Leung, Y.K., Mak, P., Hassan, S., and Ho, S.M. Estrogen receptor (ER)-beta isoforms: A key to understanding ER-beta signaling. Proc. Nat. Acad. Sci., 103, 13162-13167 (August 29, 2006).
The estrogen receptor (ER) beta-1 is a well characterized type I nuclear receptor with diverse physiological roles. This report focuses on the less well-characterized beta-2, -4, and -5 isoforms.
Protein sequence analysis and molecular modeling reveal that these isoforms, whose gene sequences differ only in the last exon, have truncated lengths of helix 11, a crucial element in the ligand binding pocket. Moreover, ER beta-1 forms physiologically important homodimers, while none of the other isoforms homodimerize. As such, they appear to be inactive, leaving only the beta-1 isoform as the seemingly meaningful receptor. Isoforms beta-2, -4, and -5 do, however, form heterodimers with beta-1 in the presence of estradiol in a dose-dependent manner. Heterodimer formation also occurrs to varying degrees in the presence of various estrogens, and a close correlation between in vivo activity and heterodimer formation can be seen. Further study of the heterodimers reveals that they exhibit higher transactivation and greater transcription activity than beta-1 homodimers. Expression of each ER beta isoform differs between human cell lines and tissues, although beta-1 is typically found at low levels. In contrast, beta-2 is highest in the intestinal tract, while beta-5 is the predominant isoform in many tissues. Thus, the ratios of dimer components differ considerably between tissues.
The results provide a new insight into the import of ER beta isoforms not previously recognized. Indeed, the data suggests that the distinction between type I and II nuclear receptors is not as clear cut as previously thought. Since heterodimer formation modulates beta-1 activity, the variable component in the dimer may limit coactivator recruitment to just one, as seen with type II nuclear receptors, while promoting association with different proteins to fine-tune regulation of gene expression in each estrogen-sensitive tissue.
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