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A novel role for helix 12 of retinoid X receptor in regulating repression
1Departments of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Abstract:
Nutrients, drugs, and hormones influence transcription during differentiation and metabolism by binding to high-affinity nuclear receptors. In the absence of ligand, some but not all nuclear receptors repress transcription as a heterodimer with retinoid X receptor (RXR). Here we define a novel role for helix 12 (H12) in sterically masking the corepressor (CoR) binding site in apo-RXR. Removing H12 converts RXR to a potent transcriptional repressor. The length but not the specific sequence of H12 is critical for masking RXR's intrinsic repression function. This contrasts with the amphipathic character required for mediating ligand-dependent activation and coactivator recruitment. Physiologically, we show that heterodimerization of RXR with apo-thyroid hormone receptor (TR) unmasks the CoR binding site in RXR and allows the TR-RXR heterodimer to repress. A molecular mechanism that involves sequence-specific interaction between RXR H12 and the coactivator-binding surface of the nuclear receptor is proposed for this heterodimerization-mediated unmasking. Peroxisome proliferator-activated receptor gamma does not interact as well with RXR H12, thus explaining its inability to repress transcription as an RXR heterodimer. The requirement to unmask RXR's latent repression function explains why only certain RXR partners repress transcription.
Insights
Retinoid X receptor (RXR) normally represses transcription when unbound to ligand. Its helix 12 (H12) region masks a corepressor binding site, but partner receptor binding can unmask this site.
Area of Science:
- Molecular biology
- Genetics
- Biochemistry
Background:
- Nuclear receptors regulate gene expression in response to nutrients, drugs, and hormones.
- Many nuclear receptors form heterodimers with retinoid X receptor (RXR) to modulate transcription.
- Unliganded (apo) nuclear receptors, particularly RXR, can repress gene transcription.
Purpose of the Study:
- To elucidate the structural and functional role of RXR's helix 12 (H12) in transcriptional repression.
- To investigate the mechanism by which RXR heterodimerization influences its repression potential.
- To explain differential repression activity among RXR heterodimers.
Main Methods:
- Structural analysis of RXR and its interaction with partner receptors.
- Mutagenesis studies to assess the role of H12 length and sequence.
- Functional assays measuring transcriptional repression activity of RXR and its heterodimers.
Main Results:
- Helix 12 (H12) of apo-RXR sterically masks a corepressor binding site, preventing repression.
- Shortening or removing H12 converts RXR into a potent transcriptional repressor.
- Heterodimerization with certain partners, like thyroid hormone receptor (TR), unmasks the RXR corepressor binding site, enabling repression.
- Interaction efficiency between RXR H12 and partner receptors dictates repression capability.
Conclusions:
- RXR's intrinsic repression function is latent and regulated by H12.
- Heterodimerization-mediated unmasking of the RXR corepressor binding site is a key mechanism for transcriptional repression.
- The specific interaction between RXR H12 and its partner receptor determines the heterodimer's ability to repress transcription.