Directed mutational scanning reveals a balance between acidic and hydrophobic residues in strong human activation domains.
Directed mutational scanning reveals a balance between acidic and hydrophobic residues in strong human activation domains.
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定向突变扫描显示，在强烈的人类激活结构域中，酸性残基和疏水残基之间存在平衡。
DOI：
10.1016/j.cels.2022.01.002
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发表时间：
2022-04-20
期刊：
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
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作者：
酸性激活结构域是转录因子结合辅激活因子的固有无序区域。激活结构域的内在无序性和低进化保守性使得难以鉴定控制活性的序列特征。为了解决这个问题，我们在七个酸性激活结构域中设计了数千种变体，并在人类细胞培养中用高通量测定法测量了它们的活性。我们发现，强激活域活性需要酸性残基和芳香族和亮氨酸残基的数量之间的平衡。这些发现激发了酸性激活结构域的预测器，该预测器扫描人类蛋白质组中嵌入高酸性区域的芳香族和亮氨酸残基簇。该预测器识别已知的激活域，并准确预测以前未识别的。我们的研究结果支持一个灵活的酸性暴露模型的激活域中的酸性残基溶解的疏水基序，使它们可以与coactivators相互作用。本文的透明同行评审过程的记录包括在补充信息中。转录激活结构域是转录因子的保守性差、本质上无序的区域，其仍然难以从蛋白质序列预测。高通量方法揭示了强激活域需要酸性和疏水残基之间的平衡。这种平衡为人类转录因子上激活结构域的准确预测提供了动力。
Acidic activation domains are intrinsically disordered regions of the transcription factors that bind coactivators. The intrinsic disorder and low evolutionary conservation of activation domains have made it difficult to identify the sequence features that control activity. To address this problem, we designed thousands of variants in seven acidic activation domains and measured their activities with a high-throughput assay in human cell culture. We found that strong activation domain activity requires a balance between the number of acidic residues and aromatic and leucine residues. These findings motivated a predictor of acidic activation domains that scans the human proteome for clusters of aromatic and leucine residues embedded in regions of high acidity. This predictor identifies known activation domains and accurately predicts previously unidentified ones. Our results support a flexible acidic exposure model of activation domains in which the acidic residues solubilize hydrophobic motifs so that they can interact with coactivators. A record of this paper’s transparent peer review process is included in the supplemental information. Transcriptional activation domains are poorly conserved, intrinsically disordered regions of the transcription factors that remain difficult to predict from protein sequences. A high-throughput method reveals how strong activation domains require a balance between acidic and hydrophobic residues. This balance powers an accurate predictor of activation domains on human transcription factors.
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影响因子：
4.8
作者：
CHANG, J;KIM, DH;SUNG, YC
通讯作者：
SUNG, YC
DOI：
10.1073/pnas.1802640115
发表时间：
2018-07-03
影响因子：
11.1
作者：
Hawkins JA;Jones SK Jr;Finkelstein IJ;Press WH
通讯作者：
Press WH
影响因子：
3.3
作者：
Gray VE;Hause RJ;Fowler DM
通讯作者：
Fowler DM
影响因子：
4.3
作者：
Colwell LJ;Brenner MP;Ribbeck K
通讯作者：
Ribbeck K
DOI：
10.1038/nrg2847
发表时间：
2010-08
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
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