Mechanism of Ψ-Pro/C-degron recognition by the CRL2FEM1B ubiquitin ligase

Xinyan Chen, Anat Raiff, Shanshan Li, Qiong Guo, Jiahai Zhang, Hualin Zhou, Richard T. Timms, Xuebiao Yao, Stephen J. Elledge, Itay Koren (), Kaiming Zhang () and Chao Xu ()
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Xinyan Chen: University of Science and Technology of China
Anat Raiff: Bar-Ilan University
Shanshan Li: University of Science and Technology of China
Qiong Guo: University of Science and Technology of China
Jiahai Zhang: University of Science and Technology of China
Hualin Zhou: University of Science and Technology of China
Richard T. Timms: University of Cambridge
Xuebiao Yao: University of Science and Technology of China
Stephen J. Elledge: Harvard Medical School
Itay Koren: Bar-Ilan University
Kaiming Zhang: University of Science and Technology of China
Chao Xu: University of Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47890-5

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