Ligand-binding and heterodimerization activities of a conserved region in the ligand-binding domain of the thyroid hormone receptor.

The ligand-binding domain of the thyroid hormone (3,5,3'-triiodothyronine) receptor (TR) contains poorly characterized subdomains involved with ligand binding, transactivation, and protein-protein interactions. The region between residues 288-331 of rat TR alpha-1 was analyzed by modeling and site-directed mutagenesis. Our results suggest that part of this sequence adopts an amphipathic alpha-helical conformation. The integrity of the putative helix is important for 3,5,3'-triiodothyronine binding but not necessarily for heterodimerization with nuclear factor(s). Mutants defective for both activities were found clustered in a region overlapping the C-terminal portion of the helix and further downstream. The sequence conservation of this particular region among the entire superfamily suggests a similar role in dimerization in other receptors.