The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily

In this study, we found that the E6-associated protein (E6-AP/UBE3A) direct ly interacts with and coactivates the transcriptional activity of the human progesterone receptor (PR) in a hormone-dependent manner, E6-AP also coact ivates the hormone-dependent transcriptional activities of the other member s of the nuclear hormone receptor superfamily. Previously, it was shown tha t E6-AP sen es the role of a ubiquitin-protein ligase (E3) in the presence of the E6 protein from human papillomavirus types 16 and 18. Our data show that the ubiquitin-protein ligase function of E6-AP is dispensable for its ability to coactivate nuclear hormone receptors, showing that E6-AP possess es two separable independent functions, as both a coactivator and a ubiquit in-protein Ligase. Disruption of the maternal copy of E6-AP is correlated w ith Angelman syndrome (AS), a genetic neurological disorder characterized b y severe mental retardation, seizures, speech impairment, and other symptom s. However, the exact mechanism by which the defective E6-AP gene causes AS remains unknown. To correlate the E6-AP coactivator function and ubiquitin -protein ligase functions with the AS phenotype,,ve expressed mutant forms of E6-AP isolated from AS patients and assessed the ability of each of thes e mutant proteins to coactivate PR or provide ubiquitin-protein ligase acti vity. This analysis revealed that in the majority of the AS patients examin ed, the ubiquitin-protein ligase function of E6-AP was defective whereas th e coactivator function was intact, This finding suggests that the AS phenot ype results from a defect in the ubiquitin-proteosome protein degradation p athway.