Cullin-4-DDB1-Cereblon E3 ubiquitin ligase complex (CRL4-CRBN)

The Cullin-4-DDB1-Cereblon (CRL4-CRBN) E3 ubiquitin ligase complex is a multi-subunit enzyme system that plays a critical role in cellular protein homeostasis by mediating the ubiquitination and subsequent proteasomal degradation of target proteins [1, 9, 13]. The complex is composed of the scaffold protein Cullin-4 (CUL4A or CUL4B), the adaptor protein DNA damage-binding protein 1 (DDB1), the RING-finger protein RBX1, and the substrate receptor Cereblon (CRBN), which provides substrate specificity [4, 13, 18]. Physiologically, it regulates diverse processes such as limb development, Wnt signaling, and the stability of various ion channels and metabolic enzymes [2, 12, 14]. This complex is the primary target for immunomodulatory imide drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide, which act as molecular glues to reprogram CRBN's substrate repertoire toward neo-substrates like IKZF1 and IKZF3 [4, 9, 18]. This redirection is the basis for their efficacy in treating multiple myeloma and other hematological malignancies [9, 15, 18]. Furthermore, the CRL4-CRBN complex is a cornerstone of targeted protein degradation (TPD) technology, serving as a recruitment site for Proteolysis Targeting Chimeras (PROTACs) [4, 8, 15]. Despite its therapeutic utility, the complex is also responsible for the severe teratogenic effects of thalidomide, primarily through the unintended degradation of the transcription factor SALL4 [1, 17].

Other names

CRL4-CRBNCRL4(CRBN)Cereblon E3 ligase complexDDB1-CUL4-CRBN complexDCX complexDDB1-CUL4-X-box complexCullin-RING ligase 4-Cereblon complex

Molecular glue degradation of neo-substrates (e.g., IKZF1, IKZF3, SALL4, CK1alpha); Targeted protein degradation via Proteolysis Targeting Chimeras (PROTACs); Inhibition of endogenous substrate binding (e.g., MEIS2).