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Interdomain communication regulating ligand binding by PPAR-γ

Nature volume 396, pages 377–380 (1998)Cite this article

Abstract

Binding to receptors in the cell nucleus is crucial for the action of lipophilic hormones and ligands. PPAR-γ (for peroxisome proliferator-activated receptor) is a nuclear hormone receptor that mediates adipocyte differentiation1,2 and modulates insulin sensitivity3, cell proliferation4 and inflammatory processes5,6. PPAR-γ ligands have been implicated in the development of atherogenic foam cells7 and as potential cancer treatments8. Transcriptional activity of PPAR-γ is induced by binding diverse ligands, including natural fatty acid derivatives9,10,11, antidiabetic thiazolidinediones12, and non-steroidal anti-inflammatory drugs13. Ligand binding by PPAR-γ, as well as by the entire nuclear-receptor superfamily, is an independent property of the carboxy-terminal ligand-binding domain (LBD) of the receptor14,15. Here we show that ligand binding by PPAR-γ is regulated by intramolecular communication between its amino-terminal A/B domain and its carboxy-terminal LBD. Modification of the A/B domain, for example by physiological phosphorylation by MAP kinase, reduces ligand-binding affinity, thus negatively regulating the transcriptional and biological functions of PPAR-γ. The ability of the A/B domain to regulate ligand binding has important implications for the evaluation and mechanism of action of potentially therapeutic ligands that bind PPAR-γ and that are likely to extend to other members of the nuclear-receptor superfamily.

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Figure 1: Potency of BRL49653 depends upon the PPAR-γ A/B domain.
Figure 2: Potency of BRL49653 in co-activator recruitment to PPAR-γ LBD depends upon the A/B domain.
Figure 3: Affinity of BRL49653 for PPAR-γ depends upon the A/B domain.
Figure 4: The A/B domain regulates potency of BRL49653 in protease protection and the conformation of unliganded PPAR-γ.

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Acknowledgements

This work was supported by grants from the National Institute of Diabetes, Digestive, and Kidney Disease at the NIH.

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Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, Diabetes, and Metabolism, Philadelphia, 19104, Pennsylvania, USA

    Dalei Shao, Shamina M. Rangwala, Shannon T. Bailey, Samuel L. Krakow & Mitchell A. Lazar

  2. Departments of Pharmacology, Philadelphia, 19104, Pennsylvania, USA

    Mauricio J. Reginato

  3. Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Mitchell A. Lazar

Authors
  1. Dalei Shao
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  6. Mitchell A. Lazar
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Correspondence to Mitchell A. Lazar.

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Shao, D., Rangwala, S., Bailey, S. et al. Interdomain communication regulating ligand binding by PPAR-γ. Nature 396, 377–380 (1998). https://doi.org/10.1038/24634

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