leucine zipper domains of ATF4, highlighting its potential regulatory significance.
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影响因子：
5.3
作者：
Lassot, I;Ségéral, E;Margottin-Goguet, F
通讯作者：
Margottin-Goguet, F
影响因子：
4.8
作者：
Liang, GS;Hai, T
通讯作者：
Hai, T
DOI：
10.1074/jbc.m109.014092
发表时间：
2010-02-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Armstrong JL;Flockhart R;Veal GJ;Lovat PE;Redfern CP
通讯作者：
Redfern CP
影响因子：
6.1
作者：
Konarev, PV;Volkov, VV;Svergun, DI
通讯作者：
Svergun, DI
影响因子：
4.8
作者：
Bagheri-Yarmand, Rozita;Sinha, Krishna M.;Gagel, Robert F.
通讯作者：
Gagel, Robert F.