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) directly interacts with and coactivates the transcriptional activity of the human progesterone receptor (PR) in a hormone-dependent manner. E6-AP also coactivates the hormone-dependent transcriptional activities of the other members of the nuclear hormone receptor superfamily. Previously, it was shown that E6-AP serves 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 possesses two separable independent functions, as both a coactivator and a ubiquitin-protein ligase. Disruption of the maternal copy of E6-AP is correlated with Angelman syndrome (AS), a genetic neurological disorder characterized by severe mental retardation, seizures, speech impairment, and other symptoms. 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, we expressed mutant forms of E6-AP isolated from AS patients and assessed the ability of each of these mutant proteins to coactivate PR or provide ubiquitin-protein ligase activity. This analysis revealed that in the majority of the AS patients examined, the ubiquitin-protein ligase function of E6-AP was defective whereas the coactivator function was intact. This finding suggests that the AS phenotype results from a defect in the ubiquitin-proteosome protein degradation pathway.
Nawaz
Z
Z
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Lonard
D M
DM
Smith
C L
CL
Lev-Lehman
E
E
Tsai
S Y
SY
Tsai
M J
MJ
O'Malley
B W
BW
D017204:Angelman Syndrome / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases
D017931:DNA Primers; D008024:Ligands; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D015534:Trans-Activators; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases