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

Mol Cell Biol. 1999 Feb;19(2):1182-9. doi: 10.1128/MCB.19.2.1182.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angelman Syndrome / genetics
  • Angelman Syndrome / metabolism*
  • Base Sequence
  • Binding Sites / genetics
  • DNA Primers / genetics
  • HeLa Cells
  • Humans
  • In Vitro Techniques
  • Ligands
  • Ligases / genetics
  • Ligases / metabolism*
  • Mutation
  • Phenotype
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcriptional Activation
  • Ubiquitin-Protein Ligases


  • DNA Primers
  • Ligands
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Receptors, Steroid
  • Trans-Activators
  • UBE3A protein, human
  • Ubiquitin-Protein Ligases
  • Ligases