| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Metabolic Research Unit (A.M., W.F., H.N., J.D.B., B.L.W.) and Departments of Biochemistry and Biophysics and Cellular and Molecular Pharmacology (R.J.F.), University of California San Francisco, San Francisco, California 94143; Center for Endocrinology, Metabolism, and Molecular Medicine (J.L.J.), Northwestern University Medical School, Chicago, Illinois 60611; and Clinical Research Institute, Center for Endocrine and Metabolic Diseases (T.T.), Kyoto National Hospital, Kyoto 612-8555, Japan
Address all correspondence and requests for reprints to: Dr. Brian L. West, Molecular Biology Department, Plexxikon, Inc., 91 Bolivar Street, Berkeley, California 94710. E-mail: bwest{at}plexxikon.com
Residues of the TR that are critical for binding the nuclear receptor corepressor (N-CoR) were identified by testing more than 100 separate mutations of the full-length human TRß that scan the surface of its ligand binding domain. The primary inferred interaction surface overlaps the surface described for binding of p160 coactivators, but differs by extending to a novel site underneath which helix 12 rests in the liganded TR, rather than including residues of helix 12. Nonconservative mutations of this surface diminished binding similarly to three isolated N-CoR receptor interaction domains (RIDs), but conservative mutations affected binding variably, consistent with a role for this surface in RID selectivity. The commonality of this surface in binding N-CoR was confirmed for the RXRs and ERs. Deletion of helix 12 increased N-CoR binding by the TR modestly, and by the RXR and ER to a much greater extent, indicating a competition between this helix and the corepressor that regulates the extent of corepressor binding by nuclear receptors. When helix 12 was deleted, N-CoR binding by the ER was stimulated by tamoxifen, and binding by the TR was stimulated by Triac, indicating that helix 12 is not the only feature that regulates corepressor binding. Two additional mutationsensitive surfaces were found alongside helix 1, near the previously described CoR box, and above helix 11, nearby but separate from residues that help link receptor in dimers. Based on effects of selected mutations on T3 and coactivator binding, and on results of combined mutations of the three sites on corepressor binding, we propose that the second and third surfaces stabilize TR unliganded conformation(s) required for efficient N-CoR binding. In transfection assays mutations of all three surfaces impaired the corepressor-mediated functions of unliganded TR repression or activation. These detailed mapping results suggest approaches for selective modulation of corepressor interaction that include the shape of the molecular binding surface, the competitive occupancy by helix 12, pharmacological stimulation, and specific conformational stabilization.
This article has been cited by other articles:
 |
|
 |
|
  R. Sanchez-Martinez, A. Zambrano, A. I. Castillo, and A. Aranda Vitamin D-Dependent Recruitment of Corepressors to Vitamin D/Retinoid X Receptor Heterodimers Mol. Cell. Biol., June 1, 2008; 28(11): 3817 - 3829. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kressler, M. B. Hock, and A. Kralli Coactivators PGC-1beta and SRC-1 Interact Functionally to Promote the Agonist Activity of the Selective Estrogen Receptor Modulator Tamoxifen J. Biol. Chem., September 14, 2007; 282(37): 26897 - 26907. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Jonas, N. Varlakhanova, F. Hayakawa, M. Goodson, and M. L. Privalsky Response of SMRT (Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor) and N-CoR (Nuclear Receptor Corepressor) Corepressors to Mitogen-Activated Protein Kinase Kinase Kinase Cascades Is Determined by Alternative mRNA Splicing Mol. Endocrinol., August 1, 2007; 21(8): 1924 - 1939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Heldring, T. Pawson, D. McDonnell, E. Treuter, J.-A. Gustafsson, and A. C. W. Pike Structural Insights into Corepressor Recognition by Antagonist-bound Estrogen Receptors J. Biol. Chem., April 6, 2007; 282(14): 10449 - 10455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lupien, M. Jeyakumar, E. Hebert, K. Hilmi, D. Cotnoir-White, C. Loch, A. Auger, G. Dayan, G.