This Article Full Text Full Text (PDF) 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 Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Northrop, J. P. Articles by Schatz, P. J. Search for Related Content PubMed PubMed Citation Articles by Northrop, J. P. Articles by Schatz, P. J.

Selection of Estrogen Receptor ß- and Thyroid Hormone Receptor ß-Specific Coactivator-Mimetic Peptides Using Recombinant Peptide Libraries

Affymax Research Institute Santa Clara, California 95051

Steroid and thyroid hormone receptors are members of the superfamily of nuclear receptors (NR) that participate in developmental and homeostatic mechanisms by changes in the transcription of specific genes. These activities are governed by the receptors’ cognate ligands and through interaction with the components of the transcriptional machinery. A number of coactivator molecules of the steroid receptor coactivator (SRC)/nuclear receptor coactivator (NCoA) family interact with activation functions within NRs through a conserved region containing helical domains of a core LXXLL sequence and, thereby, participate in transcriptional regulation. Using a mammalian-two-hybrid assay, we show that the thyroid hormone receptor ß (TRß) and estrogen receptor ß (ERß) have different LXXLL motif preferences for interactions with SRC-1. Using large random and focused (centered on the LXXLL motif) recombinant peptide diversity libraries, we have obtained novel peptide sequences that interact specifically with ERß or with TRß in a ligand-dependent manner. Random sequence libraries yielded LXXLL-containing peptides, and sequence analysis of selected clones revealed that the preferred residues within and around the LXXLL motif vary significantly between these two receptors. We compared the receptor binding of library-selected peptides to that of peptides derived from natural coactivators. The affinities of selected peptides for the ligand binding domains of ERß and TRß were similar to the best natural LXXLL motifs tested, but showed a higher degree of receptor selectivity. These selected peptides also display receptor-selective dominant inhibitory activities when introduced into mammalian cells. Finally, by directed mutations in specific residues, we were able to alter the receptor binding preference of these peptides.

This article has been cited by other articles:

				H. Wang, H. Li, L. B. Moore, M. D. L. Johnson, J. M. Maglich, B. Goodwin, O. R. R. Ittoop, B. Wisely, K. Creech, D. J. Parks, et al. The Phytoestrogen Coumestrol Is a Naturally Occurring Antagonist of the Human Pregnane X Receptor Mol. Endocrinol., April 1, 2008; 22(4): 838 - 857. [Abstract] [Full Text] [PDF]

				M. Lodrini, T. Munz, N. Coudevylle, C. Griesinger, S. Becker, and E. Pfitzner p160/SRC/NCoA coactivators form complexes via specific interaction of their PAS-B domain with the CID/AD1 domain Nucleic Acids Res., April 1, 2008; 36(6): 1847 - 1860. [Abstract] [Full Text] [PDF]

				P.-J. Tai, Y.-H. Huang, C.-H. Shih, R.-N. Chen, C.-D. Chen, W.-J. Chen, C.-S. Wang, and K.-H. Lin Direct Regulation of Androgen Receptor-Associated Protein 70 by Thyroid Hormone and Its Receptors Endocrinology, July 1, 2007; 148(7): 3485 - 3495. [Abstract] [Full Text] [PDF]

				S. Folkertsma, P. I. van Noort, A. de Heer, P. Carati, R. Brandt, A. Visser, G. Vriend, and J. de Vlieg The Use of in Vitro Peptide Binding Profiles and in Silico Ligand-Receptor Interaction Profiles to Describe Ligand-Induced Conformations of the Retinoid X Receptor {alpha} Ligand-Binding Domain Mol. Endocrinol., January 1, 2007; 21(1): 30 - 48. [Abstract] [Full Text] [PDF]

				B. N. Duong, S. Elliott, D. E. Frigo, L. I. Melnik, L. Vanhoy, S. Tomchuck, H. P. Lebeau, O. David, B. S. Beckman, J. Alam, et al. AKT Regulation of Estrogen Receptor {beta} Transcriptional Activity in Breast Cancer. Cancer Res., September 1, 2006; 66(17): 8373 - 8381. [Abstract] [Full Text] [PDF]

