Estrogen receptor transcription and transactivation: Structure-function relationship in DNA- and ligand-binding domains of estrogen receptors

The physiological effects of estrogens have long been considered mediated by a single nuclear receptor (estrogen receptor α [1,2]) through which the signal is transduced to the transcriptional machinery and chromatin template of target responsive genes. The cloning of a second estrogen receptor (ER) isoform (ERβ) ([3,4,5] and references cited therein) stimulated interest in the search for differences in tissue distribution and functioning. The ERs (ERα and ERβ) belong to the nuclear receptor (NR) superfamily representing a large group of transcriptional regulators that encompass receptors for steroid and thyroid hormones, retinoids, vitamin D, peroxisome proliferator-activated receptors and orphan receptors for which no ligand has until now been characterized.The structural organization of NRs consists of six functional regions (A-F) showing various degrees of sequence conservation (Fig. 1a). The N-terminal A/B domain, not well conserved among NRs, contains the autonomous transactivation function AF-1. The size of the domain is extremely variable, and large A/B domains, extending beyond 550 residues in the case of the human androgen receptor, characterize steroid receptors. This domain is also poorly conserved between the two ER isoforms (with little or no detectable similarity, 17% identity). No clear secondary structure can be identified in these regions and no structural data have until now been obtained. We will thus focus on the better characterized parts, for which functional and structural data are available, such as the highly conserved C region harboring the DNA-binding domain (DBD) and the conserved E region containing the ligand-binding domain (LBD). The two remaining regions, D and F, are again of variable size and are not conserved: D can be considered as a linker peptide between the DBD and the LBD, whereas F is a C-terminal extension region of the LBD.Both ERα and ERβ share a modest overall sequence identity (47%) [3]. The conservation, however, is mu