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Nuclear Receptor-Binding Sites of Coactivators Glucocorticoid Receptor Interacting Protein 1 (GRIP1) and Steroid Receptor Coactivator 1 (SRC-1): Multiple Motifs with Different Binding Specificities

Departments of Pathology and of Biochemistry and Molecular Biology (X.F.D., H.M., H.H., M.R.S.) University of Southern California Los Angeles, California 90033
Metabolic Research Unit (C.M.A., R.M.U., P.J.K.) University of California San Francisco, California 94143

The activity of the AF-2 transcriptional activation function of nuclear receptors (NR) is mediated by the partially homologous transcriptional coactivators, glucocorticoid receptor interacting protein 1 (GRIP1)/transcriptional intermediary factor 2 (TIF2) and steroid receptor coactivator 1 (SRC-1). GRIP1 and SRC-1 bound nine different NRs and exhibited similar, but not identical, NR binding preferences. The most striking difference was seen with the androgen receptor, which bound well to GRIP1 but poorly to SRC-1. GRIP1 and SRC-1 contain three copies of the NR binding motif LXXLL (called an NR Box) in their central regions. Mutation of both NR Box II and NR Box III in GRIP1 almost completely eliminated functional and binding interactions with NRs, indicating that these two sites are crucial for most of GRIP1’s NR binding activity. Interactions of GRIP1 with the estrogen receptor were more strongly affected by mutations in NR Box II, whereas interactions with the androgen receptor and glucocorticoid receptor were more strongly affected by NR Box III mutations. One isoform of SRC-1 has an additional NR Box (NR Box IV) at its extreme C terminus with an NR-binding preference somewhat different from that of the central NR-binding domain of SRC-1. GRIP1 has no NR Box in its C-terminal region and therefore no C-terminal NR-binding function. In summary, GRIP1 and SRC-1 have overlapping NR-binding preferences, but specific NRs display both coactivator and NR Box preferences that may contribute to the specificity of hormonal responses.

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				C. Teyssier, K. Belguise, F. Galtier, V. Cavailles, and D. Chalbos Receptor-Interacting Protein 140 Binds c-Jun and Inhibits Estradiol-Induced Activator Protein-1 Activity by Reversing Glucocorticoid Receptor-Interacting Protein 1 Effect Mol. Endocrinol., February 1, 2003; 17(2): 287 - 299. [Abstract] [Full Text] [PDF]

				T. Kino and G. P. Chrousos Tumor Necrosis Factor alpha Receptor- and Fas-associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators J. Biol. Chem., January 24, 2003; 278(5): 3023 - 3029. [Abstract] [Full Text] [PDF]

				I. Rogatsky, H. F. Luecke, D. C. Leitman, and K. R. Yamamoto Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts PNAS, December 24, 2002; 99(26): 16701 - 16706. [Abstract] [Full Text] [PDF]

				V. Christiaens, C. L. Bevan, L. Callewaert, A. Haelens, G. Verrijdt, W. Rombauts, and F. Claessens Characterization of the Two Coactivator-interacting Surfaces of the Androgen Receptor and Their Relative Role in Transcriptional Control* J. Biol. Chem., December 13, 2002; 277(51): 49230 - 49237. [Abstract] [Full Text] [PDF]

				Y. He, D. Szapary, and S. S. Simons Jr. Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation J. Biol. Chem., December 13, 2002; 277(51): 49256 - 49266. [Abstract] [Full Text] [PDF]

				M. A. Rao, H. Cheng, A. N. Quayle, H. Nishitani, C. C. Nelson, and P. S. Rennie RanBPM, a Nuclear Protein That Interacts with and Regulates Transcriptional Activity of Androgen Receptor and Glucocorticoid Receptor J. Biol. Chem., December 6, 2002; 277(50): 48020 - 48027. [Abstract] [Full Text] [PDF]

