1. Structural basis of the human transcriptional Mediator regulated by its dissociable kinase module.
- Author
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Chao TC, Chen SF, Kim HJ, Tang HC, Tseng HC, Xu A, Palao L 3rd, Khadka S, Li T, Huang MF, Lee DF, Murakami K, Boyer TG, and Tsai KL
- Subjects
- Humans, Binding Sites, Protein Binding, Transcription, Genetic, Models, Molecular, Structure-Activity Relationship, Intrinsically Disordered Proteins metabolism, Intrinsically Disordered Proteins chemistry, Intrinsically Disordered Proteins genetics, Mediator Complex metabolism, Mediator Complex genetics, Mediator Complex chemistry, Cyclin-Dependent Kinase 8 metabolism, Cyclin-Dependent Kinase 8 genetics, Cyclin-Dependent Kinase 8 chemistry, Cryoelectron Microscopy, RNA Polymerase II metabolism, RNA Polymerase II genetics, RNA Polymerase II chemistry
- 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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