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TitleAn IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II.
Journal, issue, pagesMol Cell, Vol. 84, Issue 14, Page 2648-2664.e10, Year 2024
Publish dateJul 25, 2024
AuthorsHaiyan 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 AbstractThe 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.
External linksMol Cell / PubMed:38955181 / PubMed Central
MethodsEM (single particle)
Resolution4.66 - 7.82 Å
Structure data

40968

8t1i

EMDB-40968, PDB-8t1i:
Atomic model of the mammalian Mediator complex with MED26 subunit
Method: EM (single particle) / Resolution: 4.68 Å

EMDB-40972: CryoEM map of TR-TRAP
Method: EM (single particle) / Resolution: 7.01 Å

EMDB-40975: CryoEM map of mouse mediator complex with alternate conformation CKM module
Method: EM (single particle) / Resolution: 7.82 Å

41107

8t9d

EMDB-41107, PDB-8t9d:
CryoEM structure of TR-TRAP
Method: EM (single particle) / Resolution: 4.66 Å

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsGENE REGULATION / mouse mediator / complex / MED26 subunit / STRUCTURAL PROTEIN / TR-TRAP / mediator / CKM module

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