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

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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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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.

References

  1. 1

    Mangelsdorf, D. J.et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 (1995).

  2. 2

    Glass, C. K. Differential recognition of target genes by nuclear receptor monomers, dimers and heterodimers. Endocrinol. Rev. 15, 1503–1519 (1994).

  3. 3

    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).

  4. 4

    Kurokawa, R.et al. Regulation of retinoid signaling by receptor polarity and allosteric control of ligand binding. Nature 371, 528–531 (1994).

  5. 5

    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).

  6. 6

    Chen, J.-Y.et al. Two distinct actions of retinoid-receptor ligands. Nature 382, 819–822 (1996).

  7. 7

    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).

  8. 8

    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).

  9. 9

    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).

  10. 10

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

  11. 11

    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).

  12. 12

    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).

  13. 13

    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).

  14. 14

    Kamei, Y.et al. ACBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85, 403–414 (1996).

  15. 15

    Hanstein, B.et al. p300 is a component of an estrogen receptor coactivator complex. Proc. Natl Acad. Sci. USA 93, 11540–11545 (1996).

  16. 16

    Chakravarti, D.et al. Role of CBP/p300 in nuclear receptor signaling. Nature 383, 99–103 (1996).

  17. 17

    Torchia, J.et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387, 677–684 (1997).

  18. 18

    Korzus, E.et al. Transcription factor-specific requirements for coactivators and their acetyltransferase functions. Science 279, 703–707 (1998).

  19. 19

    Kurokawa, R.et al. Differential use of CREB binding protein-coactivator complexes. Science 279, 700–703 (1998).

  20. 20

    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).

  21. 21

    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).

  22. 22

    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).

  23. 23

    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).

  24. 24

    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).

  25. 25

    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).

  26. 26

    Nolte, R. T.et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature(in the press).

  27. 27

    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).

  28. 28

    Chen, C. & Okayama, H. High efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell. Biol. 7, 2745–2752 (1987).

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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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Correspondence to Christopher K. Glass.

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