Angelman Syndrome-associated Point Mutations in the Zn-binding N-terminal (AZUL) Domain of UBE3A Ubiquitin Ligase Inhibit Binding to the Proteasome

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2018 Sep 28

PMID 30257870

Citations 21

Authors

Simone Kuhnle

Gustavo Martinez-Noel

Flavien Leclere

Sebastian D Hayes

J Wade Harper

Peter M Howley

Affiliations

Soon will be listed here.

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 Zn-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.

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