Dynamic inhibition of nuclear receptor activation by corepressor binding.
Nuclear receptors adopt dramatically different conformations in the presence or absence of ligand, and such liganded (holo) and unliganded (apo) receptors are specifically recognized by transcriptional coactivators and corepressors, respectively. These two states likely exist in dynamic equilibrium, contrary to the conventional model of static off and on conformations. First, corepressor SMRT [for silencing mediator of thyroid hormone receptor (TR) and retinoic acid receptor (RAR)] inhibits the interaction of coactivator steroid receptor coactivator-1 with liganded TR/RAR. Second, SMRT enables receptors to adopt apo-form even in the presence of ligand, as demonstrated with limited proteolyses and decreased binding of radiolabeled retinoid to RAR. Finally, chromatin immunoprecipitation results indicate that SMRT and steroid receptor coactivator-1 dynamically compete for receptor bindings in vivo in the presence of ligand. These results suggest that corepressor binding can drive receptors to adopt the apo-state, even in the presence of ligand, and inhibit activated liganded (holo) nuclear receptors in vivo.
Sohn
Young-Chang
YC
Department of Life Science, Pohang University of Science and Technology, Pohang 790-784, Korea.
Kim
Seung-Whan
SW
Lee
Seunghee
S
Kong
Young-Yun
YY
Na
Doe Sun
DS
Lee
Soo-Kyung
SK
Lee
Jae Woon
JW
D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D056985:Nuclear Receptor Co-Repressor 2; D056920:Nuclear Receptor Coactivator 1; D011233:Precipitin Tests; D011485:Protein Binding; D011487:Protein Conformation; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D012176:Retinoids / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection
D002843:Chromatin; D004268:DNA-Binding Proteins; D008024:Ligands; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D012176:Retinoids; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1