Faculty, Staff and Student Publications
Language
English
Publication Date
10-17-2024
Journal
Molecular Cell
DOI
10.1016/j.molcel.2024.09.001
PMID
39321804
PMCID
PMC11832219
PubMedCentral® Posted Date
10-17-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
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.
Keywords
Humans, Mediator Complex, Cyclin-Dependent Kinase 8, Cryoelectron Microscopy, RNA Polymerase II, Binding Sites, Protein Binding, Transcription, Genetic, Models, Molecular, Structure-Activity Relationship, Intrinsically Disordered Proteins
Published Open-Access
yes
Recommended Citation
Chao, Ti-Chun; Chen, Shin-Fu; Kim, Hee Jong; et al., "Structural Basis of the Human Transcriptional Mediator Regulated by Its Dissociable Kinase Module" (2024). Faculty, Staff and Student Publications. 4695.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4695
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