Mediator (coactivator)

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. Mediator interacts with transcription factors and RNA polymerase II. It mainly functions to transmit signals from the transcription factors to the polymerase.

Mediator complexes are variable at the evolutionary, compositional and conformational levels. Figure 1 shows only one "snapshot" of what a particular complex might comprise, but it is an inaccurate depiction of the conformation in vivo. During evolution, Mediator has complexified. 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 Mediator without the CDK module is shown in Figure 2.

Mediator is required for successful transcription of genes by RNA polymerase II, and contacts the polymerase in the transcription preinitiation complex. A recent model showing the polymerase associating with Mediator without DNA is shown in Figure 3. In addition to RNA polymerase II, Mediator must also associate with transcription factors and DNA; a model of such interactions is shown in Figure 4. Note that the different morphologies of Mediator do not necessarily mean that a particular model is correct; rather those differences may reflect the flexibility of Mediator as it interacts with other molecules. For example, after binding the enhancer and core promoter, the Mediator complex compositionally changes, dissociating the kinase module and associating with RNA polymerase II for transcriptional activation.

Mediator is located within the cell nucleus. It is required for successfully transcribing nearly all class II gene promoters in yeast. It works similarly in mammals. Mediator functions as a coactivator and binds to the C-terminal domain of RNA polymerase II holoenzyme, bridging this enzyme and transcription factors.