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

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The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-Erbb PLoS BIOLOGY The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBb Keith I. Pardee1,2, Xiaohui Xu1,2,3, Jeff Reinking1,2,7¤a, Anja Schuetz4¤b, Aiping Dong4, Suya Liu5, Rongguang Zhang6, Jens Tiefenbach1,2, Gilles Lajoie5, Alexander N. Plotnikov4¤b, Alexey Botchkarev4, Henry M. Krause1,2*, Aled Edwards1,2,3,4* 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 Heme is a ligand for the human nuclear receptors (NR) REV-ERBa and REV-ERBb, 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 A˚ crystal structure of the REV-ERBb 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-ERBb 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. 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-ERBb. PLoS Biol 7(2): e1000043. doi:10.1371/journal.pbio.1000043 Introduction timing, acting together with the ROR orthologue Drosophila Hormone Receptor 3 (DHR3) to control ecdysone-induced The closely related REV-ERBa and REV-ERBb proteins molting, pupariation, and eclosion [18]. To perform these generally act as transcriptional repressors, either on their own, by recruiting co-repressor proteins [1–3], or by competing with the Retinoid-related Orphan Receptors Academic Editor: Ueli Schibler, University of Geneva, Switzerland (RORs) a, b,orc for the same DNA binding sites [4–6]. Received July 24, 2008; Accepted January 12, 2009; Published Feburary 24, 2009 Physiologically, the REV-ERB proteins play a number of Copyright: Ó 2009 Pardee et al. This is an open-access article distributed under the diverse and important roles ranging from the control of terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, circadian biology to the homeostasis of lipids. REV-ERBa and transmitted, modified, built upon, or otherwise used by anyone for any lawful b directly regulate circadian rhythm, both in the brain, and in purpose. peripheral tissues, by targeting the circadian clock genes Abbreviations: BMAL1, Brain, Muscle Arnt-like protein-1; CO, carbon monoxide; Bmal1 and clock [6–11]. Regulation of lipid metabolism and Deta/NO, diethylenetriamine/NO; E75, Ecdysone-induced protein 75; HEK, human embryonic kidney; HepG2, hepatocellular carcinoma; LBD, ligand-binding domain; stimulation of adipogenesis by the REV-ERBs is mediated in mPER2, mammalian Period 2; mP, millipolarization unit; NCOR, Nuclear Receptor part through repression of the apolipoprotein A1 (ApoA1) Co-repressor; NO, nitric oxide; NPAS2, Neuronal PAS domain protein; NR, nuclear and apolipoprotein C3 (ApoCIII) gene promoters, which play receptor; RIP140, Receptor Interaction Protein 140; ROR, Retinoid-related Orphan Receptor; ROS, reactive oxidant species; siRNA, small interfering RNA; SMRT, major roles in cholesterol metabolism [12–14]. REV-ERBs also Silencing Mediator for Retinoid and Thyroid hormone receptor; SNAP, S-nitroso-N- control inflammatory responses by inducing nuclear factor acetyl-l,l-penicillamine; TCEP, tris(2-carboxyethyl)phosphine; UAS, upstream acti- vating sequences kappa-light-chain-enhancer of activated B cells (NFjB), interleukin-6 (IL6), and cyclooxygenase2 (COX2) expression, * To whom correspondence should be addressed. E-mail: aled.edwards@utoronto. ca (AE); [email protected] (HMK) and by repressing IjBa expression [15,16]. In the liver, REV- ¤a Current address: Department of Structural and Chemical Biology, Ichah Medical ERBs also help regulate gluconeogenesis, consistent with an Institute, Mount Sinai School of Medicine, New York, New York, United States of overall role in energy storage and conservation [17]. America In Drosophila, the REV-ERB homologue, Ecdysone-induced ¤b Current address: Protein Sample Production Facility, Max Delbru¨ck Center for protein 75 (E75) is best known for its role in developmental Molecular Medicine, Berlin, Germany PLoS Biology | www.plosbiology.org0384 February 2009 | Volume 7 | Issue 2 | e1000043 REV-ERB Structure and Gas Regulation 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. Figure 1. Mutagenesis of REV-ERBb Heme-Binding Residues As detemined by measurement of construct c absorption peaks (419 nm), mutation of heme binding residues reduces, but does not abolish functions, E75 appears to require heme as a requisite ligand, heme binding. bound presumably within its ligand-binding domain (LBD) doi:10.1371/journal.pbio.1000043.g001 ligand pocket. E75 is not stable in the absence of heme, nor does the bound heme dissociate readily, suggesting that heme the REV-ERB LBDs. Using crystallography and spectroscopy, is an obligate component of E75. Interestingly, the presence we determined the structure of the heme-bound REV-ERBb of heme allows E75 to also bind the diatomic gases nitric LBD from which we are able to propose a model for heme oxide (NO) and carbon monoxide (CO), which function to and gas binding. reverse E75-mediated transcription repression [19]. The REV- ERBs also bind heme but, unlike E75, the heme can readily Results dissociate from the REV-ERBs, and this reversible binding regulates REV-ERB transcription activity [17,20]. The REV- Heme Binding to REV-ERB LBD Is Reversible ERB LBDs do not appear to share the ability to bind gases or Overexpression of either of the REV-ERB LBDs in to respond to redox [20], raising the possibility that E75 and Escherichia coli produces apo forms of the repressors. The REV-ERBs have evolved two different ways to exploit heme- heme-bound form is produced only if the culture medium is binding. supplemented with hemin (Figure S1). While REV-ERBs The structural basis for heme binding in REV-ERB expressed with and without hemin supplementation appear proteins, and heme and gas binding in E75, is unknown, to be equally abundant and soluble (Figure S1), they differ although mutagenesis and transcription studies have impli- strikingly in color, with the heme-bound form intensely red, cated conserved histidine and cysteine residues in heme and the apo form colorless. Incubation of either purified binding. A crystal structure of the REV-ERBb LBD in the REV-ERBa or b apo LBD with hemin in solution, results in absence of heme has revealed a classic nuclear receptor (NR) full heme occupancy within seconds or less (unpublished fold, but the mechanisms of heme binding could not be data), while washing the heme-bound LBDs with buffer deduced from the structure, because the conserved histidine lacking heme leads to a much slower release of the bound residue points away from the putative ligand-binding pocket heme (T1/2 ;13–16 h; Figure S2). Overall a Kd of approx- and the conserved cysteine residue was not present in the imately 6 lM was observed (unpublished data). Thus, unlike construct that generated the structure. Moreover, the E75, where heme appears to act as a requisite structural putative pocket is fully occupied by hydrophobic side chains component, in the REV-ERBs it can function potentially as a [21]. The extensive structural similarities between the REV- reversible ligand. ERB and E75 LBDs coupled with the apparent mechanistic differences prompted us to explore more deeply the basis for Heme Is Coordinately Bound to Alternative His and Cys both heme binding and the potential for gas regulation.
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