+ Site Statistics
References:
52,654,530
Abstracts:
29,560,856
PMIDs:
28,072,755
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies



Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies



Journal of Biological Chemistry 280(2): 1625-1633



Retinoid receptors (RARs and RXRs) are ligand-activated transcription factors that regulate the transcription of target genes by recruiting coregulator complexes at cognate promoters. To understand the effects of heterodimerization and ligand binding on coactivator recruitment, we solved the crystal structure of the complex between the RARbeta/RXRalpha ligand-binding domain heterodimer, its 9-cis retinoic acid ligand, and an LXXLL-containing peptide (termed NR box 2) derived from the nuclear receptor interaction domain (NID) of the TRAP220 coactivator. In parallel, we measured the binding affinities of the isolated NR box 2 peptide or the full-length NID of the coactivator SRC-1 for retinoid receptors in the presence of various types of ligands. Our correlative analysis of three-dimensional structures and fluorescence data reveals that heterodimerization does not significantly alter the structure of individual subunits or their intrinsic capacity to interact with NR box 2. Similarly, we show that the ability of a protomer to recruit NR box 2 does not vary as a function of the ligand binding status of the partner receptor. In contrast, the strength of the overall association between the heterodimer and the full-length SRC-1 NID is dictated by the combinatorial action of RAR and RXR ligands, the simultaneous presence of the two receptor agonists being required for highest binding affinity. We identified an LXXLL peptide-driven mechanism by which the concerted reorientation of three phenylalanine side chains generates an "aromatic clamp" that locks the RXR activation helix H12 in the transcriptionally active conformation. Finally, we show how variations of helix H11-ligand interactions can alter the communication pathway linking helices H11, H12, and the connecting loop L11-12 to the coactivator-binding site. Together, our results reveal molecular and structural features that impact on the ligand-dependent interaction of the RAR/RXR heterodimer with nuclear receptor coactivators.

(PDF emailed within 0-6 h: $19.90)

Accession: 011851426

Download citation: RISBibTeXText

PMID: 15528208

DOI: 10.1074/jbc.M409302200


Related references

Quantitation of endogenous nuclear retinoid receptor proteins in human epidermis in vivo High levels of retinoic acid receptor gamma and retinoid X receptor alpha that bind to a retinoic acid response element exclusively as heterodimers. Journal of Investigative Dermatology 102(4): 554, 1994

Retinoic acid induction of human cellular retinoic acid-binding protein-II gene transcription is mediated by retinoic acid receptor-retinoid X receptor heterodimers bound to one far upstream retinoic acid-responsive element with 5-base pair spacing. Journal of Biological Chemistry 269(35): 22334-9, 1994

Retinoid X receptor in retinoic acid receptor-retinoid X receptor heterodimers selectively confers an RXR ligand response to target genes in epidermis. Journal of Investigative Dermatology 106(4): 819, 1996

Endogenous retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers are the major functional forms regulating retinoid-responsive elements in adult human keratinocytes. Binding of ligands to RAR only is sufficient for RAR-RXR heterodimers to confer ligand-dependent activation of hRAR beta 2/RARE (DR5). Journal of Biological Chemistry 270(7): 3001-3011, 1995

Endogenous Retinoic Acid Receptor (RAR)-Retinoid X Receptor (RXR) Heterodimers Are the Major Functional Forms Regulating Retinoid-responsive Elements in Adult Human Keratinocytes: Binding of ligands to RAR only is sufficient for RAR cntdot RXR heterodimers to confer ligand-dependent activation of hRAR-beta-2/RARE (DR5). Journal of Biological Chemistry 270(7): 3001-3011, 1995

Endogenous Retinoic Acid Receptor -Retinoid X Receptor Heterodimers Are the Major Functional Forms Regulating Retinoid-responsive Elements in Adult Human Keratinocytes Binding of ligands to RAR only is sufficient for RAR cntdot RXR heterodimers to confer ligand-dependent activation of hRAR-beta-2/RARE. Journal of Biological Chemistry 270(7): 3001-3011, 1995

Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors. Molecular and Cellular Biology 17(4): 2166-2176, 1997

Retinoic acid receptor-retinoid X receptor heterodimers are the major functional forms which regulate retinoid responsive reporter genes in cultures human keratinocytes. Journal of Investigative Dermatology 102(4): 554, 1994

Distinct retinoid X receptor-retinoic acid receptor heterodimers are differentially involved in the control of expression of retinoid target genes in F9 embryonal carcinoma cells. Molecular and Cellular Biology 17(6): 3013-3020, 1997

Endogenous retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers are the major functional forms regulating retinoid-responsive elements in adult human keratinocytes. The Journal of Biological Chemistry 270: 01-11, 1995

Retinoic acid induction of human cellular retinoic acid binding protein-II gene transcription is mediated by retinoic acid and retinoid X receptor heterodimers bound to one far upstream retinoic acid responsive element. Journal of Investigative Dermatology 102(4): 524, 1994

Retinoid X receptor - retinoic acid heterodimers dominate retinoid signaling in epidermis in vivo. Journal of Investigative Dermatology 104(4): 596, 1995

Retinoic acid receptor gamma/retinoid X receptor alpha heterodimers bind to the retinoic acid response element in the promoter of the cellular retinol binding protein gene and induce its mRNA and protein expression in human epidermis in vivo. Journal of Investigative Dermatology 102(4): 625, 1994

Retinoic acid receptor/retinoid X receptor heterodimers can be activated through both subunits providing a basis for synergistic transactivation and cellular differentiation. Journal of Biological Chemistry 272(14): 9443-9449, 1997

p21WAF1/CIP1 is a common transcriptional target of retinoid receptors: pleiotropic regulatory mechanism through retinoic acid receptor (RAR)/retinoid X receptor (RXR) heterodimer and RXR/RXR homodimer. Journal of Biological Chemistry 282(41): 29987-29997, 2007