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Molecular and Cellular Biology, November 2003, p. 7678-7688, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7678-7688.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Separation of Retinoid X Receptor Homo- and Heterodimerization Functions

Valerie Vivat-Hannah,1,2 William Bourguet,2,3 Marco Gottardis,1 and Hinrich Gronemeyer2*

Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey 08543-4000,1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Cell Biology and Signal Transduction, 67404 Illkirch Cedex, C. U. de Strasbourg,2 Centre de Biochimie Structurale, CNRS/INSERM/UM1, 34060 Montpellier, France3

Received 4 June 2003/ Accepted 22 July 2003

As a promiscuous dimerization partner the retinoid X receptor (RXR) can contribute to signaling by multiple nuclear receptors. However, the impact of RXR cosignaling and the possible existence of an RXR homodimer signaling pathway are largely unexplored. We report here on the separation of RXR homo- and heterodimerization as an essential step towards the elucidation of the roles of RXR homo- and heterodimers in retinoid-rexinoid signaling. RXR homodimerization was specifically disrupted by single mutations in the RXR dimerization interface. In contrast, even multiple mutations did not fully impair RXR heterodimerization with retinoic acid receptor (RAR). Importantly, the mutation of mouse RXR{alpha} (mRXR{alpha}) Tyr402 substantially weakened RAR heterodimerization while concomitantly increasing homodimerization. Not only did this lead to cooperatively enhanced RXR homodimer binding to DR1 or DR5 elements, but unexpectedly, the mutant acquired significant binding efficiency for noncognate DR3 or DR4 elements as well. The increased stability of RXR homodimers on DR1 correlated with increased transcriptional activity of mRXR{alpha}Y402A on DR1-based reporter genes. Weak, if any, heterodimerization was observed with thyroid, vitamin D3, or peroxisome proliferator-activating receptors. A model accounting for the structural impact of the Tyr402 mutation on dimerization is discussed. These results provide the basis for a genetic replacement of wild-type RXRs by mutants like mRXR{alpha}Y402A to elucidate the physiological impact of RXR homo- and heterodimerization.

* Corresponding author. Mailing address: IGBMC, B.P. 10142, 67404 Illkirch Cedex, France. Phone: (33) 3 88 65 34 73. Fax: (33) 3 88 65 32 01. E-mail: hg{at}igbmc.u-strasbg.fr.

Molecular and Cellular Biology, November 2003, p. 7678-7688, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7678-7688.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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