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. 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. 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.

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.

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

Subunit No.	Human gene	C. elegans gene	D. melanogaster gene	S. cerevisiae gene	Sch. pombe gene
MED1	MED1	Sop3/mdt-1.1, 1.2	MED1	MED1	med1
Med2 a				MED2
Med3 a				PGD1
MED4	MED4		MED4	MED4	med4
Med5 a				NUT1
MED6	MED6	MDT-6	MED6	MED6	med6
MED7	MED7	MDT-7/let-49	MED7	MED7	med7
MED8	MED8	MDT-8	MED8	MED8	med8
Med9	MED9		MED9	CSE2
Med10	MED10	MDT-10		NUT2	med10
Med11	MED11	MDT-11	MED11	MED11	med11
MED12	MED12	MDT-12/dpy-22	MED12	SRB8	srb8
Med12L	MED12L
MED13	MED13	MDT-13/let-19	MED13	SSN2	srb9
MED14	MED14	MDT-14/rgr-1	MED14	RGR1	med14
MED15	MED15	mdt-15	MED15	GAL11	YN91_SCHPO b
MED16	MED16		MED16	SIN4
MED17	MED17	MDT-17	MED17	SRB4	med17
Med18	MED18	MDT-18	MED18	SRB5	med18
Med19	MED19	MDT-19	MED19		med19
Med20	MED20	MDT-20	MED20	SRB2	med20
MED21	MED21	MDT-21	MED21	SRB7	med21
MED22	MED22	MDT-22	MED22	SRB6	med22
MED23	MED23	MDT-23/sur-2	MED23
MED24	MED24		MED24
MED25	MED25		MED25
MED26	MED26		MED26
MED27	MED27		MED27		med27
MED28	MED28		MED28
Med29	MED29	MDT-19	MED29	MED29
MED30	MED30		MED30
MED31	MED31	MDT-31	MED31	SOH1	med31
CCNC	CCNC	cic-1	CycC	SSN8	pch1
CDK8	CDK8	cdk-8	Cdk8	SSN3	srb10

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