The Dynamic Structure of the Estrogen Receptor

The estrogen receptor (ER) mediates most of the biological effects of estrogens at the level of gene regulation by interacting through its site-specific DNA and with other coregulatory proteins. In recent years, new information regarding the dynamic structural nature of ER has emerged. The physiological effects of estrogen are manifested through ER's two isoforms, ERα and ERβ. These two isoforms (ERα and ERβ) display distinct regions of sequence homology. The three-dimensional structures of the DNA-binding domain (DBD) and ligand-binding domain (LBD) have been solved, whereas no three-dimensional natively folded structure for the ER N-terminal domain (NTD) is available to date. However, insights about the structural and functional correlations regarding the ER NTD have recently emerged. In this paper, we discuss the knowledge about the structural characteristics of the ER in general and how the structural features of the two isoforms differ, and its subsequent role in gene regulation. 1. Introduction The estrogen receptor (ER) is a ligand-inducible intracellular transcription factor that mediates most of the biological effects of estrogens at the level of gene regulation [1–3]. Estrogen biology is exceedingly complex and important in the development and function of numerous tissues and physiological phenomena [4–6]. In the nucleus, the ER up- or downregulates the expression of target genes by interacting through its site-specific DNA and with other coregulatory proteins that include coactivators and corepressors [1–3]. The ligand-bound ER binds as homodimer to specific DNA sequences termed estrogen response elements (EREs) and regulates transcription through interaction with transcription modulators and recruitment of the general transcription machinery [7]. In recent years, new information regarding the ER structures, intra- and intermolecular interactions, posttranslational modifications, and several other factors pertaining to the ER actions has emerged [8–10]. Like other members of the nuclear hormone receptor (NHR) family, the ER is composed of several functional domains that serve specific roles [11]. Starting from NH2- to COO-terminus, the principal domains are (1) the N-terminal domain (NTD); (2) DNA-binding domain (DBD); (3) ligand-binding domain (LBD). Two activation function (AF) domains, AF1 and AF2, located within the NTD and LBD, respectively, are responsible for regulating the transcriptional activity of ER [12] (Figure 1(a)). Figure 1: (a) shows the sequence organization of the two isoforms of estrogen receptors, ER α and ER β. Different