Binding characteristics of the thyroid hormone receptor homo- and heterodimers to consensus AGGTCA repeat motifs

Abstract

Previous studies have shown that thyroid hormone receptors can form homo- and heterodimeric complexes when binding to response elements. We report here the binding characteristics of thyroid hormone receptor (TR) homo- and heterodimers binding to synthetic oligonucleotides with directly and palindromically repeated consensus motifs (AGGTCA). Binding assays showed that TR homodimer formation on DNA had a low specificity and cooperativity, and very fast off rates. In contrast, TRs and retinoic acid receptors readily formed heterodimers with higher specificity and affinity on direct repeats of the AGGTCA motif spaced by four or five nucleotides, although these heterodimer/DNA complexes were only moderately stable when compared to DNA-bound TR/retinoid X receptor heterodimers. Also, TR/retinoic acid receptor heteromeric binding to other elements, including the synthetic T3RE-pal element, was of low specificity. These biochemical results suggest that TRs are unlikely to regulate transcription as homodimers in vivo, and that TR heterodimers mediate the effects of thyroid hormone.

Dexamethasone Stimulation of Retinoic Acid-Induced Sodium Iodide Symporter Expression and Cytotoxicity of 131-I in Breast Cancer Cells

“…RXRs have been described as a common accessory nuclear protein required for highaffinity DNA binding of a group of receptors for nonsteroid ligands such as RARs, thyroid receptor, peroxisomal proliferator-activated receptor-␥, and vitamin D receptor and further to homodimerize to itself. The heterodimerization of RXR with RAR stabilizes the binding of the receptors to their cognate response elements (54,55) and leads to a promoted ligand-dependent transcriptional regulation (56,57). In a recent study, Tanosaki et al (58) hypothesized that NIS activity could be augmented by activation of both RAR/RXR and RXR/RXR pathways.…”

DNA recognition by thyroid hormone and retinoic acid receptors: 3,4,5 rule modified

“…Most nuclear receptors contact their DNA binding sites as protein dimers; therefore two half-sites are required to create a functional hormone response element (e.g. [Brent et al, 1992, Forman et al, 1992, Hirst et al, 1992, Kurokawa et al, 1993, Lazar et al, 1991, Näär et al, 1991, Perlmann et al, 1993, Umesono et al, 1991, Wahlstrom et al, 1992]). The second α-helical domain in the zinc-finger region stabilizes the overall structure and can also contribute to receptor dimerization.…”

Determinants of DNA Sequence Specificity of the Androgen, Progesterone, and Glucocorticoid Receptors: Evidence for Differential Steroid Receptor Response Elements

“…The receptor superfamily can be divided into two subfamilies based on selection of the primary sequence of the core motif: AGAACA for AR, GR, and PR subfamily; and AGGTCA, for estrogen receptor (ER) and thyroid hormone receptor (T3R) subfamily (1,(5)(6)(7)(8). Further receptor specificity of DNA-binding targets within the ER/T3R subfamily receptor occurs largely by discrimination of flanking sequence, orientation, and spacing of half-sites via other amino acid regions within the DBD (13)(14)(15)(16)(17)(18)(19)(20). Further receptor specificity of DNA-binding targets within the ER/T3R subfamily receptor occurs largely by discrimination of flanking sequence, orientation, and spacing of half-sites via other amino acid regions within the DBD (13)(14)(15)(16)(17)(18)(19)(20).…”