Interdomain communication regulating ligand binding by PPAR-γ

• Published in: Nature (London) 1998-11, Vol.396 (6709), p.377-380
• Main Authors: Lazar, Mitchell A, Shao, Dalei, Rangwala, Shamina M, Bailey, Shannon T, Krakow, Samuel L, Reginato, Mauricio J
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adipocytes - cytology; Animals; Anti-inflammatory agents; Binding Sites; Biological and medical sciences; Biology; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cancer; Cell Differentiation; Cell receptors; Cell structures and functions; Cells; Fundamental and applied biological sciences. Psychology; Histone Acetyltransferases; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Hormones; Humanities and Social Sciences; Insulin; letter; Ligands; Mice; Molecular and cellular biology; multidisciplinary; Nonsteroidal anti-inflammatory drugs; Nuclear Receptor Coactivator 1; Receptors, Cytoplasmic and Nuclear - metabolism; Science; Science (multidisciplinary); Thiazoles - metabolism; Thiazolidinediones; Transcription Factors - metabolism; Transcription, Genetic
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/24634

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 differentiation, and modulates insulin sensitivity, cell proliferation and inflammatory processes,. PPAR-γ ligands have been implicated in the development of atherogenic foam cells and as potential cancer treatments. Transcriptional activity of PPAR-γ is induced by binding diverse ligands, including natural fatty acid derivatives, antidiabetic thiazolidinediones, and non-steroidal anti-inflammatory drugs. 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 receptor,. 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.