				C. Teyssier, D. Chen, and M. R. Stallcup Requirement for Multiple Domains of the Protein Arginine Methyltransferase CARM1 in Its Transcriptional Coactivator Function J. Biol. Chem., November 22, 2002; 277(48): 46066 - 46072. [Abstract] [Full Text] [PDF]

				M. E. Torres-Padilla, F. M. Sladek, and M. C. Weiss Developmentally Regulated N-terminal Variants of the Nuclear Receptor Hepatocyte Nuclear Factor 4alpha Mediate Multiple Interactions through Coactivator and Corepressor-Histone Deacetylase Complexes J. Biol. Chem., November 15, 2002; 277(47): 44677 - 44687. [Abstract] [Full Text] [PDF]

				T. Barkhem, L.-A. Haldosen, J.-A. Gustafsson, and S. Nilsson Transcriptional Synergism on the pS2 Gene Promoter between a p160 Coactivator and Estrogen Receptor-{alpha} Depends on the Coactivator Subtype, the Type of Estrogen Response Element, and the Promoter Context Mol. Endocrinol., November 1, 2002; 16(11): 2571 - 2581. [Abstract] [Full Text] [PDF]

				C. M. Litterst and E. Pfitzner An LXXLL Motif in the Transactivation Domain of STAT6 Mediates Recruitment of NCoA-1/SRC-1 J. Biol. Chem., September 20, 2002; 277(39): 36052 - 36060. [Abstract] [Full Text] [PDF]

				S. Kaul, P. J. M. Murphy, J. Chen, L. Brown, W. B. Pratt, and S. S. Simons Jr. Mutations at Positions 547-553 of Rat Glucocorticoid Receptors Reveal That hsp90 Binding Requires the Presence, but Not Defined Composition, of a Seven-amino Acid Sequence at the Amino Terminus of the Ligand Binding Domain J. Biol. Chem., September 20, 2002; 277(39): 36223 - 36232. [Abstract] [Full Text] [PDF]

				P. Delerive, W. W. Chin, and C. S. Suen Identification of Reverbalpha as a Novel RORalpha Target Gene J. Biol. Chem., September 13, 2002; 277(38): 35013 - 35018. [Abstract] [Full Text] [PDF]

				N. Kotaja, U. Karvonen, O. A. Janne, and J. J. Palvimo The Nuclear Receptor Interaction Domain of GRIP1 Is Modulated by Covalent Attachment of SUMO-1 J. Biol. Chem., August 9, 2002; 277(33): 30283 - 30288. [Abstract] [Full Text] [PDF]

				C. Lethimonier, G. Flouriot, O. Kah, and B. Ducouret The Glucocorticoid Receptor Represses the Positive Autoregulation of the Trout Estrogen Receptor Gene by Preventing the Enhancer Effect of a C/EBP{beta}-Like Protein Endocrinology, August 1, 2002; 143(8): 2961 - 2974. [Abstract] [Full Text] [PDF]

				S. S. Koh, H. Li, Y.-H. Lee, R. B. Widelitz, C.-M. Chuong, and M. R. Stallcup Synergistic Coactivator Function by Coactivator-associated Arginine Methyltransferase (CARM) 1 and beta -Catenin with Two Different Classes of DNA-binding Transcriptional Activators J. Biol. Chem., July 12, 2002; 277(29): 26031 - 26035. [Abstract] [Full Text] [PDF]

				T. Kucera, M. Waltner-Law, D. K. Scott, R. Prasad, and D. K. Granner A Point Mutation of the AF2 Transactivation Domain of the Glucocorticoid Receptor Disrupts Its Interaction with Steroid Receptor Coactivator 1 J. Biol. Chem., July 12, 2002; 277(29): 26098 - 26102. [Abstract] [Full Text] [PDF]

				S. Cheng, S. Brzostek, S. R. Lee, A. N. Hollenberg, and S. P. Balk Inhibition of the Dihydrotestosterone-Activated Androgen Receptor by Nuclear Receptor Corepressor Mol. Endocrinol., July 1, 2002; 16(7): 1492 - 1501. [Abstract] [Full Text] [PDF]

