Abstract
Retinoid X receptor (RXR)/retinoic acid receptor (RAR) heterodimers control gene expression through recruitment of co-repressors or co-activators, depending on their hormone binding status. We show that the helix 12 of RXRalpha and RARalpha is critical for recruitment of the co-regulators and transcriptional regulation by RXRalpha, RARalpha, and RXRalpha/RARalpha. LG268, an RXR-specific agonist, was able to promote co-activator association with the heterodimers, but was unable to dissociate co-repressors. Reconstitution experiments in yeast demonstrated that LG268 was capable of activating transcription by RXRalpha/RARalpha through recruitment of the co-activator. We hypothesize that the inability to release co-repressors from RXRalpha/RARalpha is responsible for the inability of LG268 to activate RXRalpha/RARalpha heterodimers in mammalian cells. Deletion of RARalpha helix 12 (RXRalpha/RARalpha Delta403) abolished both hormone-dependent dissociation from co-repressors and hormone-dependent association with co-activators. Deletion of RXRalpha helix 12 (RXRalpha Delta443/RARalpha) resulted in a higher binding affinity for co-repressors. Unexpectedly, RXRalpha Delta443/RARalpha also gained hormone-independent co-activator binding activity. Moreover, LG268 became an antagonist to RXRalpha Delta443/RARalpha heterodimers. These data suggest that the helix 12 of RXRalpha plays an inhibitory role in the recruitment of co-activators by unliganded RXRalpha/RARalpha.
Highlights
The nuclear hormone receptors comprise a large family of transcription factors that regulate animal development, cell proliferation, and cell differentiation through the control of a network of genes involved in these processes [1, 2]
Association of Retinoic acid receptors (RARs)␣ Helix 12 Mutants with Co-repressors— To investigate the roles of helix 12 in nuclear receptor function, we focused on helix 12 of RAR␣ and Retinoid X receptors (RXRs)␣
We have examined the role of helix 12 of RAR␣ and RXR␣ on co-regulator recruitment and transcriptional regulation by RXR␣/RAR␣
Summary
The nuclear hormone receptors comprise a large family of transcription factors that regulate animal development, cell proliferation, and cell differentiation through the control of a network of genes involved in these processes [1, 2]. The ability of RXRs to form homodimers or heterodimers with other receptors generates a complex mechanism by which the ligands of RXR may or may not exert effects on target genes, depending on the dimerization partner of the receptor [5]. Receptors such as RARs and TRs (thyroid hormone receptors) dimerize with RXRs, generating a non-permissive complex in which RXR ligands are not capable of activating heterodimers In such heterodimeric complexes, RXRs are referred to as silent partners. The high resolution structure of the liganded RXR␣/RAR␣ heterodimeric complex is available [20] and provides insight into the molecular mechanism of dimerization; the crystal structure of the apo-heterodimer is currently unavailable, likely due to the unstructured helix 12. Understanding the roles of the helix 12 of dimerization partners in co-regulator recruitment is key to elucidating the molecular basis of transcriptional regulation by class II receptors
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