CRL4-Cereblon E3 Ubiquitin Ligase Complex

The CRL4-Cereblon (CRBN) E3 ubiquitin ligase complex is a multi-protein assembly that plays a central role in targeted protein degradation via the ubiquitin-proteasome pathway. It consists of CUL4A/B, RBX1/ROC1, DDB1, and Cereblon. Its primary function is to confer substrate specificity for ubiquitination, marking proteins for proteasomal degradation and regulating numerous cellular processes. Targeting CRL4(CRBN) has revolutionized treatment strategies for hematological malignancies such as multiple myeloma, and it is also being explored for PROTAC-based drug discovery.

The CRL4(CRBN) E3 ubiquitin ligase complex catalyzes the transfer of ubiquitin from an E2 enzyme to specific target proteins, marking them for proteasomal degradation. Substrate recognition is determined by cereblon or other DCAFs bound to DDB1. Small molecules like IMiDs can bind cereblon, altering its substrate specificity and redirecting it toward non-native targets. PROTACs can also hijack this system to induce proximity-driven ubiquitylation and degradation of target proteins.