SCIENCE@home

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

Xinyan Chen,Anat Raiff,Shanshan Li,Qiong Guo,Jiahai Zhang,Hualin Zhou,R. Timms,Xuebiao Yao,S. Elledge,Itay Koren,Kaiming Zhang,Chao Xu

Published 2024 in Nature Communications

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. A key question in the ubiquitin-proteasome system is how E3 ligases select their substrates. Here, the authors reveal that CRL2FEM1B E3 ligase functions as a dimer and employs a bipartite mode of substrate recognition, requiring a C-terminal proline and an upstream aromatic residue in the target.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-39 of 39 references · Page 1 of 1

CITED BY

Showing 1-19 of 19 citing papers · Page 1 of 1