scholarly journals Characterization of the hormone-binding domain of the chicken c-erbA/thyroid hormone receptor protein.

1988 ◽  
Vol 7 (1) ◽  
pp. 155-159 ◽  
Author(s):  
A. Muñoz ◽  
M. Zenke ◽  
U. Gehring ◽  
J. Sap ◽  
H. Beug ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Binding Domain ◽  
Receptor Protein ◽  
Hormone Binding ◽  
Hormone Binding Domain

scholarly journals Thyroid hormone receptor transcriptional activity is potentially autoregulated by truncated forms of the receptor.

1992 ◽  
Vol 12 (5) ◽  
pp. 2406-2417 ◽  
Author(s):  
J Bigler ◽  
W Hokanson ◽  
R N Eisenman
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Dna Binding ◽  
Hormone Receptor ◽  
Transcriptional Activity ◽  
Thyroid Hormone Receptor ◽  
Binding Domain ◽  
Full Length ◽  
Hormone Binding ◽  
Hormone Binding Domain

ErbA/thyroid hormone receptor is a nuclear receptor that can affect transcription from promoters containing a thyroid hormone response element (TRE) in a thyroid hormone (T3)-dependent manner. We reported earlier that the thyroid hormone receptor is expressed in embryonic avian erythroid cells as a nested set of four proteins with a common C terminus. The full-length receptor is capable of both high-affinity binding to thyroid hormone and specific binding to DNA. We now report that the two smallest ErbA forms, which contain the hormone-binding domain but lack the N-terminal DNA-binding domain, have the same affinity for T3 as does full-length ErbA but are incapable of specific DNA binding. In transactivation assays, these N-terminally truncated proteins are able to specifically suppress both transcriptional repression and hormone-dependent transcriptional activation by the full-length ErbA. We also find that retinoic acid-dependent transactivation by retinoic acid receptors is inhibited by the truncated ErbA proteins. Furthermore, the smaller ErbA forms inhibit binding to TREs by full-length ErbA in vitro. Results from experiments involving site-specific mutagenesis of a conserved region within the hormone-binding domain of the smaller ErbA proteins indicate that the suppressive effect of the smaller receptor forms is independent of hormone binding and that this region is important in mediating protein-hormone as well as protein-protein interactions. We have also found that full-length ErbA homodimers can be detected only in the presence of a specific DNA-binding site. However, no association between full-length and the N-terminally truncated non-DNA-binding ErbA proteins could be detected, indicating that the complex either is unstable or does not form. Our results suggest that inhibition of receptor function occurs through transient formation of heterodimers which lack DNA-binding activity or by competition for factors which positively affect DNA binding by the full-length protein. This finding raises the possibility that thyroid hormone receptor transcriptional activity is autoregulated by means of alternative receptor translation products acting in a dominant negative manner.

Thyroid hormone receptor transcriptional activity is potentially autoregulated by truncated forms of the receptor

1992 ◽  
Vol 12 (5) ◽  
pp. 2406-2417
Author(s):  
J Bigler ◽  
W Hokanson ◽  
R N Eisenman
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Dna Binding ◽  
Hormone Receptor ◽  
Transcriptional Activity ◽  
Thyroid Hormone Receptor ◽  
Binding Domain ◽  
Full Length ◽  
Hormone Binding ◽  
Hormone Binding Domain

