title: Single thyroid hormone receptor monomers are competent for co-activator-mediated transactivation.
abstract: Thyroid hormone receptor (T(3)R) belongs to the superfamily of nuclear receptors containing highly related transcription factors that transform an incoming signal in the form of a lipophilic hormone into an activation of the basal transcriptional machinery. Like many other nuclear receptors, T(3)R acts preferentially as a heterodimer with retinoid X receptor (RXR) but it also has the unique property of binding as a monomer to DNA. This study demonstrates that T(3)R monomers bind preferentially to AGGTCA binding motifs and are able to co-exist with T(3)R-RXR heterodimers in the presence of limiting amounts of RXR. DNA-bound T(3)R monomers efficiently contact all three members of the p160 co-activator family, which in turn boost T(3)R monomer-mediated transactivation. In solution T(3)R monomers take only one agonistic conformation (c2(LPD)), whereas bound to DNA they also stabilize, like T(3)R-RXR heterodimers, a second agonistic conformation (c1(LPD)). Conformation c2(LPD) seems to be of lower ligand sensitivity (10 nM), whereas, both in T(3)R-RXR heterodimers and in DNA-bound T(3)R monomers, c1(LPD) is already activated at a ligand concentration of 1 nM. Taken together, these results suggest that single T(3)R monomers are fully competent for ligand-induced transactivation and that their role in gene regulation by thyroid hormone might have been underestimated.
authors.affiliation: Institute for Physiological Chemistry I, Heinrich-Heine-University, D-40001 Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Quack
authors.forename: C
authors.initials: C
authors.lastname: Carlberg
mesh_terms: D000818:Animals; D002645:Chickens; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047488:Retinoid X Receptors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology*; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D014284:Triiodothyronine; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D010450:Endopeptidases