KLHDC2

KLHDC2 (Kelch Domain Containing 2) functions as a substrate receptor of the CRL2 (Cullin-RING Ligase 2) E3 ubiquitin ligase complex and plays a central role in protein quality control through selective recognition of C-terminal degrons.^[1] Mechanistically, KLHDC2 recognizes proteins carrying a C-terminal diglycine (Gly-Gly) C-end degron, including aberrant proteins, early-terminated selenoproteins, and proteolytic fragments, and directs their ubiquitination and proteasomal degradation.^[1] Structural studies demonstrated that KLHDC2 binds diglycine C-end degrons with nanomolar affinity through a deep substrate-binding pocket and an extensive hydrogen-bonding network, providing a molecular basis for high-specificity substrate recognition.^[1] This pathway contributes to the maintenance of protein homeostasis, and genetic studies indicate that KLHDC2 is essential for normal development because homozygous Klhdc2 knockout mice exhibit embryonic lethality.^[1] Mechanistically, KLHDC2 activity is regulated by transitions between inactive tetrameric assemblies and active monomeric CRL2^KLHDC2 complexes, in which its own C-terminal motif can mimic a degron and mediate autoinhibition.^[2] Compared with related family members such as KLHDC1, KLHDC3, and KLHDC10, KLHDC2 exhibits distinct substrate selectivity for Gly-Gly C-degrons and has emerged as a uniquely tractable E3 ligase for targeted protein degradation strategies.^[3] For experimental applications, structure-guided ligands and PROTAC platforms that recruit KLHDC2 have enabled selective degradation of target proteins, expanding the repertoire of E3 ligases available for chemical biology and drug discovery research.^[3][4]