Abstract
Some orphan nuclear receptors, including estrogen-related receptor alpha-1 (ERRalpha-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 (ERalpha)) is responsible for the constitutive activity of ERRalpha-1. The ERRalpha-1 mutant F329A lost the transactivation activity and acted as a dominant negative mutant. The mammalian cell transfection experiments revealed that the ERRalpha-1 mutant F329A, like wild-type ERalpha, recognized toxaphene (an organochlorine pesticide) as an agonist. This compound was previously shown to be an antagonist of wild-type ERRalpha-1. On the other hand, like wild-type ERRalpha-1, the ERalpha 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 ERRalpha-1 and Ala-350 in ERalpha play important roles in both ligand binding and transactivation function.
Highlights
Based on ligand binding properties, nuclear receptors can be classified into three types
Utilizing yeast-based assays and mammalian transient transfection assays, we have recently found that two organochlorine pesticides, toxaphene and chlordane, can act as antagonists of estrogenrelated receptor ␣-1 (ERR␣-1) that suppress the constitutive activity of ERR␣-1 [3]
We reviewed the amino acid sequence alignment between ERR␣-1 and estrogen receptor (ER)␣ [1] and compared the corresponding residues in ERR␣-1 with those in the ER␣ ligand-binding site that are in direct contact with E2, as shown by Tanenbaum et al [11] (Fig. 1)
Summary
Based on ligand binding properties, nuclear receptors can be classified into three types. Our results from site-directed mutagenesis experiments have revealed that Phe-329 (analogous to Ala-350 in estrogen receptor ␣ (ER␣)) is responsible for the constitutive activity of ERR␣-1. The mammalian cell transfection experiments revealed that the ERR␣-1 mutant F329A, like wild-type ER␣, recognized toxaphene (an organochlorine pesticide) as an agonist.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
