Cereblon – Cullin-4 RING E3 ubiquitin ligase complex (CRL4^CRBN) (CRL4^CRBN)

The Cereblon – Cullin-4 RING E3 ubiquitin ligase complex (CRL4^CRBN) is a multi-subunit enzyme assembly that plays a pivotal role in the cellular ubiquitin-proteasome system. It is composed of the substrate receptor Cereblon (CRBN), the scaffold protein Cullin-4 (CUL4A or CUL4B), the adaptor protein DNA damage-binding protein 1 (DDB1), and the RING finger protein RBX1 (also known as ROC1) [1, 3, 16]. Under physiological conditions, the complex regulates protein homeostasis by targeting specific substrates like MEIS2 and glutamine synthetase for degradation [9, 18]. CRL4^CRBN is the primary therapeutic target for immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide, which function as molecular glues to reprogram the ligase's substrate specificity toward neo-substrates like the transcription factors IKZF1 and IKZF3 [5, 12]. This targeted degradation is particularly effective in treating hematological malignancies like multiple myeloma and myelodysplastic syndromes [1, 17]. Furthermore, the complex is extensively utilized in the design of Proteolysis Targeting Chimeras (PROTACs) to achieve the degradation of otherwise undruggable proteins [2, 8, 10]. However, its modulation is associated with severe safety risks, most notably the teratogenic effects that led to the historical thalidomide tragedy [7, 11].

Other names

CRBN E3 ubiquitin ligase complexDDB1–CRBN E3 ubiquitin ligase complexCUL4–RBX1–DDB1–CRBN complexCRL4CRBN complexDCX E3 ligase complexCereblon

The complex functions as an E3 ubiquitin ligase that facilitates the transfer of ubiquitin from an E2 enzyme to specific substrate proteins, marking them for 26S proteasomal degradation. Drugs like immunomodulatory imide drugs (IMiDs) and Cereblon E3 ligase modulators (CELMoDs) act as molecular glues by binding to the Cereblon (CRBN) subunit, which alters its surface to recruit non-physiological neo-substrates (e.g., IKZF1, IKZF3, CK1α, GSPT1) for degradation. Additionally, the complex is utilized by Proteolysis Targeting Chimeras (PROTACs) to recruit specific proteins of interest for targeted degradation.