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Molecular and Cellular Biology, April 1999, p. 3073-3085, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Allosteric Regulation of the Discriminative Responsiveness of Retinoic Acid Receptor to Natural and Synthetic Ligands by Retinoid X Receptor and DNA

Arnaud Mouchon, Marie-Hélène Delmotte, Pierre Formstecher, and Philippe Lefebvre*

INSERM U459, Faculté de Médecine Henri Warembourg, 59045 Lille Cedex, France

Received 9 October 1998/Returned for modification 10 November 1998/Accepted 12 January 1999

Transcriptional activation by retinoids is mediated through two families of nuclear receptors, all-trans-retinoic acid (RARs) and 9-cis retinoic acid receptors (RXRs). Conformationally restricted retinoids are used to achieve selective activation of RAR isotype alpha , beta  or gamma , which reduces side effects in therapeutical applications. Synthetic retinoids mimic some of all-trans retinoic acid biological effects in vivo but interact differently with the ligand binding domain of RARalpha and induce distinct structural transitions of the receptor. In this report, we demonstrate that RAR-selective ligands have distinct quantitative activation properties which are reflected by their abilities to promote interaction of DNA-bound human RXRalpha (hRXRalpha )-hRARalpha heterodimers with the nuclear receptor coactivator (NCoA) SRC-1 in vitro. The hormone response element core motifs spacing defined the relative affinity of liganded heterodimers for two NCoAs, SRC-1 and RIP140. hRXRalpha activating function 2 was critical to confer hRARalpha full responsiveness but not differential sensitivity of hRARalpha to natural or synthetic retinoids. We also provide evidence showing that lysines located in helices 3 and 4, which define part of hRARalpha NCoA binding surface, contribute differently to (i) the transcriptional activity and (ii) the interaction of RXR-RAR heterodimers with SRC-1, when challenged by either natural or RAR-selective retinoids. Thus, ligand structure, DNA, and RXR exert allosteric regulations on hRARalpha conformation organized as a DNA-bound heterodimer. We suggest that the use of physically distinct NCoA binding interfaces may be important in controlling specific genes by conformationally restricted ligands.

* Corresponding author. Mailing address: INSERM U459, Faculté de Médecine Henri Warembourg 1, place de Verdun, 59045 Lille Cedex, France. Phone: 33.3.20.62.68.87. Fax: 33.3.20.62.68.84. E-mail: p.lefebvre{at}lille.inserm.fr.

Molecular and Cellular Biology, April 1999, p. 3073-3085, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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