Mechanism of client selection by the protein quality-control factor UBE2O.
Mechanism of client selection by the protein quality-control factor UBE2O.
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DOI：
10.1038/s41594-022-00807-6
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发表时间：
2022-08
影响因子：
16.8
通讯作者：
Shao, Sichen
中科院分区：
文献类型：
--
作者：
Yip, Matthew C. J.;Sedor, Samantha F.;Shao, Sichen
E2/E3酶UBE2O泛素化多种客户端，介导重要的过程，包括靶向未组装的“孤儿”蛋白进行质量控制和清除红细胞生成过程中的核糖体。诸如UBE2O之类的质量控制因素是如何基于异构特性选择客户的，这在很大程度上是未知的。在这里，我们发现UBE2O客户端选择受泛素结合和辅助因子NAP1L1的调节。将单个泛素连接到客户端可增强UBE2O结合和多单泛素化。ube20还重新利用组蛋白伴侣NAP1L1作为适配器来招募一部分客户。人类UBE2O与NAP1L1复合物的低温电镜结构揭示了一个可延展性的客户端招募界面，该界面被内在反应性的UBC结构域自动抑制。添加泛素化的客户端识别出客户端选择所需的独特的泛素结合sh3样结构域。我们的研究结果揭示了多价性和前馈机制如何驱动蛋白质质量控制客户的选择。
The E2/E3 enzyme UBE2O ubiquitylates diverse clients to mediate important processes, including targeting unassembled ‘orphan’ proteins for quality control and clearing ribosomes during erythropoiesis. How quality control factors such as UBE2O select clients based on heterogeneous features is largely unknown. Here, we show that UBE2O client selection is regulated by ubiquitin binding and a cofactor, NAP1L1. Attaching a single ubiquitin onto a client enhances UBE2O binding and multi-monoubiquitylation. UBE2O also repurposes the histone chaperone NAP1L1 as an adaptor to recruit a subset of clients. Cryo-EM structures of human UBE2O in complex with NAP1L1 reveal a malleable client recruitment interface which is autoinhibited by the intrinsically reactive UBC domain. Adding a ubiquitylated client identifies a distinct ubiquitin-binding SH3-like domain required for client selection. Our findings reveal how multivalency and a feed-forward mechanism drive the selection of protein quality control clients.
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