Article abstract
Nature Structural & Molecular Biology 14, 1207 - 1213 (2007)
Published online: 25 November 2007 | doi:10.1038/nsmb1344
Identification of heme as the ligand for the orphan nuclear receptors REV-ERB
and REV-ERB
Srilatha Raghuram1, Keith R Stayrook2, Pengxiang Huang1, Pamela M Rogers3, Amanda K Nosie2, Don B McClure2, Lorri L Burris2, Sepideh Khorasanizadeh4, Thomas P Burris3,5 & Fraydoon Rastinejad1,5
Abstract
The nuclear receptors REV-ERB
(encoded by NR1D1) and REV-ERB
(NR1D2) have remained orphans owing to the lack of identified physiological ligands. Here we show that heme is a physiological ligand of both receptors. Heme associates with the ligand-binding domains of the REV-ERB receptors with a 1:1 stoichiometry and enhances the thermal stability of the proteins. Results from experiments of heme depletion in mammalian cells indicate that heme binding to REV-ERB causes the recruitment of the co-repressor NCoR, leading to repression of target genes including BMAL1 (official symbol ARNTL), an essential component of the circadian oscillator. Heme extends the known types of ligands used by the human nuclear receptor family beyond the endocrine hormones and dietary lipids described so far. Our results further indicate that heme regulation of REV-ERBs may link the control of metabolism and the mammalian clock.
- Department of Pharmacology and Center for Molecular Design, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0733, USA.
- Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
- Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA.
- Department of Biochemistry & Molecular Genetics, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, Virginia 22908-0733, USA.
- These authors contributed equally to this work.
Correspondence to: Fraydoon Rastinejad1,5 e-mail: fr9c@virginia.edu
Correspondence to: Thomas P Burris3,5 e-mail: Thomas.Burris@pbrc.edu
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