Structural highlights
Disease
MED27_HUMAN Non-specific syndromic intellectual disability. The disease may be caused by variants affecting the gene represented in this entry.
Function
MED27_HUMAN Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.[1] [2]
Publication Abstract from PubMed
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.
Structural basis of the human transcriptional Mediator regulated by its dissociable kinase module.,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, Tsai KL Mol Cell. 2024 Sep 19:S1097-2765(24)00734-2. doi: 10.1016/j.molcel.2024.09.001. PMID:39321804[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Malik S, Gu W, Wu W, Qin J, Roeder RG. The USA-derived transcriptional coactivator PC2 is a submodule of TRAP/SMCC and acts synergistically with other PCs. Mol Cell. 2000 Apr;5(4):753-60. PMID:10882111 doi:10.1016/s1097-2765(00)80254-3
- ↑ Ryu S, Zhou S, Ladurner AG, Tjian R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature. 1999 Feb 4;397(6718):446-50. PMID:9989412 doi:10.1038/17141
- ↑ 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, Tsai KL. Structural basis of the human transcriptional Mediator regulated by its dissociable kinase module. Mol Cell. 2024 Sep 19:S1097-2765(24)00734-2. PMID:39321804 doi:10.1016/j.molcel.2024.09.001
