An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II

IF 14.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell Pub Date : 2024-07-01 DOI:10.1016/j.molcel.2024.06.006

Haiyan Zhao, Jiaqin Li, Yufei Xiang, Sohail Malik, Supriya V. Vartak, Giovana M.B. Veronezi, Natalie Young, McKayla Riney, Jens Kalchschmidt, Andrea Conte, Seol Kyoung Jung, Srinivas Ramachandran, Robert G. Roeder, Yi Shi, Rafael Casellas, Francisco J. Asturias

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Abstract

The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction. This restriction is eliminated by nuclear receptor (NR) binding to CKM-MED, which enables CTD binding in a MED26-dependent manner. Cryoelectron microscopy (cryo-EM) and crosslinking-mass spectrometry (XL-MS) revealed that the structural basis for modulation of CTD interaction with MED relates to a large intrinsically disordered region (IDR) in CKM subunit MED13 that blocks MED26 and CTD interaction with MED but is repositioned upon NR binding. Hence, NRs can control transcription initiation by priming CKM-MED for MED26-dependent RNA Pol II interaction.

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核受体控制 Mediator 与 RNA 聚合酶 II 交互作用的 IDR 依赖性机制

在所有真核生物中，基本介子（MED）辅激活子复合物在调控基础转录中的作用已为人们所熟知，但其在激活子依赖性转录中的作用机制仍然未知。我们研究了 MED26 亚基和 CDK8 激酶模块（CKM）的拮抗作用对元动物 MED 与 RNA 聚合酶 II（RNA Pol II）相互作用的调节。对 CKM-MED 的生化分析表明，CKM 阻碍了 RNA Pol II 羧基末端结构域（CTD）的结合，从而阻止了 RNA Pol II 的相互作用。核受体（NR）与 CKM-MED 的结合消除了这种限制，CKM-MED 使 CTD 以依赖 MED26 的方式结合。冷冻电子显微镜（cryo-EM）和交联质谱（XL-MS）显示，CTD与MED相互作用的结构基础与CKM亚基MED13中的一个大的内在无序区（IDR）有关，该区域阻碍了MED26和CTD与MED的相互作用，但在与NR结合后被重新定位。因此，NR 可通过引导 CKM-MED 与 MED26 依赖性 RNA Pol II 相互作用来控制转录的启动。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cell 生物-生化与分子生物学

CiteScore

26.00

自引率

3.80%

发文量

389

审稿时长

1 months

期刊介绍： Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.

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