ErbA/thyroid hormone receptor is a nuclear receptor that can affect transcription from promoters containing a thyroid hormone response element (TRE) in a thyroid hormone (T3)-dependent manner. We reported earlier that the thyroid hormone receptor is expressed in embryonic avian erythroid cells as a nested set of four proteins with a common C terminus. The full-length receptor is capable of both high-affinity binding to thyroid hormone and specific binding to DNA. We now report that the two smallest ErbA forms, which contain the hormone-binding domain but lack the N-terminal DNA-binding domain, have the same affinity for T3 as does full-length ErbA but are incapable of specific DNA binding. In transactivation assays, these N-terminally truncated proteins are able to specifically suppress both transcriptional repression and hormone-dependent transcriptional activation by the full-length ErbA. We also find that retinoic acid-dependent transactivation by retinoic acid receptors is inhibited by the truncated ErbA proteins. Furthermore, the smaller ErbA forms inhibit binding to TREs by full-length ErbA in vitro. Results from experiments involving site-specific mutagenesis of a conserved region within the hormone-binding domain of the smaller ErbA proteins indicate that the suppressive effect of the smaller receptor forms is independent of hormone binding and that this region is important in mediating protein-hormone as well as protein-protein interactions. We have also found that full-length ErbA homodimers can be detected only in the presence of a specific DNA-binding site. However, no association between full-length and the N-terminally truncated non-DNA-binding ErbA proteins could be detected, indicating that the complex either is unstable or does not form. Our results suggest that inhibition of receptor function occurs through transient formation of heterodimers which lack DNA-binding activity or by competition for factors which positively affect DNA binding by the full-length protein. This finding raises the possibility that thyroid hormone receptor transcriptional activity is autoregulated by means of alternative receptor translation products acting in a dominant negative manner.

scholarly journals Nuclear factors specifically favor thyroid hormone binding to c-ErbAα1 protein (thyroid hormone receptor α) over-expressed in E. coli

FEBS Letters ◽  
1995 ◽  
Vol 358 (2) ◽  
pp. 137-141 ◽  
Author(s):  
Malika Daadi ◽  
Christelle Lenoir ◽  
Alexandra Dace ◽  
Jeannine Bonne ◽  
Michèle Teboul ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hormone Binding ◽  
E Coli ◽  
Nuclear Factors ◽  
Thyroid Hormone Receptor Α

scholarly journals Mutations in the conserved C-terminal sequence in thyroid hormone receptor dissociate hormone-dependent activation from interference with AP-1 activity.

1997 ◽  
Vol 17 (8) ◽  
pp. 4687-4695 ◽  
Author(s):  
F Saatcioglu ◽  
G Lopez ◽  
B L West ◽  
E Zandi ◽  
W Feng ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Mutational Analysis ◽  
Binding Domain ◽  
Yeast Cells ◽  
Terminal Sequence

A short C-terminal sequence that is deleted in the v-ErbA oncoprotein and conserved in members of the nuclear receptor superfamily is required for normal biological function of its normal cellular counterpart, the thyroid hormone receptor alpha (T3R alpha). We carried out an extensive mutational analysis of this region based on the crystal structure of the hormone-bound ligand binding domain of T3R alpha. Mutagenesis of Leu398 or Glu401, which are surface exposed according to the crystal structure, completely blocks or significantly impairs T3-dependent transcriptional activation but does not affect or only partially diminishes interference with AP-1 activity. These are the first mutations that clearly dissociate these activities for T3R alpha. Substitution of Leu400, which is also surface exposed, does not affect interference with AP-1 activity and only partially diminishes T3-dependent transactivation. None of the mutations affect ligand-independent transactivation, consistent with previous findings that this activity is mediated by the N-terminal domain of T3R alpha. The loss of ligand-dependent transactivation for some mutants can largely be reversed in the presence of GRIP1, which acts as a strong ligand-dependent coactivator for wild-type T3R alpha. There is excellent correlation between T3-dependent in vitro association of GRIP1 with T3R alpha mutants and their ability to support T3-dependent transcriptional activation. Therefore, GRIP1, previously found to interact with the glucocorticoid, estrogen, and androgen receptors, may also have a role in T3R alpha-mediated ligand-dependent transcriptional activation. When fused to a heterologous DNA binding domain, that of the yeast transactivator GAL4, the conserved C terminus of T3R alpha functions as a strong ligand-independent activator in both mammalian and yeast cells. However, point mutations within this region have drastically different effects on these activities compared to their effect on the full-length T3R alpha. We conclude that the C-terminal conserved region contains a recognition surface for GRIP1 or a similar coactivator that facilitates its interaction with the basal transcriptional apparatus. While important for ligand-dependent transactivation, this interaction surface is not directly involved in transrepression of AP-1 activity.

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