title: Angelman syndrome-associated ubiquitin ligase UBE3A/E6AP mutants interfere with the proteolytic activity of the proteasome.
abstract: Angelman syndrome, a severe neurodevelopmental disease, occurs primarily due to genetic defects, which cause lack of expression or mutations in the wild-type E6AP/UBE3A protein. A proportion of the Angelman syndrome patients bear UBE3A point mutations, which do not interfere with the expression of the full-length protein, however, these individuals still develop physiological conditions of the disease. Interestingly, most of these mutations are catalytically defective, thereby indicating the importance of UBE3A enzymatic activity role in the Angelman syndrome pathology. In this study, we show that Angelman syndrome-associated mutants interact strongly with the proteasome via the S5a proteasomal subunit, resulting in an overall inhibitory effect on the proteolytic activity of the proteasome. Our results suggest that mutated catalytically inactive forms of UBE3A may cause defects in overall proteasome function, which could have an important role in the Angelman syndrome pathology.
authors: Tumor Virology Research Group, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, Italy.
authors: V
authors: V
authors: Tomaić
authors: Tumor Virology Research Group, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, Italy.
authors: L
authors: L
authors: Banks
mesh_terms: D017204:Angelman Syndrome / Q000201:enzymology*; D055162:Biocatalysis; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D050505:Mutant Proteins; D050725:Papillomavirus E7 Proteins; D021122:Protein Subunits; C059731:oncogene protein E7, Human papillomavirus type 16; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
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