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构象转变激活 FoxM1 转录因子。

An order-to-disorder structural switch activates the FoxM1 transcription factor.

机构信息

Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, United States.

Department of Computer Science, University of California, Santa Cruz, Santa Cruz, United States.

出版信息

Elife. 2019 May 28;8:e46131. doi: 10.7554/eLife.46131.

DOI:10.7554/eLife.46131
PMID:31134895
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6538375/
Abstract

Intrinsically disordered transcription factor transactivation domains (TADs) function through structural plasticity, adopting ordered conformations when bound to transcriptional co-regulators. Many transcription factors contain a negative regulatory domain (NRD) that suppresses recruitment of transcriptional machinery through autoregulation of the TAD. We report the solution structure of an autoinhibited NRD-TAD complex within FoxM1, a critical activator of mitotic gene expression. We observe that while both the FoxM1 NRD and TAD are primarily intrinsically disordered domains, they associate and adopt a structured conformation. We identify how Plk1 and Cdk kinases cooperate to phosphorylate FoxM1, which releases the TAD into a disordered conformation that then associates with the TAZ2 or KIX domains of the transcriptional co-activator CBP. Our results support a mechanism of FoxM1 regulation in which the TAD undergoes switching between disordered and different ordered structures.

摘要

内在无序的转录因子转录激活结构域（TAD）通过结构可塑性发挥作用，在与转录共调节剂结合时采用有序构象。许多转录因子包含一个负调节结构域（NRD），通过 TAD 的自身调节抑制转录机制的募集。我们报告了 FoxM1 中自动抑制的 NRD-TAD 复合物的溶液结构，FoxM1 是有丝分裂基因表达的关键激活剂。我们观察到，虽然 FoxM1 的 NRD 和 TAD 主要都是内在无序的结构域，但它们会相互结合并采用一种结构化的构象。我们确定了 Plk1 和 Cdk 激酶如何协同磷酸化 FoxM1，从而将 TAD 释放到无序构象，然后与转录共激活剂 CBP 的 TAZ2 或 KIX 结构域结合。我们的结果支持 FoxM1 调节的一种机制，其中 TAD 在无序和不同的有序结构之间进行切换。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a373/6538375/23a34522c6f3/elife-46131-fig7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a373/6538375/23a34522c6f3/elife-46131-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a373/6538375/33455bc060d3/elife-46131-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a373/6538375/0b3b2b5cceed/elife-46131-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a373/6538375/b68d694b7ec2/elife-46131-fig4-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a373/6538375/c5eb2ba638b7/elife-46131-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a373/6538375/28e93a73aa5d/elife-46131-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a373/6538375/8bebcaca9c49/elife-46131-fig5-figsupp2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a373/6538375/23a34522c6f3/elife-46131-fig7.jpg

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