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The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors

Nature volume 402, pages 93–96 (1999)Cite this article

Abstract

N-CoR1 and SMRT2 are transcriptional corepressors that associate with nuclear hormone receptors (NRs) in the absence of ligand. This interaction is the molecular target of differentiation therapy for acute promyelocytic leukaemia, wherein retinoic acid dissociates corepressor from leukaemogenic receptor fusion proteins3,4. Binding of ligand to NRs induces a conformation that attracts coactivator proteins containing an Leu-x-x-Leu-Leu motif (the ‘NR box’)5,6. Here we show that N-CoR and SMRT contain sequences that are similar to the NR box and are repeated in each of two NR interaction domains7,8,9,10. We show that this CoRNR (‘corner’) box is required for NR interaction, and that CoRNR box peptides specifically block corepressor interaction in vitro and repression in vivo. Sequences flanking the CoRNR box determine NR specificity. Thus, the key feature of hormone action, differential recognition of unliganded and liganded NRs by coactivators and corepressors, is due to very subtle differences between CoRNR and NR boxes. The molecular mechanisms of repression and activation by NRs are thus linked in an unexpected manner.

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Figure 1: Corepressor interaction surface is related to the coactivator interaction surface.
Figure 2: CoRNR boxes are necessary for interaction with NRs.
Figure 3: CoRNR box peptides are sufficient for interaction with NRs.
Figure 4: Role of sequences flanking CoRNR box in NR interactions.
Figure 5: Sequences flanking CoRNR and NR boxes determine ligand dependence of NR interactions.

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References

  1. Horlein,A. J. et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377, 397–404 (1995).

    Article  ADS  CAS  Google Scholar 

  2. Chen,J. D. & Evans,R. M. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377, 454–457 (1995).

    Article  ADS  CAS  Google Scholar 

  3. Lin,R. J. et al. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391, 811–814 (1998).

    Article  ADS  CAS  Google Scholar 

  4. Grignani,F. et al. Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia. Nature 391, 815–818 (1998).

    Article  ADS  CAS  Google Scholar 

  5. LeDourain,B. et al. A possible involvement of TIF1α and TIF1β in the epigenetic control of transcription by nuclear receptors. EMBO J. 15, 6701–6715 (1996).

    Article  Google Scholar 

  6. Heery,D. M., Kalkhoven,E., Hoare,S. & Parker,M. G. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733–736 (1997).

    Article  ADS  CAS  Google Scholar 

  7. Seol,W., Mahon,M. J., Lee,Y.-K. & Moore,D. D. Two receptor interacting domains in the nuclear hormone receptor corepressor RIP13/N-CoR. Mol. Endocrinol. 10, 1646–1655 (1996).

    CAS  PubMed  Google Scholar 

  8. Zamir,I. et al. A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with different repression domains. Mol. Cell. Biol. 16, 5458–5465 (1996).

    Article  CAS  Google Scholar 

  9. Cohen,R. N., Wondisford,F. E. & Hollenberg,A. N. Two separate NCoR (nuclear receptor corepressor) interaction domains mediate corepressor action on thyroid hormone response elements. Mol. Endocrinol. 12, 1567–1581 (1998).

    Article  CAS  Google Scholar 

  10. Wong,C. W. & Privalsky,M. L. Transcriptional silencing is defined by isoform and heterodimer-specific interactions between nuclear hormone receptors and corepressors. Mol. Cell. Biol. 18, 5724–5733 (1998).

    Article  CAS  Google Scholar 

  11. Wagner,R. L. et al. A structural role for hormone in the thyroid hormone receptor. Nature 378, 690–697 (1995).

    Article  ADS  CAS  Google Scholar 

  12. Collingwood,T. N. et al. Thyroid hormone-mediated enhancement of heterodimer formation between thyroid hormone receptor β and retinoid X receptor. J. Biol. Chem. 272, 13060–13065 (1997).

    Article  CAS  Google Scholar 

  13. Zhang,J., Zamir,I. & Lazar,M. A. Differential recognition of liganded and unliganded thyroid hormone receptor by retinoid X receptor regulates transcriptional repression. Mol. Cell. Biol. 17, 6887–6897 (1997).

