Formation of NR-MED1 Coactivator Complex

Stable Identifier
Homo sapiens
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THE NUCLEAR RECEPTOR-MED1 REACTION: The Nuclear Receptor (NR) proteins are a highly conserved family of DNA-binding transcription factors that bind certain hormones, vitamins, and other small, diffusible signaling molecules. The non-liganded NRs recruit specific corepressor complexes of the NCOR/SMRT type, to mediate transcriptional repression of the target genes to which they are bound. During signaling, ligand binding to a specific domain in the NR proteins induces a conformational change that results in the exchange of the associated corepressor complex, and its replacement by a specific coactivator complex of either the TRAP/DRIP/Mediator type, or the p160/SRC type. The Mediator coactivator complexes typically nucleate around the MED1 coactivator protein, which is directly bound to the NR transcription factor (reviewed in Freedman, 1999; Malik, 2005).

A general feature of the NR proteins is that they each contain a specific protein interaction domain (PID), or domains, that mediates the specific binding interactions with the MED1 proteins. In the ligand-bound state, NRs each take part in an NR-MED1 binding reaction to form an NR-MED1 complex. The bound MED1 then functions to nucleate the assembly of additional specific coactivator proteins, depending on the cell and DNA context, such as what specific target gene promoter or enhancer they are bound to, and in what cell type.

The formation of specific MED1-containing coactivator complexes on specific NR proteins has been well-characterized for a number of the human NR proteins. For example, binding of Vitamin D to the human Vitamin D3 Receptor was found to result in the recruitment of a specific complex of D Receptor Interacting Proteins - the DRIP coactivator complex (Rachez, 1998). Within the DRIP complex, the DRIP205 subunit was later renamed human "MED1", based on sequence similarities with yeast MED1 (reviewed in Bourbon, 2004).

Similarly, binding of thyroid hormone (TH) to the human TH Receptor (THRA or THRB) was found to result in the recruitment of a specific complex of Thyroid Receptor Associated Proteins - the TRAP coactivator complex (Yuan, 1998). The TRAP220 subunit was later identified to be the Mediator 1 (MED1) homologue (summarized in Bourbon, et al., 2004; Table 1).

The 48 human NR proteins each contain the PID(s) known to mediate interaction with the human MED1 protein. Direct NR-MED1 protein-protein interactions have been shown for a number of the NR proteins. The MED1-interacting PIDs are conserved in all of the human NRs. Therefore, each of the human NRs is known or expected to interact with MED1 in the appropriate cell context, depending on the cell type, the cell state, and the target gene regulatory region involved.

Literature References
PubMed ID Title Journal Year
10542397 Multimeric Coactivator Complexes for Steroid/Nuclear Receptors

Freedman, LP

Trends Endocrinol Metab 1999
10235266 Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex

Rachez, C, Lemon, BD, Suldan, Z, Bromleigh, V, Gamble, M, Näär, AM, Erdjument-Bromage, H, Tempst, P, Freedman, LP

Nature 1999
11865025 Biological roles and mechanistic actions of co-repressor complexes

Jepsen, K, Rosenfeld, MG

J Cell Sci 2002
15896744 Dynamic regulation of pol II transcription by the mammalian Mediator complex

Malik, S, Roeder, RG

Trends Biochem Sci 2005
15175151 A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II

Bourbon, HM, Aguilera, A, Ansari, AZ, Asturias, FJ, Berk, AJ, Bjorklund, S, Blackwell, TK, Borggrefe, T, Carey, M, Carlson, M, Conaway, JW, Conaway, RC, Emmons, SW, Fondell, JD, Freedman, LP, Fukasawa, T, Gustafsson, CM, Han, M, He, X, Herman, PK, Hinnebusch, AG, Holmberg, S, Holstege, FC, Jaehning, JA, Kim, YJ, Kuras, L, Leutz, A, Lis, JT, Meisterernest, M, Naar, AM, Nasmyth, K, Parvin, JD, Ptashne, M, Reinberg, D, Ronne, H, Sadowski, I, Sakurai, H, Sipiczki, M, Sternberg, PW, Stillman, DJ, Strich, R, Struhl, K, Svejstrup, JQ, Tuck, S, Winston, F, Roeder, RG, Kornberg, RD

Mol Cell 2004
16751179 Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response

Rosenfeld, MG, Lunyak, VV, Glass, CK

Genes Dev 2006
9653119 The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion

Yuan, CX, Ito, M, Fondell, JD, Fu, ZY, Roeder, RG

Proc Natl Acad Sci U S A 1998
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