Interdomain communication regulating ligand binding by PPAR-gamma

Nature. 1998 Nov 26;396(6709):377-80. doi: 10.1038/24634.


Binding to receptors in the cell nucleus is crucial for the action of lipophilic hormones and ligands. PPAR-gamma (for peroxisome proliferator-activated receptor) is a nuclear hormone receptor that mediates adipocyte differentiation and modulates insulin sensitivity, cell proliferation and inflammatory processes. PPAR-gamma ligands have been implicated in the development of atherogenic foam cells and as potential cancer treatments. Transcriptional activity of PPAR-gamma is induced by binding diverse ligands, including natural fatty acid derivatives, antidiabetic thiazolidinediones, and non-steroidal anti-inflammatory drugs. Ligand binding by PPAR-gamma, as well as by the entire nuclear-receptor superfamily, is an independent property of the carboxy-terminal ligand-binding domain (LBD) of the receptor. Here we show that ligand binding by PPAR-gamma 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-gamma. 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-gamma and that are likely to extend to other members of the nuclear-receptor superfamily.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Adipocytes / cytology
  • Animals
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Differentiation
  • Histone Acetyltransferases
  • Ligands
  • Mice
  • Nuclear Receptor Coactivator 1
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Rosiglitazone
  • Thiazoles / metabolism
  • Thiazolidinediones*
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Rosiglitazone
  • Histone Acetyltransferases
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Calcium-Calmodulin-Dependent Protein Kinases