Molecular basis for C-degron recognition by CRL2APPBP2 ubiquitin ligase
Molecular basis for C-degron recognition by CRL2APPBP2 ubiquitin ligase
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DOI：
10.1073/pnas.2308870120
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发表时间：
2023-10
影响因子：
11.1
通讯作者：
Shidong Zhao;Diana Olmayev-Yaakobov;Wenwen Ru;Shanshan Li;Xinyan Chen;Jiahai Zhang;Xuebiao Yao;Itay Koren;Kaiming Zhang;Chao Xu
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文献类型：
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作者：
Shidong Zhao;Diana Olmayev-Yaakobov;Wenwen Ru;Shanshan Li;Xinyan Chen;Jiahai Zhang;Xuebiao Yao;Itay Koren;Kaiming Zhang;Chao Xu
泛素-蛋白酶体系统是调控蛋白质底物降解的主要选择性途径。APPBP2是已知的Cullin 2-RING连接酶（CRL2）的底物识别受体，靶向底物的c端线性R-x-x-G基序进行c -degron介导的降解。通过求解不同R-x-x-G/C-degron结合的CRL2APPBP2 E3连接酶的几个结构，我们发现CRL2APPBP2 E3连接酶复合物组装成一个同二聚体，并解开了APPBP2保守的R-x-x-G/C-degron识别模式。结构生物学，结合实验和基于细胞的分析，不仅表征了appbp2介导的底物识别，而且为靶向CRL2 E3连接酶的蛋白水解靶向嵌合体（PROTACs）的发展提供了结构见解。
Significance The ubiquitin–proteasome system represents the major selective route regulating the degradation of protein substrates. APPBP2, a known substrate recognition receptor of Cullin 2-RING ligase (CRL2), targets a C-terminal linear R-x-x-G motif of substrates for C-degron-mediated degradation. By solving several structures of CRL2APPBP2 E3 ligase bound with different R-x-x-G/C-degrons, we revealed that CRL2APPBP2 E3 ligase complex assembles into a homodimer and unraveled the conserved R-x-x-G/C-degron recognition mode by APPBP2. Structural biology, complemented by binding experiments and cell-based assays, not only characterize the APPBP2-mediated substrate recognition, but also provide structural insight into the development of proteolysis targeting chimeras (PROTACs) targeting CRL2 E3 ligase.