Coactivator proteins

Monden T, Wondisford FE, Hollenberg AN (1997) Isolation and characterization of a novel ligand-dependent thyroid hormone receptor-coactivating protein. J Biol Chem 272 29834-29841 Moore SD, Herrick SR, Ince TA, Kleinman MS, Cin PD, Morton CC, Quade BJ (2004) Uterine leiomyomata with t(10 17) disrupt the histone acetyltransferase MORF. Cancer Res 64 5570-5577... 

Thompson, P.R., Kurooka, H., Nakatani, Y. and Cole, P.A. (2001) Transcriptional coactivator protein p300. Kinetic characterization of its histone acetyltransferase activity. The Journal of Biological Chemistry, 276, 33721-33729. 

Coactivator Protein Complexes Most transcription requires the presence of additional protein complexes. Some major regulatory protein complexes that interact with Pol II have been defined both genetically and biochemically. These coactivator complexes act as intermediaries between the DNA-binding transactivators and the Pol II complex. 

The effects of DNA-binding transactivators on Pol II are mediated by coactivator protein complexes such as TFIID or mediator. The modular structures of the transactivators have distinct activation and DNA-binding domains. Other protein complexes, including histone acetyltransferases such as GCN5-ADA2-ADA3 and ATP-dependent complexes such as SWI/SNF and NURF, reversibly remodel chromatin structure. 

Each steroid hormone diffuses across the plasma membrane of its target cell and binds to a specific cytosolic or nuclear receptor. These receptor-ligand complexes accumulate in the nucleus, dimerize, and bind to specific regulatory DIMA sequences (hormone-response elements) in association with coactivator proteins, thereby causing promoter activation and increased transcription of targeted genes. 

The two ERs share many functional characteristics based on their well conserved modular structure. As summarized above, AF-2 is responsible for estrogen-dependent activation through recruitment of coactivator proteins including members of the steroid receptor coactivator (SRC) family (Anzick et al., 1997 Chen et al., 1997 Hong et al., 1996 Kamei et al., 1996 Li et al., 1997 Onate et al., 1995 Torchia et al., 1997 Voegel et al., 1996). On the other hand, AF-1 activity is constitutive and ligand-independent (Berry et al., 1990 Kumar et al., 1987 Metzger et al., 1995). 

That other proteins are associated with the MFGM coat is probable, particularly proteins associated with the surface of intracellular lipid droplets. However, several of the proteins identified as being associated with intracellular lipid droplets (Wu et al., 2000) have yet to be identified as constituents of the MFGM coat. Two proteins associated with intracellular lipid droplets, protein disulfide isomerase (Ghosal et al., 1994) and the nuclear coactivator protein plOO (Keenan et al., 2000) are absent from MFGM preparations. Thus, there apparently is some selectivity in which of the proteins associated with intracellular lipid droplets are secreted. 

Keenan, T.W., Winter, S., Rackwitz, H-R., Heid, H.W. 2000. Nuclear coactivator protein plOO is present in endoplasmic reticulum and lipid droplets of milk secreting cells. Biochim. Biophys. Acta 1523, 84-90. 

The glucocorticoid cortisol is secreted from the adrenal cortex as a stress response under the control of adrenocorticotropic hormone (ACTH, corticotropin) produced by the anterior pituitary. Cortisol promotes catabolism by inducing synthesis of specific proteins. Cortisol binds to a cytosolic cortisol receptor which then translocates to the nucleus and switches on the expression of specific genes, notably that for PEP carboxykinase (PEPCK). Cortisol-induced expression of the key gluconeogenesis enzyme PEPCK increases levels of the enzyme and hence increases gluconeogenesis and available blood glucose. The cAMP-and cortisol-mediated pathways for induction of PEPCK expression are further linked by CREB-dependent expression of a coactivator protein PGC-1 that promotes cortisol-dependent expression of PEPCK. 

How does the phosphorylation of CREB affect its ability to activate transcription Phosphorylation does not appear to alter the DNA-binding properties of this protein. Instead, phosphorylated CREB binds a coactivator protein termed CBP, for CREB-Z)inding /rotein. CBP possesses a highly revealing domain structure (Figure 31.32). 

Monden T, Wondisford FE, Hollenberg AN. 1997. Isolation and characterization of a novel ligand-dependent thyroid hormone receptor-coactivating protein. J. Biol. Chem. 272 29834 41... 

Figure 1A A portion of the X-ray structure (205) cf rosiglitazone co-crystallized with the PPARy ligand-binding domain (LED) and a fragment of the coactivator protein SRC-1, showing the bound con-fo rmation of rosiglitazone. Coordinates were obtained from the Protein Data Bank (212) and displayed with RasMol.

In summary, transcriptional activation mediated by RAR-RXR complexes is a complex, multistep process that is not entirely understood at the molecular level. However, it is clear that agonist-induced, RAR-RXR conformational change, which is crucial for dissociation of the corepressor complex and induction of a receptor conformation that facilitates interaction of the receptor with two distinct classes of coactivator proteins, the HAT and TRAP proteins, plays a central role in the signaling pathways of RAR-RXR complexes leading to transcriptional activation. 

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