Molecular basis for the constitutive activity of estrogen-related receptor α-1

Some orphan nuclear receptors, including estrogen-related receptor alpha -1 (ERR alpha -1), can activate gene transcription in a constitutive manner. Little is known about the molecular basis of the constitutive activity of these receptors. Our results from site-directed mutagenesis experiments have revealed that Phe-329 (analogous to Ala-350 in estrogen receptor alpha (ER alpha)) is responsible for the constitutive activity of ERR alpha -1. The ERR alpha -1 mutant F329A lost the transactivation activity and acted as a dominant negative mutant. The mammalian cell transfection experiments revealed that the ERR alpha -1 mutant F329A, like wild-type ER alpha, recognized toxaphene (an organochlorine pesticide) as an agonist. This compound was previously shown to be an antagonist of wild-type ERR alpha -1. On the other hand, like wild-type ERR alpha -1, the ER alpha mutant A350F was found to be constitutively active (as demonstrated by mammalian cell transfection and yeast two-hybrid assays). These results indicate that Phe-329 in ERR alpha -1 and Ala-350 in ER alpha play important roles in both ligand binding and transactivation function.