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Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators

Nature volume 395, pages 199–202 (1998)Cite this article

Abstract

Retinoic-acid receptor-α (RAR-α) and peroxisome proliferator-activated receptor-γ (PPAR-γ) are members of the nuclear-receptor superfamily that bind to DNA as heterodimers with retinoid-X receptors (RXRs)1,2. PPAR–RXR heterodimers can be activated by PPAR or RXR ligands3, whereas RAR–RXR heterodimers are selectively activated by RAR ligands only, because of allosteric inhibition of the binding of ligands to RXR by RAR4,5. However, RXR ligands can potentiate the transcriptional effects of RAR ligands in cells6. Transcriptional activation by nuclear receptors requires a carboxy-terminal helical region, termed activation function-2 (AF-2) (refs 7,8,9), that forms part of the ligand-binding pocket and undergoes a conformational change required for the recruitment of co-activator proteins, including NCoA-1/SRC-1 (refs 10,11,12,13,14,15,16,17). Here we show that allosteric inhibition of RXR results from a rotation of the RXR AF-2 helix that places it in contact with the RAR coactivator-binding site. Recruitment of an LXXLL motif of SRC-1 to RAR in response to ligand displaces the RXR AF-2 domain, allowing RXR ligands to bind and promote the binding of a second LXXLL motif from the same SRC-1 molecule. These results may partly explain the different responses of nuclear-receptor heterodimers to RXR-specific ligands.

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Figure 1: Recruitment of CBP to RAR–RXR heterodimers by SRC-1.
Figure 2: The nuclear-receptor-interaction domain of NCoA-1/SRC-1 allosterically regulates RXR heterodimers.
Figure 3: Structural requirements for combinatorial effects of RAR, PPAR-γ and RXR ligands on interactions of NCoA-1/SRC-1 with nuclear receptors.
Figure 4: Interaction of an LXXLL motif with RAR relieves allosteric inhibition of RXR.
Figure 5: Mechanism of allosteric inhibition and co-activator assembly.

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Acknowledgements

We thank R. Heyman for making [3H]LGD1069 available, S. Green for help with radio-iodination of peptides and T. Schneiderman for help with manuscript preparation. S.W. was supported by grants from The Swedish Cancer Society and a training grant from the NIH. M.G.R. acknowledges support from the HHMI. C.K.G. is an Established Investigator of the American Heart Association. This work was also supported by grants from the NIH (to C.K.G. and M.G.R.).

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Authors and Affiliations

  1. Division of Cellular and Molecular Medicine, San Diego, 9500 Gilman Drive, La Jolla, 92093-0651, California, USA

    Stefan Westin, Riki Kurokawa & Christopher K. Glass

  2. Division of Endocrinology and Metabolism, San Diego, 9500 Gilman Drive, La Jolla, 92093-0651, California, USA

    Stefan Westin, Riki Kurokawa, David W. Rose, Michael G. Rosenfeld & Christopher K. Glass

  3. Department of Medicine, Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0651, California, USA

    Eileen M. McInerney & Michael G. Rosenfeld

  4. Department of Structural Chemistry, GlaxoWellcome Inc., Research Triangle Park, North Carolina, 27709, USA

    Robert T. Nolte, G. Bruce Wisely & Michael V. Milburn

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Correspondence to Christopher K. Glass.

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Westin, S., Kurokawa, R., Nolte, R. et al. Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators. Nature 395, 199–202 (1998). https://doi.org/10.1038/26040

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