Cereblon-DDB1-CUL4A-ROC1 E3 ubiquitin ligase complex (CRL4-CRBN) (CRL4-CRBN)

The Cereblon-DDB1-CUL4A-ROC1 E3 ubiquitin ligase complex (CRL4-CRBN) is a multi-subunit enzyme assembly that mediates the ubiquitination and subsequent proteasomal degradation of specific protein substrates (Ito et al., 2010, Science 327:1345-1350). The complex is composed of Cereblon (CRBN), which serves as the substrate receptor, DNA damage-binding protein 1 (DDB1), Cullin-4A (CUL4A), and the RING-finger protein ROC1 (also known as RBX1) (Chamberlain et al., 2014, Nat Struct Mol Biol 21:803-809). Under physiological conditions, the complex regulates various cellular processes, including DNA repair, cell cycle progression, and metabolic homeostasis. It is the primary molecular target for immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide, which act as molecular glues (Fischer et al., 2014, Nature 512:49-53). These drugs bind to the CRBN subunit and alter its substrate specificity, inducing the degradation of neo-substrates like the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are critical for the survival of B-cell malignancies (Petzold et al., 2016, Nature 532:127-130). Furthermore, the CRL4-CRBN complex is widely utilized in the development of Proteolysis Targeting Chimeras (PROTACs) to achieve targeted degradation of diverse disease-relevant proteins. Clinically, targeting this complex is a cornerstone in the treatment of multiple myeloma and myelodysplastic syndromes, though it is associated with significant safety concerns including teratogenicity and myelosuppression.

Other names

CRBN-DDB1 complexCereblon E3 ligaseCRL4(CRBN) E3 ubiquitin ligaseCereblon-DDB1-CUL4A-RBX1 complexCereblon-DDB1-Cullin-4A-ROC1 complex

Molecular glue degradation of neo-substrates, recruitment of E3 ligase for targeted protein degradation (PROTACs), and modulation of ubiquitin ligase activity.