Corepressor interaction differentiates the permissive and non-permissive retinoid X receptor heterodimers

Nurr1 is an orphan nuclear receptor regulating transcription both as a monomer and as a heterodimer with retinoid X receptor (RXR). RXR–Nurr1 heterodimers are permissive RXR heterodimers as they activate transcription in response to RXR ligands. In contrast, heterodimers formed by RXR and retinoic acid receptor (RAR) are non-permissive as they activate transcription only upon RAR ligand binding. We studied the mechanism mediating permissiveness and non-permissiveness by creating receptor chimeras between Nurr1 and RAR. We show that the amino-terminal part of the Nurr1 ligand binding domain conveys permissiveness to RXR–Nurr1 heterodimers. This region is involved in interactions with the corepressors SMRT and NcoR. The corepressors were released from RXR–Nurr1 heterodimers by RXR ligand binding. In contrast, RXR ligand increased the interaction between RXR–RAR heterodimers and the corepressors. The corepressors were released only upon binding of RAR ligand. In conclusion, corepressor interaction differentiates the permissive RXR–Nurr1 heterodimers from the non-permissive RXR–RAR heterodimers.