A mutation mimicking ligand-induced conformational change yields a constitutive RXR that senses allosteric effects in heterodimers

Abstract

Mutations of a single residue in the retinoid X receptor α (RXRα) ligand‐binding pocket (LBP) generate constitutive, ligand‐binding‐competent mutants with structural and functional characteristics similar to those of agonist‐bound wild‐type RXR. Modelling of the mouse RXRαF318A LBP suggests that, like agonist binding, the mutation disrupts a cluster of van der Waals interactions that maintains helix H11 in the apo‐receptor location, thereby shifting the thermodynamic equilibrium to the holo form. Heterodimerization with some apo‐receptors (retinoic acid, thyroid hormone and vitamin D3 receptors) results in ‘silencing’ of RXRαF318A constitutive activity, which, on the other hand, efficiently contributes to synergistic transactivation within NGFI‐B‐RXR heterodimers. RAR mutants disabled for corepressor binding and/or lacking a functional AF‐2 activation domain, do not relieve RXR ‘silencing’. Not only RAR agonists, but also the RAR antagonist BMS614 induce conformational changes allowing RXR to exert constitutive (RXRαF318A) or agonist‐induced (wild‐type RXR) activity in heterodimers. Interestingly, the RXRαF318A constitutive activity generated within heterodimers in the presence of BMS614 requires the integrity of both RXR and RAR AF‐2 domains. These observations suggest that, within RXR‐RAR heterodimers, RAR can adopt a structure distinct from that of the active holo‐RAR, thus allowing RXR to become transcriptionally responsive to agonists.

9-cis-Retinoic Acid (9cRA), a Retinoid X Receptor (RXR) Ligand, Exerts Immunosuppressive Effects on Dendritic Cells by RXR-Dependent Activation: Inhibition of Peroxisome Proliferator-Activated Receptor γ Blocks Some of the 9cRA Activities, and Precludes Them to Mature Phenotype Development

“…9cRA is a ligand for RXR, and the PPAR␥-RXR and LXR-RXR heterodimers are know to retain ligand-dependent activation of RXR together with specific PPAR␥ or LXR activation (10,24,(53)(54)(55)(56). It is possible that 9cRA act in DCs via the RXR moiety of PPAR␥-RXR, or LXR-RXR heterodimers (57)(58)(59) or even by activation of RXR homodimers (which have recently been described to be able to bind to functional PPAR response elements) (22,60).…”

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

“…It has been previously shown that 9-cis RA strongly enhances the transcriptional activity of the NGFI-B/RXR heterodimer in vitro ( Nuclear receptors and neuroleptic effects I Éthier et al Vivat et al, 1997). More recently, DHA has been identified as a natural ligand for retinoid receptors (de Urquiza et al, 2000;Egea et al, 2002).…”

“…Based on these considerations, it is tempting to suggest that both NGFI-B and RXR, possibly as a transcriptional complex, may be involved in the signaling cascade induced by haloperidol. Indeed, it has been shown that NGFI-B and RXR can form an heterodimer that is active on transcription (Vivat et al, 1997;Castillo et al, 1998) and that 9-cis RA strongly enhances the transcriptional activity of the NGFI-B/RXR heterodimer in vitro (Heyman et al, 1992;Vivat et al, 1997). The acute effect of retinoid ligands on haloperidolinduced catalepsy may be too rapid to support an alteration of retinoid receptor-dependent transcriptional activities.…”

“…Thus, we can hypothesize that addition of a RXR agonist (9-cis RA or DHA) modifies the transcriptional activity of the complex (for a ligand-dependent activity) that interferes with haloperidol-induced effects. Such a twist from constitutive to ligand-induced activity can be observed in vitro after specific mutations in the ligand-binding pocket of RXR (Vivat et al, 1997).…”

The NR4A nuclear receptor family in eosinophils

“…Among the three genes (Nur77, Nurr1, and NOR1) which constitute the NR4A nuclear receptor family, Nur77 and Nurr1 have similar molecular biological characteristics, in that both receptors function as transcription factors forming heterodimers with retinoic X receptor (RXR) (Perlmann and Jansson 1995;Zetterstrom et al 1996a;Vivat et al 1997;Maira et al 1999). They can mediate efficient transactivation through a DR-5 element in response to the RXRspecific ligand, 9-cis retinoic acid.…”