IDENTIFICATION AND CHARACTERIZATION OF THE AF-1 TRANSACTIVATION DOMAIN OF THYROID-HORMONE RECEPTOR BETA-1

Physiological responses to thyroid hormones are regulated by a set of nuclear receptors (TRs) related to the steroid receptor superfamily of ligand-dependent transcription factors. Although TR isoforms are high ly conserved in their DNA binding, ligand binding, and carboxyl-termin al transactivation domains, their aminoterminal regions are completely divergent. We examined the contribution of these amino-terminal seque nces to TR beta 1 function. An amino-terminally truncated version of r at TR beta 1 lacking amino acids 4-89 was impaired in hormone-dependen t activation in both yeast and mammalian cells. This defect was not du e to impairment of DNA binding, because the truncated receptor display ed enhanced homodimer binding on several different TREs, indicating th at residues in the amino-terminal domain of TR beta 1 interfere with h omodimerization of the receptor. The presence of an autonomous transac tivation domain in the amino-terminal region was demonstrated by its a bility to activate transcription in a constitutive manner when fused t o the GAL4 DNA binding domain, Deletional analyses localized the resid ues comprising the amino-terminal transactivation region of TR beta 1 to 19 amino acids residing between residues 69 and 89. Thus, the amino -terminal region of TR beta 1 contains an activation domain (AF-1) tha t call modulate the function of the receptor and may allow for the fin e-tuning of receptor activity in various target tissues.