    Article  CAS  Google Scholar 

  14. Zhang,J., Hu,X. & Lazar,M. A. A novel role for helix 12 of RXR in regulating repression. Mol. Cell. Biol. 19, 6448–6457 (1999).

    Article  CAS  Google Scholar 

  15. Schulman,I. G., Juguilon,H. & Evans,R. M. Activation and repression by nuclear hormone receptors: hormone modulates an equilibrium between active and repressive states. Mol. Cell. Biol. 16, 3807–3813 (1996).

    Article  CAS  Google Scholar 

  16. Feng,W. et al. Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science 280, 1747–1749 (1998).

    Article  ADS  CAS  Google Scholar 

  17. Nolte,R. T. et al. Ligand binding and co-activator assembly of the peroxisome prolierator-activated receptor-γ. Nature 395, 137–143 (1998).

    Article  ADS  CAS  Google Scholar 

  18. Darimont,B. D. et al. Structure and specificity of nuclear receptor–coactivator interactions. Genes Dev. 12, 3343–3356 (1998).

    Article  CAS  Google Scholar 

  19. Shiau,A. K. et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95, 927–937 (1998).

    Article  CAS  Google Scholar 

  20. Moras,D. & Gronemeyer,H. The nuclear receptor ligand-binding domain: structure and function. Curr. Opin. Cell Biol. 10, 384–391 (1998).

    Article  CAS  Google Scholar 

  21. Dressel,U. et al. Alien, a highly conserved protein with characteristics of a corepressor for members of the nuclear hormone receptor superfamily. Mol. Cell. Biol. 19, 3383–3394 (1999).

    Article  CAS  Google Scholar 

  22. Zamir,I. et al. Cloning and characterization of a corepressor and potential component of the nuclear hormone receptor repression complex. Proc. Natl Acad. Sci. USA 94, 14400–14495 (1997).

    Article  ADS  CAS  Google Scholar 

  23. Forman,B. M. et al. Androstane metabolites bind to and deactivate the nuclear receptor CARβ. Nature 395, 612–615 (1998).

    Article  ADS  CAS  Google Scholar 

  24. Onate,S. A. et al. The steroid receptor coactivator-1 contains multiple receptor interacting and activation domains that cooperatively enhance the activation function 1 (AF1) and AF2 domains of steroid receptors. J. Biol. Chem. 273, 12101–12108 (1998).

    Article  CAS  Google Scholar 

  25. Voegel,J. J., Heine,M. J. S., Zechel,C., Chambon,P. & Gronemeyer,H. TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation fucntion AF-2 of nuclear receptors. EMBO J. 15, 3667–3675 (1996).

    Article  CAS  Google Scholar 

  26. McInerney,E. M. et al. Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. Genes Dev. 12, 3357–3368 (1998).

    Article  CAS  Google Scholar 

  27. Mak,H. Y., Hoare,S., Henttu,P. M. & Parker,M. G. Molecular determinants of the estrogen receptor-coactivator interface. Mol. Cell. Biol. 19, 3895–3903 (1999).

    Article  CAS  Google Scholar 

  28. Zamir,I., Zhang,J. & Lazar,M. A. Stoichiometric and steric principles governing repression by nuclear hormone receptors. Genes Dev. 11, 835–846 (1997).

    Article  CAS  Google Scholar 

  29. Yoh,S. M., Chatterjee,V. K. K. & Privalsky,M. L. Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. Mol. Endocrinol. 11, 470–480 ().

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Acknowledgements

We thank J. Zhang for helpful discussions, and D. Moore for providing VP16-CAR. This work was supported by grants from the National Institute of Diabetes, Digestive and Kidney Diseases of the NIH to M.A.L.

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Authors and Affiliations

  1. Division of Endocrinology, Departments of Medicine and Genetics, Diabetes, and Metabolism, and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Xiao Hu & Mitchell A. Lazar

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  1. Xiao Hu
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  2. Mitchell A. Lazar
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Correspondence to Mitchell A. Lazar.

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Hu, X., Lazar, M. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402, 93–96 (1999). https://doi.org/10.1038/47069

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