The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERB[beta]
Heme is a ligand for the human nuclear receptors (NR) REV-ERBα and REV-ERBβ, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcription r...
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Published in | PLoS biology Vol. 7; no. 2 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Public Library of Science
01.02.2009
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Heme is a ligand for the human nuclear receptors (NR) REV-ERBα and REV-ERBβ, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcription repression mediated by heme-bound REV-ERBs is reversed by the addition of nitric oxide (NO), and that the heme and NO effects are mediated by the C-terminal ligand-binding domain (LBD). A 1.9 Å crystal structure of the REV-ERBβ LBD, in complex with the oxidized Fe(III) form of heme, shows that heme binds in a prototypical NR ligand-binding pocket, where the heme iron is coordinately bound by histidine 568 and cysteine 384. Under reducing conditions, spectroscopic studies of the heme-REV-ERBβ complex reveal that the Fe(II) form of the LBD transitions between penta-coordinated and hexa-coordinated structural states, neither of which possess the Cys384 bond observed in the oxidized state. In addition, the Fe(II) LBD is also able to bind either NO or CO, revealing a total of at least six structural states of the protein. The binding of known co-repressors is shown to be highly dependent upon these various liganded states. REV-ERBs are thus highly dynamic receptors that are responsive not only to heme, but also to redox and gas. Taken together, these findings suggest new mechanisms for the systemic coordination of molecular clocks and metabolism. They also raise the possibility for gas-based therapies for the many disorders associated with REV-ERB biological functions. |
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AbstractList |
Heme is a ligand for the human nuclear receptors (NR) REV-ERBα and REV-ERBβ, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcription repression mediated by heme-bound REV-ERBs is reversed by the addition of nitric oxide (NO), and that the heme and NO effects are mediated by the C-terminal ligand-binding domain (LBD). A 1.9 Å crystal structure of the REV-ERBβ LBD, in complex with the oxidized Fe(III) form of heme, shows that heme binds in a prototypical NR ligand-binding pocket, where the heme iron is coordinately bound by histidine 568 and cysteine 384. Under reducing conditions, spectroscopic studies of the heme-REV-ERBβ complex reveal that the Fe(II) form of the LBD transitions between penta-coordinated and hexa-coordinated structural states, neither of which possess the Cys384 bond observed in the oxidized state. In addition, the Fe(II) LBD is also able to bind either NO or CO, revealing a total of at least six structural states of the protein. The binding of known co-repressors is shown to be highly dependent upon these various liganded states. REV-ERBs are thus highly dynamic receptors that are responsive not only to heme, but also to redox and gas. Taken together, these findings suggest new mechanisms for the systemic coordination of molecular clocks and metabolism. They also raise the possibility for gas-based therapies for the many disorders associated with REV-ERB biological functions. |
Author | Dong, Aiping Botchkarev, Alexey Lajoie, Gilles Krause, Henry Zhang, Rongguang Pardee, Keith Liu, Suya Schuetz, Anja Tiefenbach, Jens Plotnikov, Alexander Edwards, Aled Xu, Xiaohui Reinking, Jeff |
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Copyright | 2009 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: Pardee KI, Xu X, Reinking J, Schuetz A, Dong A, et al. (2009) The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERB?. PLoS Biol 7(2): e1000043. doi:10.1371/journal.pbio.1000043 |
Copyright_xml | – notice: 2009 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Citation: Pardee KI, Xu X, Reinking J, Schuetz A, Dong A, et al. (2009) The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERB?. PLoS Biol 7(2): e1000043. doi:10.1371/journal.pbio.1000043 |
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Keywords | Protein Structure, Tertiary Oxidation-Reduction Humans Repressor Proteins Transcriptional Activation Nitric Oxide Circadian Rhythm Protein Interaction Domains & Motifs Heme Cell Line, Tumor Ligands Transcription, Genetic Transcription Factors Binding Sites DNA-Binding Proteins Receptors, Cytoplasmic & Nuclear |
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Heme is a ligand for the human nuclear receptors (NR) REV-ERBα and REV-ERBβ, which are transcriptional repressors that play important roles in circadian... |
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SubjectTerms | Apolipoproteins Atherosclerosis Brain research Cancer Circadian rhythm Diabetes Insects Ligands Medical research Nitric oxide Proteins Rodents |
Title | The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERB[beta] |
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