| Structural highlights
Function
SSN3_YEAST Component of the SRB8-11 complex. The SRB8-11 complex is a regulatory module of the Mediator complex which is itself involved in regulation of basal and activated RNA polymerase II-dependent transcription. The SRB8-11 complex may be involved in the transcriptional repression of a subset of genes regulated by Mediator. It may inhibit the association of the Mediator complex with RNA polymerase II to form the holoenzyme complex. The SRB8-11 complex phosphorylates the C-terminal domain (CTD) of the largest subunit of RNA polymerase II RPB1 at serines 2 and 5. The SSN3/SRB10 and SSN8/SRB11 kinase-cyclin pair may also positively and negatively regulate numerous transcriptional activators in response to changes in nutritional and physiological conditions. Phosphorylates GCN4, promoting its ubiquitin-mediated degradation, and MSN2, promoting its nuclear exclusion. Phosphorylates STE12, thereby promoting its degradation and inhibition of filamentous growth. Phosphorylates GAL4, and this phosphorylation is required for efficient galactose-inducible transcription. Also phosphorylates BDF1 and the TAF2 subunit of the TFIID complex.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Publication Abstract from PubMed
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.
Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module.,Li YC, Chao TC, Kim HJ, Cholko T, Chen SF, Li G, Snyder L, Nakanishi K, Chang CE, Murakami K, Garcia BA, Boyer TG, Tsai KL Sci Adv. 2021 Jan 15;7(3):eabd4484. doi: 10.1126/sciadv.abd4484. Print 2021 Jan. PMID:33523904[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hirst M, Kobor MS, Kuriakose N, Greenblatt J, Sadowski I. GAL4 is regulated by the RNA polymerase II holoenzyme-associated cyclin-dependent protein kinase SRB10/CDK8. Mol Cell. 1999 May;3(5):673-8. PMID:10360183 doi:10.1016/s1097-2765(00)80360-3
- ↑ Zaman Z, Ansari AZ, Koh SS, Young R, Ptashne M. Interaction of a transcriptional repressor with the RNA polymerase II holoenzyme plays a crucial role in repression. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2550-4. PMID:11226276 doi:10.1073/pnas.041611198
- ↑ Chi Y, Huddleston MJ, Zhang X, Young RA, Annan RS, Carr SA, Deshaies RJ. Negative regulation of Gcn4 and Msn2 transcription factors by Srb10 cyclin-dependent kinase. Genes Dev. 2001 May 1;15(9):1078-92. PMID:11331604 doi:10.1101/gad.867501
- ↑ Kang JS, Kim SH, Hwang MS, Han SJ, Lee YC, Kim YJ. The structural and functional organization of the yeast mediator complex. J Biol Chem. 2001 Nov 9;276(45):42003-10. Epub 2001 Sep 12. PMID:11555651 doi:http://dx.doi.org/10.1074/jbc.M105961200
- ↑ Borggrefe T, Davis R, Erdjument-Bromage H, Tempst P, Kornberg RD. A complex of the Srb8, -9, -10, and -11 transcriptional regulatory proteins from yeast. J Biol Chem. 2002 Nov 15;277(46):44202-7. PMID:12200444 doi:10.1074/jbc.M207195200
- ↑ Nelson C, Goto S, Lund K, Hung W, Sadowski I. Srb10/Cdk8 regulates yeast filamentous growth by phosphorylating the transcription factor Ste12. Nature. 2003 Jan 9;421(6919):187-90. PMID:12520306 doi:10.1038/nature01243
- ↑ Liu Y, Kung C, Fishburn J, Ansari AZ, Shokat KM, Hahn S. Two cyclin-dependent kinases promote RNA polymerase II transcription and formation of the scaffold complex. Mol Cell Biol. 2004 Feb;24(4):1721-35. PMID:14749387 doi:10.1128/MCB.24.4.1721-1735.2004
- ↑ Hallberg M, Polozkov GV, Hu GZ, Beve J, Gustafsson CM, Ronne H, Björklund S. Site-specific Srb10-dependent phosphorylation of the yeast Mediator subunit Med2 regulates gene expression from the 2-microm plasmid. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3370-5. PMID:14988503 doi:10.1073/pnas.0400221101
- ↑ Green SR, Johnson AD. Promoter-dependent roles for the Srb10 cyclin-dependent kinase and the Hda1 deacetylase in Tup1-mediated repression in Saccharomyces cerevisiae. Mol Biol Cell. 2004 Sep;15(9):4191-202. PMID:15240822 doi:10.1091/mbc.e04-05-0412
- ↑ Larschan E, Winston F. The Saccharomyces cerevisiae Srb8-Srb11 complex functions with the SAGA complex during Gal4-activated transcription. Mol Cell Biol. 2005 Jan;25(1):114-23. PMID:15601835 doi:10.1128/MCB.25.1.114-123.2005
- ↑ Ansari AZ, Ogirala A, Ptashne M. Transcriptional activating regions target attached substrates to a cyclin-dependent kinase. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2346-9. PMID:15687503 doi:10.1073/pnas.0409671102
- ↑ Nair D, Kim Y, Myers LC. Mediator and TFIIH govern carboxyl-terminal domain-dependent transcription in yeast extracts. J Biol Chem. 2005 Oct 7;280(40):33739-48. Epub 2005 Aug 2. PMID:16076843 doi:http://dx.doi.org/M506067200
- ↑ van de Peppel J, Kettelarij N, van Bakel H, Kockelkorn TT, van Leenen D, Holstege FC. Mediator expression profiling epistasis reveals a signal transduction pathway with antagonistic submodules and highly specific downstream targets. Mol Cell. 2005 Aug 19;19(4):511-22. PMID:16109375 doi:http://dx.doi.org/10.1016/j.molcel.2005.06.033
- ↑ Andrau JC, van de Pasch L, Lijnzaad P, Bijma T, Koerkamp MG, van de Peppel J, Werner M, Holstege FC. Genome-wide location of the coactivator mediator: Binding without activation and transient Cdk8 interaction on DNA. Mol Cell. 2006 Apr 21;22(2):179-92. PMID:16630888 doi:http://dx.doi.org/S1097-2765(06)00189-4
- ↑ Liao SM, Zhang J, Jeffery DA, Koleske AJ, Thompson CM, Chao DM, Viljoen M, van Vuuren HJ, Young RA. A kinase-cyclin pair in the RNA polymerase II holoenzyme. Nature. 1995 Mar 9;374(6518):193-6. PMID:7877695 doi:10.1038/374193a0
- ↑ Hengartner CJ, Myer VE, Liao SM, Wilson CJ, Koh SS, Young RA. Temporal regulation of RNA polymerase II by Srb10 and Kin28 cyclin-dependent kinases. Mol Cell. 1998 Jul;2(1):43-53. PMID:9702190 doi:10.1016/s1097-2765(00)80112-4
- ↑ Holstege FC, Jennings EG, Wyrick JJ, Lee TI, Hengartner CJ, Green MR, Golub TR, Lander ES, Young RA. Dissecting the regulatory circuitry of a eukaryotic genome. Cell. 1998 Nov 25;95(5):717-28. PMID:9845373
- ↑ Li YC, Chao TC, Kim HJ, Cholko T, Chen SF, Li G, Snyder L, Nakanishi K, Chang CE, Murakami K, Garcia BA, Boyer TG, Tsai KL. Structure and noncanonical Cdk8 activation mechanism within an Argonaute-containing Mediator kinase module. Sci Adv. 2021 Jan 15;7(3):eabd4484. PMID:33523904 doi:10.1126/sciadv.abd4484
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