Estrogen-Related Receptor α1 Functionally Binds as a Monomer to Extended Half-Site Sequences Including Ones Contained within Estrogen-Response Elements

The human estrogen-related receptor a1 (hERRa1) is an orphan member of the steroid/thyroid hormone receptor superfamily. A cDNA encoding this protein was originally isolated on the basis of sequence similarity in its DNA-binding domain with estrogen receptor a (ERa). Previously, we reported the purification of hERRa1 from HeLa cell nuclear extracts on the basis of its ability to bind two sites in the late promoter of simian virus 40 (SV40). We have now determined the primary structure and the DNA and protein binding specificities of hERRa1 and developed in vivo and in vitro assays for its functional activities. hERRa1 was found to bind as a monomer, with a high-affinity binding site containing the extended half-site sequence 5*-TCAAGGTCA-3*. Binding sites for hERRa1 were identified in many cellular promoters, including some that were previously shown to function as estrogenresponse elements (EREs). hERRa1 was shown to function as a sequence-specific repressor of the SV40 late promoter in both cell culture and cell-free transcription sytems. It was also shown to interact with both ERa and the transcription factor TFIIB by direct protein-protein contacts. Thus, hERRa1 may play a role in the response of some genes to estrogen via heterodimerization with ERs or competition with ERs for binding to EREs. (Molecular Endocrinology 11: 342‐352, 1997)