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Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module.

  • Author(s): Li, Yi-Chuan;
  • Chao, Ti-Chun;
  • Kim, Hee Jong;
  • Cholko, Timothy;
  • Chen, Shin-Fu;
  • Li, Guojie;
  • Snyder, Laura;
  • Nakanishi, Kotaro;
  • Chang, Chia-En;
  • Murakami, Kenji;
  • Garcia, Benjamin A;
  • Boyer, Thomas G;
  • Tsai, Kuang-Lei
  • et al.
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 Saccharomyces cerevisiae 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.

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