7KPX

Structure of the yeast CKM

Summary for 7KPX

• Entry DOI: 10.2210/pdb7kpx/pdb
• EMDB information: 22991
• Descriptor: Meiotic mRNA stability protein kinase SSN3, RNA polymerase II holoenzyme cyclin-like subunit, Mediator of RNA polymerase II transcription subunit 12, ... (4 entities in total)
• Functional Keywords: mediator, transcription, kinase, cdk8, med13, med12, cycc, cdk, argonaute, rna polymerase ii, piwi.
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); More
• Total number of polymer chains: 4
• Total formula weight: 431302.39

Authors

Li, Y.C.,Chao, T.C.,Kim, H.J.,Cholko, T.,Chen, S.F.,Nakanishi, K.,Chang, C.E.,Murakami, K.,Garcia, B.A.,Boyer, T.G.,Tsai, K.L. (deposition date: 2020-11-12, release date: 2021-01-27, Last modification date: 2024-03-06)

Primary citation

Li, Y.C.,Chao, T.C.,Kim, H.J.,Cholko, T.,Chen, S.F.,Li, G.,Snyder, L.,Nakanishi, K.,Chang, C.E.,Murakami, K.,Garcia, B.A.,Boyer, T.G.,Tsai, K.L.
Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module.
Sci Adv, 7:-, 2021

PubMed Abstract: The Cdk8 kinase module (CKM) in Mediator, comprising Med13, Med12, CycC, and Cdk8, regulates RNA polymerase II transcription through kinase-dependent and -independent functions. Numerous pathogenic mutations causative for neurodevelopmental disorders and cancer congregate in CKM subunits. However, the structure of the intact CKM and the mechanism by which Cdk8 is non-canonically activated and functionally affected by oncogenic CKM alterations are poorly understood. Here, we report a cryo-electron microscopy structure of CKM that redefines prior CKM structural models and explains the mechanism of Med12-dependent Cdk8 activation. Med12 interacts extensively with CycC and activates Cdk8 by stabilizing its activation (T-)loop through conserved Med12 residues recurrently mutated in human tumors. Unexpectedly, Med13 has a characteristic Argonaute-like bi-lobal architecture. These findings not only provide a structural basis for understanding CKM function and pathological dysfunction, but also further impute a previously unknown regulatory mechanism of Mediator in transcriptional modulation through its Med13 Argonaute-like features.

PubMed: 33523904
DOI: 10.1126/sciadv.abd4484

Experimental method

ELECTRON MICROSCOPY (4.4 Å)