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-Structure paper
Title | Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module. |
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Journal, issue, pages | Sci Adv, Vol. 7, Issue 3, Year 2021 |
Publish date | Jan 15, 2021 |
Authors | Yi-Chuan Li / Ti-Chun Chao / Hee Jong Kim / Timothy Cholko / Shin-Fu Chen / Guojie Li / Laura Snyder / Kotaro Nakanishi / Chia-En Chang / Kenji Murakami / Benjamin A Garcia / Thomas G Boyer / Kuang-Lei Tsai / |
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 ...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. |
External links | Sci Adv / PubMed:33523904 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.8 - 4.9 Å |
Structure data | EMDB-22989, PDB-7kpv: EMDB-22990, PDB-7kpw: EMDB-22991, PDB-7kpx: |
Source |
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Keywords | TRANSCRIPTION / Mediator / Kinase / Cdk8 / Med13 / Med12 / CycC / CDK / Argonaute / RNA Polymerase II / PIWI. / PIWI |