Ubiquitin Binding by a CUE Domain Regulates Ubiquitin Chain Formation by ERAD E3 Ligases
Ubiquitin Binding by a CUE Domain Regulates Ubiquitin Chain Formation by ERAD E3 Ligases
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DOI：
10.1016/j.molcel.2013.04.005
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发表时间：
2013-05-23
期刊：
影响因子：
16
通讯作者：
Sommer, Thomas
中科院分区：
文献类型：
--
作者：
Bagola, Katrin;von Delbrueck, Maximilian;Sommer, Thomas
泛素结合域(UBD)识别泛素(UB)修饰。其中一些与Mono-UB特异性结合，如CUE结构域所示。有趣的是，到目前为止还没有观察到酵母Cue1p的线索结构域有明显的泛素结合。Cue1p是泛素结合酶Ubc7p的受体和激活剂。它将Ubc7p整合到内质网(ER)膜结合的泛素连接酶复合体中，从而对ER相关蛋白降解(ERAD)起关键作用。在这里，我们发现Cue1p的提示结构域与泛素链结合，这对于体外有效地形成K48连接的多泛素链是至关重要的。通过Cue1p取消泛素结合的突变会影响体内ERAD底物的周转。我们的数据强烈暗示，提示结构域通过稳定ERAD泛素连接酶上不断增长的泛素链来促进底物泛素化。因此，我们展示了UBD在调节泛素链合成中意想不到的功能。
Ubiquitin-binding domains (UBDs) differentially recognize ubiquitin (ub) modifications. Some of them specifically bind mono-ub, as has been shown for the CUE domain. Interestingly, so far no significant ubiquitin binding has been observed for the CUE domain of yeast Cue1p. Cue1p is receptor and activator of the ubiquitin-conjugating enzyme Ubc7p. It integrates Ubc7p into endoplasmic reticulum (ER) membrane-bound ubiquitin ligase complexes, and thus, it is crucial for ER-associated protein degradation (ERAD). Here we show that the CUE domain of Cue1p binds ubiquitin chains, which is pivotal for the efficient formation of K48-linked polyubiquitin chains in vitro. Mutations that abolish ubiquitin binding by Cue1p affect the turnover of ERAD substrates in vivo. Our data strongly imply that the CUE domain facilitates substrate ubiquitylation by stabilizing growing ubiquitin chains at the ERAD ubiquitin ligases. Hence, we demonstrate an unexpected function of a UBD in the regulation of ubiquitin chain synthesis.