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Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3 ligase.

Cul2FEM1 E3连接酶识别精氨酸C端degron的分子基础。

  • 影响因子:9.33
  • DOI:10.1038/s41589-020-00704-3
  • 作者列表:"Chen X","Liao S","Makaros Y","Guo Q","Zhu Z","Krizelman R","Dahan K","Tu X","Yao X","Koren I","Xu C
  • 发表时间:2021-03-01
Abstract

:Degrons are elements within protein substrates that mediate the interaction with specific degradation machineries to control proteolysis. Recently, a few classes of C-terminal degrons (C-degrons) that are recognized by dedicated cullin-RING ligases (CRLs) have been identified. Specifically, CRL2 using the related substrate adapters FEM1A/B/C was found to recognize C degrons ending with arginine (Arg/C-degron). Here, we uncover the molecular mechanism of Arg/C-degron recognition by solving a subset of structures of FEM1 proteins in complex with Arg/C-degron-bearing substrates. Our structural research, complemented by binding assays and global protein stability (GPS) analyses, demonstrates that FEM1A/C and FEM1B selectively target distinct classes of Arg/C-degrons. Overall, our study not only sheds light on the molecular mechanism underlying Arg/C-degron recognition for precise control of substrate turnover, but also provides valuable information for development of chemical probes for selectively regulating proteostasis.

摘要

: Degrons是蛋白质底物中的元件,其介导与特定降解机制的相互作用以控制蛋白水解。最近,已经鉴定了由专用的cullin-环连接酶 (crl) 识别的几类C-末端degrons (C-degrons)。具体地,发现使用相关基底适配器FEM1A/B/C的CRL2识别以精氨酸 (Arg/C-degron) 结束的C degrons。在这里,我们通过求解与Arg/C-degron-承载底物复合的FEM1蛋白的结构子集来揭示Arg/C-degron识别的分子机制。我们的结构研究,辅以结合测定和全局蛋白稳定性 (GPS) 分析,证明FEM1A/C和FEM1B选择性靶向不同类别的Arg/C-degrons。总的来说,我们的研究不仅揭示了Arg/C-degron识别精确控制底物周转的分子机制,而且为开发选择性调节蛋白沉积的化学探针提供了有价值的信息。

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