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• W2892484285 endingPage "18399" @default.
• W2892484285 startingPage "18387" @default.
• W2892484285 abstract "Deregulation of the HECT ubiquitin ligase UBE3A/E6AP has been implicated in Angelman syndrome as well as autism spectrum disorders. We and others have previously identified the 26S proteasome as one of the major UBE3A-interacting protein complexes. Here, we characterize the interaction of UBE3A and the proteasomal subunit PSMD4 (Rpn10/S5a). We map the interaction to the highly conserved Zn2+-binding N-terminal (AZUL) domain of UBE3A, the integrity of which is crucial for binding to PSMD4. Interestingly, two Angelman syndrome point mutations that affect the AZUL domain show an impaired ability to bind PSMD4. Although not affecting the ubiquitin ligase or the estrogen receptor α–mediated transcriptional regulation activities, these AZUL domain mutations prevent UBE3A from stimulating the Wnt/β-catenin signaling pathway. Taken together, our data indicate that impaired binding to the 26S proteasome and consequential deregulation of Wnt/β-catenin signaling might contribute to the functional defect of these mutants in Angelman syndrome. Deregulation of the HECT ubiquitin ligase UBE3A/E6AP has been implicated in Angelman syndrome as well as autism spectrum disorders. We and others have previously identified the 26S proteasome as one of the major UBE3A-interacting protein complexes. Here, we characterize the interaction of UBE3A and the proteasomal subunit PSMD4 (Rpn10/S5a). We map the interaction to the highly conserved Zn2+-binding N-terminal (AZUL) domain of UBE3A, the integrity of which is crucial for binding to PSMD4. Interestingly, two Angelman syndrome point mutations that affect the AZUL domain show an impaired ability to bind PSMD4. Although not affecting the ubiquitin ligase or the estrogen receptor α–mediated transcriptional regulation activities, these AZUL domain mutations prevent UBE3A from stimulating the Wnt/β-catenin signaling pathway. Taken together, our data indicate that impaired binding to the 26S proteasome and consequential deregulation of Wnt/β-catenin signaling might contribute to the functional defect of these mutants in Angelman syndrome." @default.
• W2892484285 created "2018-10-05" @default.
• W2892484285 creator A5018786974 @default.
• W2892484285 creator A5019693269 @default.
• W2892484285 creator A5028609556 @default.
• W2892484285 creator A5068043324 @default.
• W2892484285 creator A5075817676 @default.
• W2892484285 creator A5089706444 @default.
• W2892484285 date "2018-11-01" @default.
• W2892484285 modified "2023-10-14" @default.
• W2892484285 title "Angelman syndrome–associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome" @default.
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• W2892484285 doi "https://doi.org/10.1074/jbc.ra118.004653" @default.

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