This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Renaud, J.-P. Articles by Muscat, G. E .O. Search for Related Content PubMed PubMed Citation Articles by Renaud, J.-P. Articles by Muscat, G. E .O.

Structure-Function Analysis of the Rev-erbA and RVR Ligand-Binding Domains Reveals a Large Hydrophobic Surface That Mediates Corepressor Binding and a Ligand Cavity Occupied by Side Chains

Centre Nationale de la Recherche Scientifique UPR9004 Laboratoire de Biologie et Genomic Structurales (J.P.R.) Institut de Génétique et Biologie Moléculaire et Cellulaire F-67404 Illkirch, France
University of Queensland (J.M.H., L.J.B., M.D., G.E.O.M.) Institute for Molecular Bioscience (I.M.B.) Centre for Molecular and Cellular Biology Ritchie Research Laboratories B402A St. Lucia, 4072 Queensland, Australia

Rev-erbA/RVR are closely related orphan nuclear receptors (NRs) functioning as dominant transcriptional silencers through an association with the nuclear receptor corepressor N-CoR. In contrast with ligand-regulated NRs, Rev-erbA/RVR lack the ligand-binding domain (LBD) C-terminal activation helix, H12. In the case of retinoid acid receptor and thyroid hormone receptor, ligand binding is thought to reposition H12, causing corepressor dissociation and coactivator recruitment, thus leading to transcriptional activation. Here we present homology models of the Rev-erbA/RVR LBDs, which show that the putative ligand cavity is occupied by side chains, suggesting the absence of endogenous ligands. Modeling also revealed a very hydrophobic surface due to the absence of H12, exposing residues from H3, loop 3–4, H4, and H11. Mutation of specific residues from this surface severely impaired the in vitro and in vivo interaction of the Rev-erbA/RVR LBD with the receptor-interacting domain of the corepressors N-CoR or its splice variant RIP131, reinforcing the view of the physical association of N-CoR with a LBD surface encompassing H3-H4 and H11. Furthermore, mutations in the LBD surface significantly reduced the ability of Rev-erbA and RVR to function as repressors of transcription. Interestingly, a hydrophobic surface comprised of H3-H4 and H12 in liganded NRs mediates the interaction with coactivators. Hence, it appears that corepressors and coactivators bind to overlapping surfaces of NR LBDs, the conformational change associated with H12 upon ligand binding resulting in a switch from a corepressor- to a coactivator-binding surface.

This article has been cited by other articles:

				S. Hummasti and P. Tontonoz Adopting New Orphans into the Family of Metabolic Regulators Mol. Endocrinol., August 1, 2008; 22(8): 1743 - 1753. [Abstract] [Full Text] [PDF]

				L. Michalik, V. Zoete, G. Krey, A. Grosdidier, L. Gelman, P. Chodanowski, J. N. Feige, B. Desvergne, W. Wahli, and O. Michielin Combined Simulation and Mutagenesis Analyses Reveal the Involvement of Key Residues for Peroxisome Proliferator-activated Receptor{alpha} Helix 12 Dynamic Behavior J. Biol. Chem., March 30, 2007; 282(13): 9666 - 9677. [Abstract] [Full Text] [PDF]

				G. Benoit, A. Cooney, V. Giguere, H. Ingraham, M. Lazar, G. Muscat, T. Perlmann, J.-P. Renaud, J. Schwabe, F. Sladek, et al. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors Pharmacol. Rev., December 1, 2006; 58(4): 798 - 836. [Abstract] [Full Text] [PDF]

				F. Molnar, M. Matilainen, and C. Carlberg Structural Determinants of the Agonist-independent Association of Human Peroxisome Proliferator-activated Receptors with Coactivators J. Biol. Chem., July 15, 2005; 280(28): 26543 - 26556. [Abstract] [Full Text] [PDF]

				S. N. Ramakrishnan, P. Lau, L. J. Burke, and G. E. O. Muscat Rev-erb{beta} Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells: EVIDENCE FOR CROSS-TALK BETWEEN ORPHAN NUCLEAR RECEPTORS AND MYOKINES J. Biol. Chem., March 11, 2005; 280(10): 8651 - 8659. [Abstract] [Full Text] [PDF]

