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Separation of Retinoid X Receptor Homo- and Heterodimerization Functions

By Valerie Vivat-Hannah, William Bourguet, Marco Gottardis and Hinrich Gronemeyer


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 RXRα (mRXRα) 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 mRXRαY402A 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 mRXRαY402A to elucidate the physiological impact of RXR homo- and heterodimerization

Topics: Transcriptional Regulation
Publisher: American Society for Microbiology
Year: 2003
DOI identifier: 10.1128/MCB.23.21.7678-7688.2003
OAI identifier:
Provided by: PubMed Central
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