Coactivator-complex proteins

Finally, the binding of specific transcription factors to cognate DNA elements may result in disruption of nucleosomal structure. Many eukaryotic genes have multiple protein-binding DNA elements. The serial binding of transcription factors to these elements—in a combinatorial fashion—may either directly disrupt the structure of the nucleosome or prevent its re-formation or recruit, via protein-protein interactions, multiprotein coactivator complexes that have the ability to covalently modify or remodel nucleosomes. These reactions result in chromatin-level structural changes that in the end increase DNA accessibifity to other factors and the transcription machinery. 

A small number of proteins, including NCoR and SMRT, comprise the corepressor family. They function, at least in part, as described in Figure 43-2. Another family includes the TRAPs, DRIPs, and ARC (Table 43-6). These so-called mediator-related proteins range in size from 80 kDa to 240 kDa and are thought to be involved in linking the nuclear receptor-coactivator complex to RNA polymerase II and the other components of the basal transcription apparatus. 

Kurokawa R, Kalafus D, OgUastro MH, Kioussi C, Xu L, Torchia J, Rosenfeld MG, Glass CK (1998) Differential use of CREB binding protein-coactivator complexes. Science 279 700-703 Kwok RP, Lundblad JR, Chrivia,JC, Richards JP, Bachinger HP, Brennan RG, Roberts SG, Green MR, Goodman RH (1994) Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370 223-226... 

Baek, S.H., Ohgi, K.A., Rose, D.W., Koo, E.H., Glass, C.K., Rosenfeld, M.G. (2002) Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappa-B and beta-amyloid precursor protein. Cell, 110, 55-67. 

In the resting state, the lysine residues in the N-terminal tail of the histones (see p. 238) are not acetylated. In this state, which can be produced by histone deacetylases [1], the nucleosomes are stable. It is only the interaction of activator and regulator proteins with their control elements that allows the binding of coactivator complexes that have histone acetylase activity [2]. They acetylate the histone tails and thereby loosen the nu-cleosome structure suf ciently for the basal transcription complex to form. 

Lee, Y.H., Coonrod, S.A., Kraus, W.L, Jelinek, M.A. and Stallcup, M.R. (2005) Regulation of coactivator complex assembly and frmction by protein arginine methylation and demethylimination. Proceedings of the National Academy of Sciences of the United States of America, 102, 3611-3616. 

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. 

Another important coactivator consists of 20 or more polypeptides in a protein complex called mediator (Fig. 28-27) the 20 core polypeptides are highly conserved from fungi to humans. Mediator binds tightly to the carboxyl-terminal domain (CTD) of the largest subunit of Pol II. The mediator complex is required for both basal and regulated transcription at promoters used by Pol II, and it also stimulates the phosphorylation of the CTD by TFIIH. Both mediator and TFIID are required at some promoters. As with TFIID, some DNA-binding transactivators interact with one or more components of the mediator complex. Coactivator complexes function at or near the promoter s TATA box. 

Figure 2 A model for RAR/RXR acting in concert with coactivator or corepressor complex for gene activation or silencing. In the presence of ligands (+RA), the holo-receptor pair binds to the RA response element (RARE) and recruits coactivator complex, which encodes histone acetyl transferase (HAT) activity. HAT acetylates histone proteins, opens up the chromatin, and allows the transcription machinery to act on the promoter for active gene transcription. In the absence of ligands (—RA), the apo-receptor pair binds to the RARE and recruits corepressor that encodes histone deacetylase (HDAC) activity, inducing histone deacetylation, chromatin condensation, and gene silencing.

Barletta F, Freedman LP, Christakos S. 2002. Enhancement of VDR-mediated transcription by phosphorylation correlation with increased interaction between the VDR and DRIP205, a subunit of the VDR-interacting protein coactivator complex. Mol. Endocrinol. 16 301-14... 

Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG. 1998. The TRAP220 component of a thyroid hormone receptor-associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand dependent fashion. Proc. Natl. Acad Sci. USA 95 7939 14... 

Interaction of the HAT coactivatorcomplex with the ligand-activated receptors is apparently transient as dissociation is believed to occur as a result of acetylation of one or more coactivators on lysine residues adjacent to the signature LXXLL motif (187). Subsequently, the activated receptor presumably recruits a second class of multi-protein, transcriptional coactivator complexes to the template, and this latter complex, referred to as the thyroid hormone receptor-associated protein (TRAP)... 

Saleh, A., Lang, V., Cook, R., and Brandi, C.J. (1997) Identification of native complexes containing the yeast coactivator/repressor proteins Ngglp/ Ada3p and Ada2p. The Journal of Biological Chemistry, 272, 5571-5578. 

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