				G. Triqueneaux, S. Thenot, T. Kakizawa, M. P Antoch, R. Safi, J. S Takahashi, F. Delaunay, and V. Laudet The orphan receptor Rev-erb{alpha} gene is a target of the circadian clock pacemaker J. Mol. Endocrinol., December 1, 2004; 33(3): 585 - 608. [Abstract] [Full Text] [PDF]

				C. Fontaine, G. Dubois, Y. Duguay, T. Helledie, N. Vu-Dac, P. Gervois, F. Soncin, S. Mandrup, J.-C. Fruchart, J. Fruchart-Najib, et al. The Orphan Nuclear Receptor Rev-Erb{alpha} Is a Peroxisome Proliferator-activated Receptor (PPAR) {gamma} Target Gene and Promotes PPAR{gamma}-induced Adipocyte Differentiation J. Biol. Chem., September 26, 2003; 278(39): 37672 - 37680. [Abstract] [Full Text] [PDF]

				K. D. S. A. Wansa, J. M. Harris, G. Yan, P. Ordentlich, and G. E. O. Muscat The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine J. Biol. Chem., June 27, 2003; 278(27): 24776 - 24790. [Abstract] [Full Text] [PDF]

				E. Raspe, G. Mautino, C. Duval, C. Fontaine, H. Duez, O. Barbier, D. Monte, J. Fruchart, J.-C. Fruchart, and B. Staels Transcriptional Regulation of Human Rev-erbalpha Gene Expression by the Orphan Nuclear Receptor Retinoic Acid-related Orphan Receptor alpha J. Biol. Chem., December 13, 2002; 277(51): 49275 - 49281. [Abstract] [Full Text] [PDF]

				C. Brendel, K. Schoonjans, O. A. Botrugno, E. Treuter, and J. Auwerx The Small Heterodimer Partner Interacts with the Liver X Receptor {alpha} and Represses Its Transcriptional Activity Mol. Endocrinol., September 1, 2002; 16(9): 2065 - 2076. [Abstract] [Full Text] [PDF]

				K. D. S. A. Wansa, J. M. Harris, and G. E. O. Muscat The Activation Function-1 Domain of Nur77/NR4A1 Mediates Trans-activation, Cell Specificity, and Coactivator Recruitment J. Biol. Chem., August 30, 2002; 277(36): 33001 - 33011. [Abstract] [Full Text] [PDF]

				H. Coste and J. C. Rodriguez Orphan Nuclear Hormone Receptor Rev-erbalpha Regulates the Human Apolipoprotein CIII Promoter J. Biol. Chem., July 19, 2002; 277(30): 27120 - 27129. [Abstract] [Full Text] [PDF]

				T. M. Willson and J. T. Moore Minireview: Genomics Versus Orphan Nuclear Receptors--A Half-Time Report Mol. Endocrinol., June 1, 2002; 16(6): 1135 - 1144. [Abstract] [Full Text] [PDF]

				J. M. Harris, P. Lau, S. L. Chen, and G. E. O. Muscat Characterization of the Retinoid Orphan-Related Receptor-{alpha} Coactivator Binding Interface: A Structural Basis for Ligand-Independent Transcription Mol. Endocrinol., May 1, 2002; 16(5): 998 - 1012. [Abstract] [Full Text] [PDF]

				A. Marimuthu, W. Feng, T. Tagami, H. Nguyen, J. L. Jameson, R. J. Fletterick, J. D. Baxter, and B. L. West TR Surfaces and Conformations Required to Bind Nuclear Receptor Corepressor Mol. Endocrinol., February 1, 2002; 16(2): 271 - 286. [Abstract] [Full Text] [PDF]

				R. N. Cohen, S. Brzostek, B. Kim, M. Chorev, F. E. Wondisford, and A. N. Hollenberg The Specificity of Interactions between Nuclear Hormone Receptors and Corepressors Is Mediated by Distinct Amino Acid Sequences within the Interacting Domains Mol. Endocrinol., July 1, 2001; 15(7): 1049 - 1061. [Abstract] [Full Text] [PDF]

				X. Hu, Y. Li, and M. A. Lazar Determinants of CoRNR-Dependent Repression Complex Assembly on Nuclear Hormone Receptors Mol. Cell. Biol., March 1, 2001; 21(5): 1747 - 1758. [Abstract] [Full Text]