Structural insights into CRL2FEM1C ubiquitin ligase-mediated protein ubiquitination

Structural insights into CRL2 FEM1C ubiquitin ligase-mediated protein ubiquitinationDear Editor ,The ubiquitin-proteasome system plays a key role in protein quality control by eliminating damaged, misfolded, or unnecessary proteins (Hershko and Ciechanover, 1998 ).Typically, the ubiquitination of a substrate is achieved through a cascade of reactions involving ubiquitin-activating (E1), ubiquitinconjugating (E2), and ubiquitin ligase (E3) enzymes (Scheffner et al., 1995 ).Recent studies have revealed that specific protein features located at the substrate C-terminus, termed Cdegrons, serve as destabilizing signals to recruit cullin-RING ubiquitin ligases (CRLs) for protein ubiquitination and subsequent proteasomal degradation.The substrate receptors (SRs) of CRLs were found to recognize C-degrons in a sequence-specific manner (Koren et al., 2018 ;Lin et al., 2018 ).A CRL complex is named for its cullin protein with the interchangeable SR subunit in superscript.For example, CRL2 FEM1C refers to the CRL2 complex with Cullin-2 (CUL2) and FEM1C as the scaffold and SR, respectively.Importantly, CRL function depends on the activation by neddylation, which induces structural changes that enhance the capacity to engage substrates and promote ubiquitination (Chen et al., 2024 ).Our previous studies revealed the molecular mechanisms underlying Arg/C-degron recognition by FEM1 family proteins, including FEM1A, FEM1B, and FEM1C (Chen et al.,