-A. Pinard, J.-M. Wurtz, et al. Raloxifene and ICI182,780 Increase Estrogen Receptor-{alpha} Association with a Nuclear Compartment via Overlapping Sets of Hydrophobic Amino Acids in Activation Function 2 Helix 12 Mol. Endocrinol., April 1, 2007; 21(4): 797 - 816. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Flamant, K. Gauthier, and J. Samarut Thyroid Hormones Signaling Is Getting More Complex: STORMs Are Coming Mol. Endocrinol., February 1, 2007; 21(2): 321 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Padron, L. Li, E. M. Kofoed, and F. Schaufele Ligand-Selective Interdomain Conformations of Estrogen Receptor-{alpha} Mol. Endocrinol., January 1, 2007; 21(1): 49 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Flamant, J. D. Baxter, D. Forrest, S. Refetoff, H. Samuels, T. S. Scanlan, B. Vennstrom, and J. Samarut International Union of Pharmacology. LIX. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Thyroid Hormone Receptors Pharmacol. Rev., December 1, 2006; 58(4): 705 - 711. [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Santos, V. Afonso, G. B. Barra, M. Togashi, P. Webb, F. A. R. Neves, N. Lomri, and A. Lomri Negative Regulation of Superoxide Dismutase-1 Promoter by Thyroid Hormone Mol. Pharmacol., September 1, 2006; 70(3): 793 - 800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Moran and G. Jimenez The tailless nuclear receptor acts as a dedicated repressor in the early Drosophila embryo. Mol. Cell. Biol., May 1, 2006; 26(9): 3446 - 3454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Togashi, P. Nguyen, R. Fletterick, J. D. Baxter, and P. Webb Rearrangements in Thyroid Hormone Receptor Charge Clusters That Stabilize Bound 3,5',5-Triiodo-L-thyronine and Inhibit Homodimer Formation J. Biol. Chem., July 8, 2005; 280(27): 25665 - 25673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Wang, C. Zhang, A. Marimuthu, H. I. Krupka, M. Tabrizizad, R. Shelloe, U. Mehra, K. Eng, H. Nguyen, C. Settachatgul, et al. The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1 PNAS, May 24, 2005; 102(21): 7505 - 7510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Meng, P. Webb, Y.-F. Yang, M. Shuen, A. F. Yousef, J. D. Baxter, J. S. Mymryk, and P. G. Walfish E1A and a nuclear receptor corepressor splice variant (N-CoRI) are thyroid hormone receptor coactivators that bind in the corepressor mode PNAS, May 3, 2005; 102(18): 6267 - 6272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Goodson, B. A. Jonas, and M. L. Privalsky Alternative mRNA Splicing of SMRT Creates Functional Diversity by Generating Corepressor Isoforms with Different Affinities for Different Nuclear Receptors J. Biol. Chem., March 4, 2005; 280(9): 7493 - 7503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Jyrkkarinne, B. Windshugel, J. Makinen, M. Ylisirnio, M. Perakyla, A. Poso, W. Sippl, and P. Honkakoski Amino Acids Important for Ligand Specificity of the Human Constitutive Androstane Receptor J. Biol. Chem., February 18, 2005; 280(7): 5960 - 5971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Farboud and M. L. Privalsky Retinoic Acid Receptor-{alpha} Is Stabilized in a Repressive State by Its C-Terminal, Isotype-Specific F Domain Mol. Endocrinol., December 1, 2004; 18(12): 2839 - 2853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kawai, S. Sasaki, H. Morita, T. Ito, S. Suzuki, H. Misawa, and H. Nakamura Unliganded Thyroid Hormone Receptor-{beta}1 Represses Liver X Receptor {alpha}/Oxysterol-Dependent Transactivation Endocrinology, December 1, 2004; 145(12): 5515 - 5524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Buchholz, A. Tomita, L. Fu, B. D. Paul, and Y.-B. Shi Transgenic Analysis Reveals that Thyroid Hormone Receptor Is Sufficient To Mediate the Thyroid Hormone Signal in Frog Metamorphosis Mol. Cell. Biol., October 15, 2004; 24(20): 9026 - 9037. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ishii, M. Yamada, T. Satoh, T. Monden, K. Hashimoto, N. Shibusawa, K. Onigata, A. Morikawa, and M. Mori Aberrant Dynamics of Histone Deacetylation at the Thyrotropin-Releasing Hormone Gene in Resistance to Thyroid Hormone Mol. Endocrinol., July 1, 2004; 18(7): 1708 - 1720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Wang, J. A. Blackford Jr., L.