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      The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBβ


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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.

          Author Summary

          Much of human biology, such as sleeping, eating, and even the prevalence of heart attacks, occurs in daily cycles. These cycles are orchestrated by a master “clock” located in the brain. The basic components of this clock are proteins that control the expression of important genes. In this study, we analyze one of these regulatory proteins, named REV-ERB, and show that it is regulated by the combination of heme and nitric oxide gas, both of which are important regulators of human physiology. By determining the 3-D structure of the REV-ERB protein, we were able to uncover clues as to how this regulation occurs. REV-ERB belongs to a protein family called nuclear hormone receptors, which are known to be excellent drug targets. Thus, this paper opens the door to possible gas-based therapies for diseases known to involve REV-ERB, such as diabetes, atherosclerosis, inflammation, and cancer.


          The heme-regulated nuclear hormone receptor REV-ERB is one of the core transcription factors regulating circadian rhythms. We found that transcription by heme-bound REV-ERB is regulated by NO gas, and a crystal structure of the heme-bound protein uncovers the basis for heme and gas binding.

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            Coordinated transcription of key pathways in the mouse by the circadian clock.

            In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed approximately 650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver. Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components. Major processes regulated by the SCN and liver were found to be under circadian regulation. Importantly, rate-limiting steps in these various pathways were key sites of circadian control, highlighting the fundamental role that circadian clocks play in cellular and organismal physiology.
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              The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.

              Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb. Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms. Here, we identify the orphan nuclear receptor REV-ERBalpha as the major regulator of cyclic Bmal1 transcription. Circadian Rev-erbalpha expression is controlled by components of the general feedback loop. Thus, REV-ERBalpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERBalpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation.

                Author and article information

                Role: Academic Editor
                PLoS Biol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                February 2009
                24 February 2009
                : 7
                : 2
                [1 ] Banting and Best Department of Medical Research, The Department of Molecular Genetics, University of Toronto, Toronto, Canada
                [2 ] Terrence Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, Canada
                [3 ] Midwest Center for Structural Genomics, University of Toronto, Toronto, Canada
                [4 ] Structural Genomics Consortium, University of Toronto, Toronto, Canada
                [5 ] Department of Biochemistry, University of Western Ontario, London, Ontario, Canada
                [6 ] Midwest Center for Structural Genomics, Argonne National Lab, Argonne, Illinois, United States of America
                [7 ] Department of Biology, State University of New York at New Paltz, New Paltz, New York, United States of America
                University of Geneva, Switzerland
                Author notes
                * To whom correspondence should be addressed. E-mail: aled.edwards@ 123456utoronto.ca (AE); h.krause@ 123456utoronto.ca (HMK)
                08-PLBI-RA-3073R3 plbi-07-02-14
                Copyright: © 2009 Pardee et al. This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                Page count
                Pages: 1
                Research Article
                Cell Biology
                Diabetes and Endocrinology
                Custom metadata
                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-ERBβ. PLoS Biol 7(2): e1000043. doi: 10.1371/journal.pbio.1000043

                Life sciences
                Life sciences


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