Mediator (coactivator)

Mediator is a multiprotein complex that functions as a transcriptional coactivator in all eukaryotes. It was discovered by Roger D. Kornberg, winner of the 2006 Nobel Prize in Chemistry. It is also referred to in scientific literature as the vitamin D receptor interacting protein (DRIP) coactivator complex and the thyroid hormone receptor-associated proteins (TRAP).

The mediator complex is required for the successful transcription of nearly all class II gene promoters in yeast.^[1] It works in the same manner in mammals. The human Mediator complex has 31+ subunits and is 1.2 MDa in size. Its large surface area provides great potential for protein–protein interaction, even though its sequences do not contain many predicted functional domains. Mediator has been shown to associate with general transcription factors, as well as RNA polymerase II, and is essential for activator-dependent transcription. It has also been demonstrated that the Mediator complex is involved in activator-independent transcription, implying that it may provide a fundamental control of the formation of the initiation complex^[2] 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.^[3][4]

General structure

The Mediator complex is composed of up to at least 31 subunits in all eukaryotes studied: MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED28, MED29, MED30, MED31, CCNC, and CDK8. There are three fungal-specific components, referred to as Med2, Med3 and Med5.^[5]

The subunits form at least three structurally distinct submodules. The head and the middle modules interact directly with RNA polymerase II, whereas the elongated tail module interacts with gene-specific regulatory proteins. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation.

• The head module contains: MED6, MED8, MED11, SRB4/MED17, SRB5/MED18, ROX3/MED19, SRB2/MED20 and SRB6/MED22.
• The middle module contains: MED1, MED4, NUT1/MED5, MED7, CSE2/MED9, NUT2/MED10, SRB7/MED21 and SOH1/MED31. CSE2/MED9 interacts directly with MED4.
• The tail module contains: MED2, PGD1/MED3, RGR1/MED14, GAL11/MED15 and SIN4/MED16.
• The CDK8 module contains: MED12, MED13, CCNC and CDK8. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.

Table of Mediator complex subunits present in humans and model organisms^[6]

• ^a Fungal-specific
• ^b Protein-name in Sch. pombe

References