Angelman syndrome-associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome
Angelman syndrome-associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome
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DOI：
10.1074/jbc.ra118.004653
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发表时间：
2018-11-23
影响因子：
4.8
通讯作者：
Howley, Peter M.
中科院分区：
文献类型：
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作者：
Kuhnle, Simone;Martinez-Noel, Gustavo;Howley, Peter M.
HECT泛素连接酶UBE 3A/E6 AP的失调与Angelman综合征以及自闭症谱系障碍有关。我们和其他人以前已经确定了26 S蛋白酶体作为一个主要的UBE 3A相互作用的蛋白质复合物。在这里，我们描述了UBE 3A和蛋白酶体亚基PSMD 4（Rpn 10/S5 a）的相互作用。我们将相互作用映射到UBE 3A的高度保守的Zn 2+结合N-末端（阿苏尔）结构域，其完整性对于结合PSMD 4至关重要。有趣的是，影响阿苏尔结构域的两个Angelman综合征点突变显示出结合PSMD 4的能力受损。虽然不影响泛素连接酶或雌激素受体介导的转录调节活性，但这些阿苏尔结构域突变阻止UBE 3A刺激Wnt/β-连环蛋白信号通路。两者合计，我们的数据表明，受损的结合26 S蛋白酶体和随之而来的失调Wnt/-连环蛋白信号可能有助于这些突变体在Angelman综合征的功能缺陷。
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 -mediated transcriptional regulation activities, these AZUL domain mutations prevent UBE3A from stimulating the Wnt/-catenin signaling pathway. Taken together, our data indicate that impaired binding to the 26S proteasome and consequential deregulation of Wnt/-catenin signaling might contribute to the functional defect of these mutants in Angelman syndrome.