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

Autor:	Zhao H; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA., Li J; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA., Xiang Y; Center of Protein Engineering and Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Malik S; Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New York, NY 10065, USA., Vartak SV; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Veronezi GMB; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA., Young N; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA., Riney M; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA., Kalchschmidt J; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Conte A; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Jung SK; Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, MD 20892, USA., Ramachandran S; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA., Roeder RG; Laboratory of Biochemistry and Molecular Biology, Rockefeller University, New York, NY 10065, USA., Shi Y; Center of Protein Engineering and Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Casellas R; Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA., Asturias FJ; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical School, Aurora, CO 80045, USA. Electronic address: francisco.asturias@cuanschutz.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Jul 25; Vol. 84 (14), pp. 2648-2664.e10. Date of Electronic Publication: 2024 Jul 01.
DOI:	10.1016/j.molcel.2024.06.006
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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