Cereblon-based E3 ubiquitin ligase complex (CRL4-CRBN) (CRL4-CRBN)

The Cereblon-based E3 ubiquitin ligase complex (CRL4-CRBN) is a multi-protein enzyme assembly that plays a pivotal role in cellular proteostasis by tagging specific proteins for degradation. The complex is composed of the substrate receptor Cereblon (CRBN), the adaptor protein DNA damage-binding protein 1 (DDB1), the scaffold protein Cullin-4 (CUL4A or CUL4B), and the RING-finger protein ROC1 (RBX1) (Fischer et al., Nature, 2014). Its primary function is to catalyze the polyubiquitination of substrate proteins, signaling their destruction by the 26S proteasome (Ito et al., Science, 2010). This complex is the molecular target of Immunomodulatory Imide Drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide, which function as molecular glues to redirect the ligase toward non-native substrates such as the transcription factors Ikaros and Aiolos (Kronke et al., Science, 2014). In addition to IMiDs, the CRL4-CRBN complex is extensively utilized in the design of Proteolysis Targeting Chimeras (PROTACs) to achieve targeted degradation of various disease-associated proteins (Bondeson et al., Nat Chem Biol, 2015). Clinically, the complex is central to the treatment of multiple myeloma and other hematological malignancies, though its modulation carries risks such as teratogenicity and the development of drug resistance (Zhu et al., Blood, 2011).

Other names

CRBN-CRL4 complexCullin-4-RING E3 ubiquitin ligase complexCRBN-DDB1-CUL4-ROC1 complexCereblon-containing E3 ligase

Molecular glue degradation (recruitment of neo-substrates like IKZF1/3) and PROTAC-mediated protein degradation (Ito et al., Science, 2010; Bondeson et al., Nat Chem Biol, 2015).