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Title | An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II. |
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Journal, issue, pages | Mol Cell, Vol. 84, Issue 14, Page 2648-2664.e10, Year 2024 |
Publish date | Jul 25, 2024 |
![]() | 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 / ![]() |
PubMed 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 ...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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Methods | EM (single particle) |
Resolution | 4.66 - 7.82 Å |
Structure data | EMDB-40968, PDB-8t1i: ![]() EMDB-40972: CryoEM map of TR-TRAP ![]() EMDB-40975: CryoEM map of mouse mediator complex with alternate conformation CKM module EMDB-41107, PDB-8t9d: |
Source |
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![]() | GENE REGULATION / mouse mediator / complex / MED26 subunit / STRUCTURAL PROTEIN / TR-TRAP / mediator / CKM module |