Functional differences between the amino-terminal domains of estrogen receptors α and β

Human estrogen receptors alpha (ER alpha) and beta (ER beta) are ligand-inducible transcription factors that are highly homologous in their central DNA-binding and carboxyl-terminal ligand-binding domains. In contrast, there is very little conservation between ER alpha and ER beta in the amino-terminal domain. Using different human cell lines, we show that wild-type ER beta transcriptional activity is lower or similar to that of ER alpha, depending on the cell type. Deletion of the amino-terminal domain in both ER subtypes resulted in no or a lower decrease of transcriptional activity of ER beta compared with ER alpha, suggesting that the ER beta amino-terminal domain contains a weaker transcriptional activation function-1. Using ER alpha and ER beta deletion mutants, we showed that the amino-terminal transcriptional activity of ER beta maps to amino acids 1-31. Interestingly, this domain contains a six amino-acid motif (amino acids 5-10 in human ER beta) that is part of the ER alpha-activation function-1 region (amino acids 49-54 in human ER alpha) and highly conserved among all mammalian ER alpha amino-terminal domains. Despite this similarity between the two ER subtypes, no autonomous and ligand-independent activity of the ER beta-amino-terminal domain was observed in yeast and mammalian cells in contrast to ER alpha. This study provides a molecular basis for the difference in transcriptional activity between ER alpha and ER beta and establishes that ER beta contains a structurally and functionally restricted amino-terminal transcriptional activity.