				Y. Maeda, C. Rachez, L. Hawel III, C. V. Byus, L. P. Freedman, and F. M. Sladek Polyamines Modulate the Interaction between Nuclear Receptors and Vitamin D Receptor-Interacting Protein 205 Mol. Endocrinol., July 1, 2002; 16(7): 1502 - 1510. [Abstract] [Full Text] [PDF]

				B. C. Freeman and K. R. Yamamoto Disassembly of Transcriptional Regulatory Complexes by Molecular Chaperones Science, June 21, 2002; 296(5576): 2232 - 2235. [Abstract] [Full Text] [PDF]

				A. Vottero, T. Kino, H. Combe, P. Lecomte, and G. P. Chrousos A Novel, C-Terminal Dominant Negative Mutation of the GR Causes Familial Glucocorticoid Resistance through Abnormal Interactions with p160 Steroid Receptor Coactivators J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2658 - 2667. [Abstract] [Full Text] [PDF]

				W. Shao, S. Halachmi, and M. Brown ERAP140, a Conserved Tissue-Specific Nuclear Receptor Coactivator Mol. Cell. Biol., May 15, 2002; 22(10): 3358 - 3372. [Abstract] [Full Text] [PDF]

				N. Kotaja, M. Vihinen, J. J. Palvimo, and O. A. Janne Androgen Receptor-interacting Protein 3 and Other PIAS Proteins Cooperate with Glucocorticoid Receptor-interacting Protein 1 in Steroid Receptor-dependent Signaling J. Biol. Chem., May 10, 2002; 277(20): 17781 - 17788. [Abstract] [Full Text] [PDF]

				M. D. Ruse Jr., M. L. Privalsky, and F. M. Sladek Competitive Cofactor Recruitment by Orphan Receptor Hepatocyte Nuclear Factor 4{alpha}1: Modulation by the F Domain Mol. Cell. Biol., March 15, 2002; 22(6): 1626 - 1638. [Abstract] [Full Text] [PDF]

				B. He, J. T. Minges, L. W. Lee, and E. M. Wilson The FXXLF Motif Mediates Androgen Receptor-specific Interactions with Coregulators J. Biol. Chem., March 15, 2002; 277(12): 10226 - 10235. [Abstract] [Full Text] [PDF]

				H. Liu, W.-C. Park, D. J. Bentrem, K. P. McKian, A. D. L. Reyes, J. A. Loweth, J. M. Schafer, J. W. Zapf, and V. C. Jordan Structure-Function Relationships of the Raloxifene-Estrogen Receptor-alpha Complex for Regulating Transforming Growth Factor-alpha Expression in Breast Cancer Cells J. Biol. Chem., March 8, 2002; 277(11): 9189 - 9198. [Abstract] [Full Text] [PDF]

				J. M. Hall, D. P. McDonnell, and K. S. Korach Allosteric Regulation of Estrogen Receptor Structure, Function, and Coactivator Recruitment by Different Estrogen Response Elements Mol. Endocrinol., March 1, 2002; 16(3): 469 - 486. [Abstract] [Full Text] [PDF]

				R. V. Weatherman, C.-Y. Chang, N. J. Clegg, D. C. Carroll, R. N. Day, J. D. Baxter, D. P. McDonnell, T. S. Scanlan, and F. Schaufele Ligand-Selective Interactions of ER Detected in Living Cells by Fluorescence Resonance Energy Transfer Mol. Endocrinol., March 1, 2002; 16(3): 487 - 496. [Abstract] [Full Text] [PDF]

				S. Fan, Y. X. Ma, C. Wang, R.-Q. Yuan, Q. Meng, J.-A. Wang, M. Erdos, I. D. Goldberg, P. Webb, P. J. Kushner, et al. p300 Modulates the BRCA1 Inhibition of Estrogen Receptor Activity Cancer Res., January 1, 2002; 62(1): 141 - 151. [Abstract] [Full Text] [PDF]