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

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