The ubiquitin-proteasome system (UPS) is a major pathway regulating eukaryotic protein levels. Selectivity for UPS protein substrates, containing terminal destabilizing motifs (degrons), is largely governed by E3 ligases, which modify proteins with ubiquitin (UB) to target them for degradation.<br>KLHDC2 is a substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation.<br>Autoinhibition of KLHDC2 involves the self-assembly of its C-terminal Gly-Ser motif, which mimics a C-degron and engages the substrate-binding domain of another protomer in the homotetramer. This autoinhibited state prevents the binding of diGly substrates, ensuring that only true substrates that can displace the C-degron mimic can bind and activate the E3 ligase for ubiquitylation.