8tqc
Structure of the human CDK8 kinase module
Structural highlights
DiseaseMED12_HUMAN FG syndrome type 1;Blepharophimosis-intellectual disability syndrome, MKB type;X-linked non-syndromic intellectual disability;Lujan-Fryns syndrome;Blepharophimosis-intellectual disability syndrome, Ohdo type;Hardikar syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionMED12_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 pre-initiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway.[1] [2] [3] Publication Abstract from PubMedThe 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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