The physiological role of estrogen receptor functional domains

Abstract

Estrogen receptor (ER) is a member of the nuclear receptor superfamily whose members share conserved domain structures, including a DNA-binding domain (DBD) and ligand-binding domain (LBD). Estrogenic chemicals work as ligands for activation or repression of ER-mediated transcriptional activity derived from two transactivation domains: AF-1 and AF-2. AF-2 is localized in the LBD, and helix 12 of the LBD is essential for controlling AF-2 functionality. The positioning of helix 12 defines the ER alpha (ERα) ligand properties as agonists or antagonists. In contrast, it is still less well defined as to the ligand-dependent regulation of N-terminal AF-1 activity. It has been thought that the action of selective estrogen receptor modulators (SERMs) is mediated by the regulation of a tissue specific AF-1 activity rather than AF-2 activity. However, it is still unclear how SERMs regulate AF-1 activity in a tissue-selective manner. This review presents some recent observations toward information of ERα mediated SERM actions related to the ERα domain functionality, focusing on the following topics. (1) The F-domain, which is connected to helix 12, controls 4-hydroxytamoxifen (4OHT) mediated AF-1 activation associated with the receptor dimerization activity. (2) The zinc-finger property of the DBD for genomic sequence recognition. (3) The novel estrogen responsive genomic DNA element, which contains multiple long-spaced direct-repeats without a palindromic ERE sequence, is differentially recognized by 4OHT and E2 ligand bound ERα transactivation complexes.

Keywords: DNA binding domain; estrogen receptor; estrogen responsive element; ligand binding domain; selective estrogen receptor modulators; transactivation.

FIGURE 1.. ESR1 mutations found in the breast cancer patients.

The mutation residues in breast cancer patients, which were reported by Robinson et al. [] and Toy et al. [], are marked on the E2-bound ERα LBD dimer (right; 1ERE) and 4OHT-bound ERα LBD dimer (left; 3ERT). The residues marked yellow correspond to the position of patient mutations. The residues marked green correspond to the position of AF2ER mutation. The allows in the pink molecule indicate helices 11 and 12. Bottom; the residues found in the breast cancer patients (yellow) and AF2ER mutation (green).

FIGURE 2.

a potential model of 4OHT-mediated long-spaced direct-repeat ERE binding. The X-ray crystal structure of human ERα D538G mutant LBD with 4OHT (4Q50) is shown [16]. This crystal structure showed that two LBD dimers interact throw the helix12 (H12). Interestingly, the F-domain (orange line) of two molecules could be localized close position on this model. It might suggest that this type of interaction occurs when 4OHT binds to ERα and could explain a possible reason for the F-domain contribution to the 4OHT-mediated LBD-dimerization. Also, the multimeric ERα dimers could target several spaced EREs. This model may support differential motif recognition between 4OHT and E2 bound ERα on the multiple direct repeats containing ERE.