Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interaction
Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interaction
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DOI：
10.1038/nature06924
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发表时间：
2008-05-22
期刊：
影响因子：
64.8
通讯作者：
Groll, Michael
中科院分区：
文献类型：
--
作者：
Schreiner, Patrick;Chen, Xiang;Groll, Michael
蛋白质的靶向性降解在很大程度上是通过泛素-蛋白酶体途径进行的，在该途径中，底物蛋白质由共价连接的泛素链标记，这些泛素链介导蛋白酶体的识别。目前尚不清楚蛋白酶体如何识别其底物，因为蛋白酶体固有的唯一已建立的泛素受体是Rpn10/S5a(参考文献。1)，这对泛素介导的芽殖酵母蛋白质降解不是必需的(2)。在随附的手稿中，我们报道了Rpn13(参考文献3-7)，作为九亚基蛋白酶体碱基的一个组成部分，作为泛素受体(8)的功能，补充了其在脱泛素化酶Uch37/UCHL5(参考文献4-6)与蛋白酶体对接的已知作用。在这里，我们结合结晶学和核磁共振数据来描述Rpn13的泛素结合机制。我们确定了Rpn13单独和与泛素络合的结构。共络合物揭示了一种新的泛素结合模式，在这种模式下，使用环而不是二级结构元素来捕获泛素。Rpn13能够同时结合泛素和蛋白酶体亚基Rpn2/S1，进一步支持Rpn13作为蛋白酶体泛素受体的作用。最后，我们提供了Rpn13与泛素络合的模型结构，这为了解Rpn13作为泛素受体是如何通过Uch37偶联底物去泛素化提供了见解。
Targeted protein degradation is largely performed by the ubiquitin-proteasome pathway, in which substrate proteins are marked by covalently attached ubiquitin chains that mediate recognition by the proteasome. It is currently unclear how the proteasome recognizes its substrates, as the only established ubiquitin receptor intrinsic to the proteasome is Rpn10/S5a (ref. 1), which is not essential for ubiquitin- mediated protein degradation in budding yeast(2). In the accompanying manuscript we report that Rpn13 (refs 3-7), a component of the nine-subunit proteasome base, functions as a ubiquitin receptor(8), complementing its known role in docking de-ubiquitinating enzyme Uch37/UCHL5 (refs 4-6) to the proteasome. Here we merge crystallography and NMRdata to describe the ubiquitin-binding mechanism of Rpn13. We determine the structure of Rpn13 alone and complexed with ubiquitin. The co-complex reveals a novel ubiquitin-binding mode in which loops rather than secondary structural elements are used to capture ubiquitin. Further support for the role of Rpn13 as a proteasomal ubiquitin receptor is demonstrated by its ability to bind ubiquitin and proteasome subunit Rpn2/S1 simultaneously. Finally, we provide a model structure of Rpn13 complexed to diubiquitin, which provides insights into how Rpn13 as a ubiquitin receptor is coupled to substrate deubiquitination by Uch37.