RXR Agonist Modulates TR: Corepressor Dissociation Upon 9-cis Retinoic Acid Treatment

Abstract

Transcriptional regulation controlled by thyroid hormone receptor (TR) drives events such as development, differentiation, and metabolism. TRs may act either as homodimers or as heterodimers with retinoid X receptor (RXR). Thyroid hormone T3 preferentially binds TR-RXR heterodimers, which activate transcription through coactivator recruitment. However, it is unclear whether TR-RXR heterodimers may also be responsive to the canonical RXR agonist 9-cis retinoic acid (9C) in the context of physiological gene regulation. New structural studies suggest that 9C promotes the displacement of bound coactivators from the heterodimer, modifying TR-RXR activity. To shed light on the molecular mechanisms that control TR-RXR function, we used biophysical approaches to characterize coregulator recruitment to TR-TR or to TR-RXR in the presence of T3 and/or 9C as well as cell-based assays to establish the functional significance of biophysical findings. Using cell-based and fluorescence assays with mutant and wild-type TR, we show that 9C does indeed have a function in the TR-RXR heterodimer context, in which it induces the release of corepressors. Furthermore, we show that 9C does not promote detectable conformational changes in the structure of the TR-RXR heterodimer and does not affect coactivator recruitment. Finally, our data support the view that DNA binding domain and Hinge regions are important to set up NR-coactivator binding interfaces. In summary, we showed that the RXR agonist 9C can regulate TR function through its modulation of corepressor dissociation.

Evolution of Regulated Transcription

“…An important principle is that heterodimerization not only yields factors with different affinities for DNA, but also combines activators from different groups, which carry DBDs of different affinities and have ADs of different properties. For example, the thyroid hormone nuclear receptor (TR) can form a TR/TR pair and a pair with the retinoid X-receptor, TR/RXR, which binds DNA more strongly than TR/TR [ 195 , 196 ]. Dimerization of MyoD (see below) with the ubiquitously expressed protein E12 or E47 is required for its maximal DNA-binding activity [ 197 , 198 ].…”

BDE-99, but not BDE-47, is a transient aryl hydrocarbon receptor agonist in zebrafish liver cells

“…However, Rxrb has two subtypes, Rxrba and Rxrbb, and Rxrba has several variants. A literature review revealed that little information is available on specific RXR with TR heterodimerization (Leid et al, 1992;Nagpal et al, 1993;Germain et al, 2006;Fattori et al, 2015). Therefore, we cloned LBDs from both zebrafish Rxrba-and Rxrbb.…”

ADAM17 cytoplasmic domain modulates Thioredoxin-1 conformation and activity

“…Three independent experiments were performed. Besides, to evaluate if the mutation in ADAM17cyto was able to change its secondary structure, circular dichroism analysis was performed with both proteins (ADAM17cytoWT and ADAM17cytoF730A) as previously described [ 49 ]. One independent experiment was performed.…”