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TitleStructural basis of the human transcriptional Mediator regulated by its dissociable kinase module.
Journal, issue, pagesMol Cell, Vol. 84, Issue 20, Page 3932-3949.e10, Year 2024
Publish dateOct 17, 2024
AuthorsTi-Chun Chao / Shin-Fu Chen / Hee Jong Kim / Hui-Chi Tang / Hsiang-Ching Tseng / An Xu / Leon Palao / Subash Khadka / Tao Li / Mo-Fan Huang / Dung-Fang Lee / Kenji Murakami / Thomas G Boyer / Kuang-Lei Tsai /
PubMed AbstractThe eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex ...The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex formation in a manner repressed by the CKM through mechanisms presently unknown. Herein, we report cryoelectron microscopy structures of the complete human Mediator and its CKM. The CKM binds to multiple regions on cMED through both MED12 and MED13, including a large intrinsically disordered region (IDR) in the latter. MED12 and MED13 together anchor the CKM to the cMED hook, positioning CDK8 downstream and proximal to the transcription start site. Notably, the MED13 IDR obstructs the recruitment of RNA Pol II/MED26 onto cMED by direct occlusion of their respective binding sites, leading to functional repression of cMED-dependent transcription. Combined with biochemical and functional analyses, these structures provide a conserved mechanistic framework to explain the basis for CKM-mediated repression of cMED function.
External linksMol Cell / PubMed:39321804 / PubMed Central
MethodsEM (single particle)
Resolution3.4 - 8.2 Å
Structure data

41499

8tq2

EMDB-41499, PDB-8tq2:
Structure of the kinase lobe of human CDK8 kinase module
Method: EM (single particle) / Resolution: 3.8 Å

41502

8tqc

EMDB-41502, PDB-8tqc:
Structure of the human CDK8 kinase module
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-41507: The Middle-IDR of the human transcriptional Mediator complex
Method: EM (single particle) / Resolution: 4.9 Å

EMDB-41509: The CKM-Hook of the human transcriptional Mediator complex
Method: EM (single particle) / Resolution: 6.7 Å

EMDB-41511: The Head-IDR of the human transcriptional Mediator complex
Method: EM (single particle) / Resolution: 4.9 Å

EMDB-41512: The Head-IDRc of the human core Mediator complex
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-41513: The Middle-IDRc of the human core Mediator complex
Method: EM (single particle) / Resolution: 3.9 Å

41565

8tqw

EMDB-41565, PDB-8tqw:
Structure of human transcriptional Mediator complex
Method: EM (single particle) / Resolution: 8.2 Å

41580

8trh

EMDB-41580, PDB-8trh:
The IDRc bound human core Mediator complex
Method: EM (single particle) / Resolution: 3.7 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSCRIPTION / Mediator / CDK8 / MED12 / CKM. / MED13 / Mediator.

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