				H. J. Dubbink, R. Hersmus, A. C. W. Pike, M. Molier, A. O. Brinkmann, G. Jenster, and J. Trapman Androgen Receptor Ligand-Binding Domain Interaction and Nuclear Receptor Specificity of FXXLF and LXXLL Motifs as Determined by L/F Swapping Mol. Endocrinol., August 1, 2006; 20(8): 1742 - 1755. [Abstract] [Full Text] [PDF]

				J. M. R. Moore and R. K. Guy Coregulator Interactions with the Thyroid Hormone Receptor Mol. Cell. Proteomics, April 1, 2005; 4(4): 475 - 482. [Abstract] [Full Text] [PDF]

				C M Klinge, S C Jernigan, K A Mattingly, K E Risinger, and J Zhang Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors {alpha} and {beta} by coactivators and corepressors J. Mol. Endocrinol., October 1, 2004; 33(2): 387 - 410. [Abstract] [Full Text] [PDF]

				J. M. R. Moore, S. J. Galicia, A. C. McReynolds, N.-H. Nguyen, T. S. Scanlan, and R. K. Guy Quantitative Proteomics of the Thyroid Hormone Receptor-Coregulator Interactions J. Biol. Chem., June 25, 2004; 279(26): 27584 - 27590. [Abstract] [Full Text] [PDF]

				M. A. Iannone, C. A. Simmons, S. H. Kadwell, D. L. Svoboda, D. E. Vanderwall, S.-J. Deng, T. G. Consler, J. Shearin, J. G. Gray, and K. H. Pearce Correlation between in Vitro Peptide Binding Profiles and Cellular Activities for Estrogen Receptor-Modulating Compounds Mol. Endocrinol., May 1, 2004; 18(5): 1064 - 1081. [Abstract] [Full Text] [PDF]

				A.-M. Leduc, J. O. Trent, J. L. Wittliff, K. S. Bramlett, S. L. Briggs, N. Y. Chirgadze, Y. Wang, T. P. Burris, and A. F. Spatola Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions PNAS, September 30, 2003; 100(20): 11273 - 11278. [Abstract] [Full Text] [PDF]

				J. Liu, K. S. Knappenberger, H. Kack, G. Andersson, E. Nilsson, C. Dartsch, and C. W. Scott A Homogeneous in Vitro Functional Assay for Estrogen Receptors: Coactivator Recruitment Mol. Endocrinol., March 1, 2003; 17(3): 346 - 355. [Abstract] [Full Text] [PDF]

				Y. Wu, W. W. Chin, Y. Wang, and T. P. Burris Ligand and Coactivator Identity Determines the Requirement of the Charge Clamp for Coactivation of the Peroxisome Proliferator-activated Receptor gamma J. Biol. Chem., February 28, 2003; 278(10): 8637 - 8644. [Abstract] [Full Text] [PDF]

				L. Ko, G. R. Cardona, T. Iwasaki, K. S. Bramlett, T. P. Burris, and W. W. Chin Ser-884 Adjacent to the LXXLL Motif of Coactivator TRBP Defines Selectivity for ERs and TRs Mol. Endocrinol., January 1, 2002; 16(1): 128 - 140. [Abstract] [Full Text] [PDF]

				K. S. Bramlett, Y. Wu, and T. P. Burris Ligands Specify Coactivator Nuclear Receptor (NR) Box Affinity for Estrogen Receptor Subtypes Mol. Endocrinol., June 1, 2001; 15(6): 909 - 922. [Abstract] [Full Text] [PDF]

				J. M. Hall, C.-y. Chang, and D. P. McDonnell Development of Peptide Antagonists That Target Estrogen Receptor {beta}-Coactivator Interactions Mol. Endocrinol., December 1, 2000; 14(12): 2010 - 2023. [Abstract] [Full Text]

				A. Warnmark, T. Almlof, J. Leers, J.-A. Gustafsson, and E. Treuter Differential Recruitment of the Mammalian Mediator Subunit TRAP220 by Estrogen Receptors ERalpha and ERbeta J. Biol. Chem., June 22, 2001; 276(26): 23397 - 23404. [Abstract] [Full Text] [PDF]