Open AccessThe physiological role of estrogen receptor functional domains
Author(s) -
Yukitomo Arao,
Kenneth S. Korach
Publication year - 2021
Publication title -
essays in biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.351
H-Index - 66
eISSN - 1744-1358
pISSN - 0071-1365
DOI - 10.1042/ebc20200167
Subject(s) - transactivation , estrogen receptor , nuclear receptor , estrogen receptor alpha , estrogen receptor beta , microbiology and biotechnology , selective estrogen receptor modulator , ligand (biochemistry) , chemistry , dna binding domain , biology , receptor , transcription factor , biochemistry , gene , genetics , cancer , breast cancer
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.