-N. Song, Y. Huang, S. Cho, and S. S. Simons Jr. Equilibrium Interactions of Corepressors and Coactivators with Agonist and Antagonist Complexes of Glucocorticoid Receptors Mol. Endocrinol., June 1, 2004; 18(6): 1376 - 1395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Borngraeber, M.-J. Budny, G. Chiellini, S. T. Cunha-Lima, M. Togashi, P. Webb, J. D. Baxter, T. S. Scanlan, and R. J. Fletterick Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor PNAS, December 23, 2003; 100(26): 15358 - 15363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Benko, J. D. Love, M. Beladi, J. W. R. Schwabe, and L. Nagy Molecular Determinants of the Balance between Co-repressor and Co-activator Recruitment to the Retinoic Acid Receptor J. Biol. Chem., October 31, 2003; 278(44): 43797 - 43806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. U. Agoulnik, W. C. Krause, W. E. Bingman III, H. T. Rahman, M. Amrikachi, G. E. Ayala, and N. L. Weigel Repressors of Androgen and Progesterone Receptor Action J. Biol. Chem., August 15, 2003; 278(33): 31136 - 31148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Lehmann, J.-M. Wurtz, J.-P. Renaud, P. Sassone-Corsi, and E. Lalli Structure-function analysis reveals the molecular determinants of the impaired biological function of DAX-1 mutants in AHC patients Hum. Mol. Genet., May 1, 2003; 12(9): 1063 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Fischer, S. M. G. Dias, M. A. M. Santos, A. C. Alves, N. Zanchin, A. F. Craievich, J. W. Apriletti, J. D. Baxter, P. Webb, F. A. R. Neves, et al. Low Resolution Structures of the Retinoid X Receptor DNA-binding and Ligand-binding Domains Revealed by Synchrotron X-ray Solution Scattering J. Biol. Chem., April 25, 2003; 278(18): 16030 - 16038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Liang, P. Webb, A. Marimuthu, S. Zhang, and D. G. Gardner Triiodothyronine Increases Brain Natriuretic Peptide (BNP) Gene Transcription and Amplifies Endothelin-dependent BNP Gene Transcription and Hypertrophy in Neonatal Rat Ventricular Myocytes J. Biol. Chem., April 18, 2003; 278(17): 15073 - 15083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Farboud, H. Hauksdottir, Y. Wu, and M. L. Privalsky Isotype-Restricted Corepressor Recruitment: a Constitutively Closed Helix 12 Conformation in Retinoic Acid Receptors {beta} and {gamma} Interferes with Corepressor Recruitment and Prevents Transcriptional Repression Mol. Cell. Biol., April 15, 2003; 23(8): 2844 - 2858. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Webb, P. Nguyen, and P. J. Kushner Differential SERM Effects on Corepressor Binding Dictate ERalpha Activity in Vivo J. Biol. Chem., February 21, 2003; 278(9): 6912 - 6920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Makowski, S. Brzostek, R. N. Cohen, and A. N. Hollenberg Determination of Nuclear Receptor Corepressor Interactions with the Thyroid Hormone Receptor Mol. Endocrinol., February 1, 2003; 17(2): 273 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R. Huber, M. Desclozeaux, B. L. West, S. T. Cunha-Lima, H. T. Nguyen, J. D. Baxter, H. A. Ingraham, and R. J. Fletterick Thyroid Hormone Receptor-{beta} Mutations Conferring Hormone Resistance and Reduced Corepressor Release Exhibit Decreased Stability in the N-Terminal Ligand-Binding Domain Mol. Endocrinol., January 1, 2003; 17(1): 107 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Huang, J. D. Norris, and D. P. McDonnell Identification of a Negative Regulatory Surface within Estrogen Receptor {alpha} Provides Evidence in Support of a Role for Corepressors in Regulating Cellular Responses to Agonists and Antagonists Mol. Endocrinol., August 1, 2002; 16(8): 1778 - 1792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Ghosh, X. Yang, A. Zhang, M. H. Lambert, H. Li, H. E. Xu, and J. D. Chen Interactions that determine the assembly of a retinoid X receptor/corepressor complex PNAS, April 30, 2002; 99(9): 5842 - 5847. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Ghosh, X. Yang, A. Zhang, M. H. Lambert, H. Li, H. E. Xu, and J. D. Chen Interactions that determine the assembly of a retinoid X receptor/corepressor complex PNAS, April 30, 2002; 99(9): 5842 - 5847. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
