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Publication Abstract from PubMed

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 CRL2(FEM1B) bound to different C-degrons, we elucidate the dimeric assembly of the complex. Furthermore, we reveal distinct dimerization states of unmodified and neddylated CRL2(FEM1B) to uncover the NEDD8-mediated activation mechanism of CRL2(FEM1B). 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 CRL2(FEM1B)-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.

Mechanism of Psi-Pro/C-degron recognition by the CRL2(FEM1B) ubiquitin ligase.,Chen X, Raiff A, Li S, Guo Q, Zhang J, Zhou H, Timms RT, Yao X, Elledge SJ, Koren I, Zhang K, Xu C Nat Commun. 2024 Apr 26;15(1):3558. doi: 10.1038/s41467-024-47890-5. PMID:38670995^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.