Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators (original) (raw)
- Letter
- Published: 10 September 1998
- Riki Kurokawa1,2,
- Robert T. Nolte4,
- G. Bruce Wisely4,
- Eileen M. McInerney3,
- David W. Rose2,
- Michael V. Milburn4,
- Michael G. Rosenfeld2,3 &
- …
- Christopher K. Glass1,2
Nature volume 395, pages 199–202 (1998)Cite this article
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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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References
- Mangelsdorf, D. J.et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 (1995).
Article CAS Google Scholar - Glass, C. K. Differential recognition of target genes by nuclear receptor monomers, dimers and heterodimers. Endocrinol. Rev. 15, 1503–1519 (1994).
Google Scholar - Kliewer, S. A., Umesono, K., Noonan, D. J., Heyman, R. A. & Evans, R. M. Convergence of 9- cis retinoic acid and peroxisome proliferator signaling pathways through heterodimer formation of their receptors. Nature 358, 771–774 (1992).
Article ADS CAS Google Scholar - Kurokawa, R.et al. Regulation of retinoid signaling by receptor polarity and allosteric control of ligand binding. Nature 371, 528–531 (1994).
Article ADS CAS Google Scholar - Forman, B. M., Umesono, K., Chen, J. & Evans, R. M. Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell 81, 541–550 (1995).
Article CAS Google Scholar - Chen, J.-Y.et al. Two distinct actions of retinoid-receptor ligands. Nature 382, 819–822 (1996).
Article ADS CAS Google Scholar - Durand, B.et al. Activation function 2 (AF2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF2 activity. EMBO J. 13, 5370–5382 (1994).
Article CAS Google Scholar - Danielian, P. S., White, R., Lees, J. A. & Parker, M. G. Identification of a conserved region required for hormone-dependent transcriptional activation by steroid hormone receptors. EMBO J. 11, 1025–1033 (1992).
Article CAS Google Scholar - Barettino, D., Vivanco Ruiz, M. M. & Stunnenberg, H. G. Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor. EMBO J. 13, 3039–3049 (1994).
Article CAS Google Scholar - Wagner, R. L.et al. Astructural role for hormone in the thyroid hormone receptor. Nature 378, 690–697 (1995).
Article ADS CAS Google Scholar - Bourguet, W., Ruffr, M., Chambon, P., Gronemeyer, H. & Moras, D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α. Nature 375, 377–382 (1995).
Article ADS CAS Google Scholar - Renaud, J.-P.et al. Crystal structure of the RAR-γ ligand-binding domain bound to all- trans retinoic acid. Nature 378, 681–689 (1995).
Article ADS CAS Google Scholar - Oñate, S. A., Tsai, S. Y., Tsai, M.-J. & O'Malley, B. W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270, 1354–1357 (1995).
Article ADS Google Scholar - Kamei, Y.et al. ACBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85, 403–414 (1996).
Article CAS Google Scholar - Hanstein, B.et al. p300 is a component of an estrogen receptor coactivator complex. Proc. Natl Acad. Sci. USA 93, 11540–11545 (1996).
Article ADS CAS Google Scholar - Chakravarti, D.et al. Role of CBP/p300 in nuclear receptor signaling. Nature 383, 99–103 (1996).
Article ADS CAS Google Scholar - Torchia, J.et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387, 677–684 (1997).
Article ADS CAS Google Scholar - Korzus, E.et al. Transcription factor-specific requirements for coactivators and their acetyltransferase functions. Science 279, 703–707 (1998).
Article ADS CAS Google Scholar - Kurokawa, R.et al. Differential use of CREB binding protein-coactivator complexes. Science 279, 700–703 (1998).
Article ADS CAS Google Scholar - Heery, D. M., Kalkhoven, E., Hoare, S. & Parker, M. G. Asignature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733–736 (1997).
Article ADS CAS Google Scholar - Ding, X. F.et al. Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol. Endocrinol. 12, 302–313 (1998).
Article CAS Google Scholar - Le Douarin, B.et al. Apossible involvement of TIF1α and TIF1β in the epigenetic control of transcription by nuclear recetors. EMBO J. 15, 6701–6715 (1996).
Article CAS Google Scholar - Voegel, J. J.et al. The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J. 17, 507–519 (1998).
Article CAS Google Scholar - Kalkhoven, E., Valentine, J. E., Heery, D. M. & Parker, M. G. Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J. 17, 232–243 (1998).
Article CAS Google Scholar - Yao, T.-P., Ku, G., Zhou, N., Scully, R. & Livingston, D. M. The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc. Natl Acad. Sci. USA 93, 10626–10631 (1996).
Article ADS CAS Google Scholar - Nolte, R. T.et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature(in the press).
- Fraker, P. J. & Speck, J. C. J. Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1,3,4,6-tetrachloro-3a 6a-diphrenylglycoluril. Biochem. Biophys. Res. Commun. 80, 849–857 (1978).
Article CAS Google Scholar - Chen, C. & Okayama, H. High efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell. Biol. 7, 2745–2752 (1987).
Article CAS Google Scholar
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
- Division of Cellular and Molecular Medicine, San Diego, 9500 Gilman Drive, La Jolla, 92093-0651, California, USA
Stefan Westin, Riki Kurokawa & Christopher K. Glass - 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 - 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 - 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 toChristopher 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
- Received: 20 June 1998
- Accepted: 03 August 1998
- Issue Date: 10 September 1998
- DOI: https://doi.org/10.1038/26040