Mediator (coactivator)

Diagram of mediator with cyclin-dependent kinase module

Mediator is a multiprotein complex that functions as a transcriptional coactivator in all eukaryotes. It was discovered in 1990 in the lab of Roger D. Kornberg, recipient of the 2006 Nobel Prize in Chemistry.[1][2] Mediator[a] complexes interact with transcription factors and RNA polymerase II. The main function of mediator complexes is to transmit signals from the transcription factors to the polymerase.[3]

Mediator complexes are variable at the evolutionary, compositional and conformational levels.[3] The first image shows only one "snapshot" of what a particular mediator complex might be composed of,[b] but it certainly does not accurately depict the conformation of the complex in vivo. During evolution, mediator has become more complex. The yeast Saccharomyces cerevisiae (a simple eukaryote) is thought to have up to 21 subunits in the core mediator (exclusive of the CDK module), while mammals have up to 26.

Individual subunits can be absent or replaced by other subunits under different conditions. Also, there are many intrinsically disordered regions in mediator proteins, which may contribute to the conformational flexibility seen both with and without other bound proteins or protein complexes. A more realistic model of a mediator complex without the CDK module is shown in the second figure.[4]

The mediator complex is required for the successful transcription by RNA polymerase II. Mediator has been shown to make contacts with the polymerase in the transcription preinitiation complex.[3] A recent model showing the association of the polymerase with mediator in the absence of DNA is shown in the figure to the left.[4] In addition to RNA polymerase II, mediator must also associate with transcription factors and DNA. A model of such interactions is shown in the figure to the right.[5] Note that the different morphologies of mediator do not necessarily mean that one of the models is correct; rather those differences may reflect the flexibility of mediator as it interacts with other molecules.[c] For example, after binding the enhancer and core promoter, the mediator complex undergoes a compositional change in which the kinase module dissociates from the complex to allow association with RNA polymerase II and transcriptional activation.[6]

The Mediator complex is located within the cell nucleus. It is required for the successful transcription of nearly all class II gene promoters in yeast.[7] It works in the same manner in mammals. The mediator functions as a coactivator and binds to the C-terminal domain of RNA polymerase II holoenzyme, acting as a bridge between this enzyme and transcription factors.[8]

  1. ^ Kelleher RJ, Flanagan PM, Kornberg RD (June 1990). "A novel mediator between activator proteins and the RNA polymerase II transcription apparatus". Cell. 61 (7): 1209–15. doi:10.1016/0092-8674(90)90685-8. PMID 2163759. S2CID 4971987.
  2. ^ Flanagan PM, Kelleher RJ, Sayre MH, Tschochner H, Kornberg RD (April 1991). "A mediator required for activation of RNA polymerase II transcription in vitro". Nature. 350 (6317): 436–8. Bibcode:1991Natur.350..436F. doi:10.1038/350436a0. PMID 2011193. S2CID 4323957.
  3. ^ a b c d Allen BL, Taatjes DJ (March 2015). "The Mediator complex: a central integrator of transcription". Nature Reviews Molecular Cell Biology. 16 (3): 155–66. doi:10.1038/nrm3951. PMC 4963239. PMID 25693131.
  4. ^ a b Robinson PJ, Trnka MJ, Pellarin R, Greenberg CH, Bushnell DA, Davis R, Burlingame AL, Sali A, Kornberg RD (September 2015). "Molecular architecture of the yeast Mediator complex". eLife. 4: e08719. doi:10.7554/eLife.08719. PMC 4631838. PMID 26402457.
  5. ^ Bernecky C, Grob P, Ebmeier CC, Nogales E, Taatjes DJ (March 2011). "Molecular architecture of the human Mediator-RNA polymerase II-TFIIF assembly". PLOS Biology. 9 (3): e1000603. doi:10.1371/journal.pbio.1000603. PMC 3066130. PMID 21468301.
  6. ^ Petrenko, N; Jin, Y; Wong, KH; Struhl, K (3 November 2016). "Mediator Undergoes a Compositional Change during Transcriptional Activation". Molecular Cell. 64 (3): 443–454. doi:10.1016/j.molcel.2016.09.015. PMC 5096951. PMID 27773675.
  7. ^ Biddick R, Young ET (September 2005). "Yeast mediator and its role in transcriptional regulation". Comptes Rendus Biologies. 328 (9): 773–82. doi:10.1016/j.crvi.2005.03.004. PMID 16168358.
  8. ^ Björklund S, Gustafsson CM (May 2005). "The yeast Mediator complex and its regulation". Trends in Biochemical Sciences. 30 (5): 240–4. doi:10.1016/j.tibs.2005.03.008. PMID 15896741.


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