德隆
泛素连接酶
DNA连接酶
机制(生物学)
泛素
泛素蛋白连接酶类
细胞生物学
化学
生物化学
生物
DNA
基因
哲学
认识论
作者
Xinyan Chen,Anat Raiff,Li S,Qiong Guo,Jiahai Zhang,Haoli Zhou,Richard T. Timms,Xuebiao Yao,Stephen J. Elledge,Itay Koren,Kaiming Zhang,Chao Xu
标识
DOI:10.1038/s41467-024-47890-5
摘要
The E3 ligase-degron interaction determines the specificity of the ubiquitin‒proteasome system. We recently discovered that FEM1B, a substrate receptor of Cullin 2-RING ligase (CRL2), recognizes C-degrons containing a C-terminal proline. By solving several cryo-EM structures of CRL2FEM1B bound to different C-degrons, we elucidate the dimeric assembly of the complex. Furthermore, we reveal distinct dimerization states of unmodified and neddylated CRL2FEM1B to uncover the NEDD8-mediated activation mechanism of CRL2FEM1B. Our research also indicates that, FEM1B utilizes a bipartite mechanism to recognize both the C-terminal proline and an upstream aromatic residue within the substrate. These structural findings, complemented by in vitro ubiquitination and in vivo cell-based assays, demonstrate that CRL2FEM1B-mediated polyubiquitination and subsequent protein turnover depend on both FEM1B-degron interactions and the dimerization state of the E3 ligase complex. Overall, this study deepens our molecular understanding of how Cullin-RING E3 ligase substrate selection mediates protein turnover.
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