The Ubiquitin-associated Domain of Cellular Inhibitor of Apoptosis Proteins Facilitates Ubiquitylation
The Ubiquitin-associated Domain of Cellular Inhibitor of Apoptosis Proteins Facilitates Ubiquitylation
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DOI：
10.1074/jbc.m113.545475
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发表时间：
2014-09-12
影响因子：
4.8
通讯作者：
Day, Catherine L.
中科院分区：
文献类型：
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作者：
Budhidarmo, Rhesa;Day, Catherine L.
细胞凋亡抑制因子（cIAP）蛋白是调节细胞凋亡和炎症反应的必需RING E3泛素连接酶。cIAP含有泛素相关（乌巴）结构域，其结合泛素并参与细胞存活和蛋白酶体降解的调节。我们发现cIAP 1的乌巴结构域中的MGF和LL基序的突变引起cIAP 1的解折叠和增加cIAP 1的多单泛素化。通过开发一种破坏泛素结合但不破坏乌巴结构域结构的乌巴突变体，我们发现乌巴结构域增强cIAP 1和cIAP 2泛素化。我们证明，乌巴结构域结合UbcH5 b类似于Ub共轭，这促进环结构域依赖性monoubiquitylation。这项研究建立了泛素结合模块，如乌巴结构域，作为重要的调节模块，可以微调E3连接酶的活性。
The cellular inhibitor of apoptosis (cIAP) proteins are essential RING E3 ubiquitin ligases that regulate apoptosis and inflammatory responses. cIAPs contain a ubiquitin-associated (UBA) domain that binds ubiquitin and is implicated in the regulation of cell survival and proteasomal degradation. Here we show that mutation of the MGF and LL motifs in the UBA domain of cIAP1 caused unfolding and increased cIAP1 multi-monoubiquitylation. By developing a UBA mutant that disrupted ubiquitin binding but not the structure of the UBA domain, we found that the UBA domain enhances cIAP1 and cIAP2 ubiquitylation. We demonstrate that the UBA domain binds to the UbcH5b similar to Ub conjugate, and this promotes RING domain-dependent monoubiquitylation. This study establishes ubiquitin-binding modules, such as the UBA domain, as important regulatory modules that can fine tune the activity of E3 ligases.