STEROID-RECEPTOR TRANSCRIPTIONAL SYNERGY IS POTENTIATED BY DISRUPTIONOF THE DNA-BINDING DOMAIN DIMER INTERFACE

The dimer interface within the DNA-binding domain (DBD) of the steroid receptors stabilizes receptor binding to a palindromic DNA site terme d a hormone response element (HRE) and is essential for receptor trans criptional activity when a single HRE drives transcription of a target gene. However, most steroid-responsive genes are driven by multiple H REs, and synergy between HREs is an important determinant of receptor activity. We have examined the effects of mutations within the DBD dim er interface on synergistic transcriptional activation by the mineralo corticoid and glucocorticoid receptors. As expected, mutations in eith er the mineralocorticoid receptor or glucocorticoid receptor that dest abilized the DBD dimer interface disrupted receptor binding and activi ty at a single HRE. However, in striking contrast, these same mutation s markedly increased receptor synergistic activity on a reporter gene containing multiple HREs and modestly increased DNA binding. Reestabli shing intersubunit contacts by compensatory mutation or by coexpressio n of complementary mutants returned activity to near-wild type levels. These observations strongly suggest that the DBD dimer interface rest rains steroid receptor transcriptional synergy and may play an unexpec ted role in the regulation of receptor activity.