The estrogen receptor (ER) belongs to a nuclear receptor superfamily of ligand-regulatable transcription factors. The ER is a modular protein consisting of an amino-terminal region (A/В domain) that influences transcriptional activity, a centrally located DNA binding region (C domain), and the carboxyl-terminal region (domain E), which enables the receptor to bind to its ligand, estradiol.
The hinge region (domain D) is located between the DNA and hormone binding domains, while the F domain is located at the extreme carboxyl terminus of the molecule. It is well established that estradiol binding to the ER, which is accompanied by a conformational change in the hormone binding domain, results in the activation of this receptor and increased transcription of ER target genes. Two distinct regions within the ER contribute to its transcriptional activity: the constitutively active, amino-terminal activation function (AF-1) and the ligand-regulatable AF-2 domain, which is located in the carboxyl-terminal portion of the molecule (Fig. 1). Depending on the cell type and promoter examined, AF-1 and AF-2 may regulate transcription independently or synergistically. Although the F domain is not required for hormone binding, it does modulate transcriptional activity.