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Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators

Nature volume 415, pages 549–553 (2002)Cite this article

Abstract

Nuclear hormone receptors are ligand-activated transcription factors that regulate the expression of genes that are essential for development, reproduction and homeostasis1. The hormone response is mediated through recruitment of p160 receptor coactivators and the general transcriptional coactivator CBP/p300, which function synergistically to activate transcription2. These coactivators exhibit intrinsic histone acetyltransferase activity, function in the remodelling of chromatin, and facilitate the recruitment of RNA polymerase II and the basal transcription machinery3. The activities of the p160 coactivators are dependent on CBP. Both coactivators are essential for proper cell-cycle control, differentiation and apoptosis, and are implicated in cancer and other diseases4,5,6,7. To elucidate the molecular basis of assembling the multiprotein activation complex, we undertook a structural and thermodynamic analysis of the interaction domains of CBP and the activator for thyroid hormone and retinoid receptors8. Here we show that although the isolated domains are intrinsically disordered, they combine with high affinity to form a cooperatively folded helical heterodimer. Our study uncovers a unique mechanism, called ‘synergistic folding’, through which p160 coactivators recruit CBP/p300 to allow transmission of the hormonal signal to the transcriptional machinery.

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Figure 1: Structural and thermodynamic characterization of free and complexed ACTR and CBP.
Figure 2: Solution structure of the ACTR–CBP complex.
Figure 3: Conserved interactions in the ACTR–CBP complex.

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Acknowledgements

We thank M. Allen for technical help and M. Pique for help with computer graphics. This work was supported by grants from the NIH and by the Skaggs Institute for Chemical Biology. S.J.D. was supported by a fellowship from the NIH.

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Author notes

  1. Peter E. Wright

    Present address: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

  2. Hongwu Chen

    Present address: Department of Biological Chemistry, Cancer Center, University of California, Davis, California, 95817, USA

Authors and Affiliations

  1. Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Stephen J. Demarest, Maria Martinez-Yamout, John Chung, H. Jane Dyson & Peter E. Wright

  2. Howard Hughes Medical Institute and The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Hongwu Chen, Wei Xu & Ronald M. Evans

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Correspondence to Peter E. Wright.

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Demarest, S., Martinez-Yamout, M., Chung, J. et al. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 415, 549–553 (2002). https://doi.org/10.1038/415549a

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