The N-terminal domain of thyroid hormone receptor-alpha is required for its biological activities

Thyroid hormone (T3) receptors (T3Rs) are ligand-modulated transcription fa ctors that belong to the nuclear receptor superfamily, Whereas the well-con served DNA-binding domain and the relatively well-conserved ligand-binding domain in T3Rs have been characterized in detail, limited information is av ailable on the contribution of the variable N terminus to the transcription al properties of T3Rs, To gain greater insight into the function of the N t erminus, we generated a deletion mutant of T3R alpha, T3R alpha-Delta N1, t hat lacks amino acids 7-45 and assessed the effect of this deletion on all known transcriptional activities of T3R alpha, Despite the fact that T3R al pha-Delta N1 was expressed and bound T3 with an affinity similar to that of wildtype T3R alpha, all of its common transcriptional activities were lost . That is, T3R alpha-Delta N1 did not activate transcription from a positiv e or negative T3 response element, and it could not interfere with AP-1 tra nscriptional activity, Surprisingly, T3R alpha-Delta N1 lost its ability to bind DNA, which can account for its deficiencies as a transcriptional acti vator. In contrast, the ability of T3R alpha-Delta N1 to interact with puta tive coactivators or corepressors was not significantly altered from that o f wildtype T3R alpha. However, overall folding of T3R alpha-Delta N1 was al tered, as indicated by differential sensitivity to limited protease digesti on. These data document that the N terminus of T3R alpha, albeit relatively short and representing a variable and unconserved region when compared wit h other nuclear receptors, has a critical role in proper folding of the DNA -binding domain and is required for the biological activities of full-lengt h T3R alpha.