Cereblon (CRBN) in the Cullin-4-RING E3 ubiquitin ligase complex (CRL4-CRBN)

Cereblon (CRBN) is a protein that functions as the substrate receptor for the Cullin-4-RING E3 ubiquitin ligase (CRL4) complex, which also comprises Cullin-4 (CUL4A or CUL4B), DNA damage-binding protein 1 (DDB1), and Regulator of Cullins 1 (RBX1) [UniProt: Q96SW2]. In its native biological role, CRBN is involved in brain development and the regulation of large-conductance calcium-activated potassium channels, and mutations in the CRBN gene are associated with autosomal recessive intellectual disability [PubMed: 20224193]. The CRL4-CRBN complex is the primary molecular target for immunomodulatory imide drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide [PubMed: 24445239]. These drugs function as "molecular glues" that bind to the thalidomide-binding domain of CRBN, altering its surface to recruit "neo-substrates" such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) for polyubiquitination and subsequent proteasomal degradation [PubMed: 24284190]. This mechanism is central to the anti-tumor and immunomodulatory effects of IMiDs in treating multiple myeloma and myelodysplastic syndromes. However, the recruitment of other neo-substrates, such as SALL4, is linked to the severe teratogenic effects associated with thalidomide exposure during pregnancy [PubMed: 30061385].

Other names

CRBNCRL4-CRBNCullin-4-RING E3 ubiquitin ligase complexThalidomide-binding protein

Molecular glue degradation; the drug binds to the cereblon substrate receptor, redirecting the E3 ligase complex to ubiquitinate and degrade specific neo-substrate proteins (e.g., IKZF1, IKZF3, CK1α) [PubMed: 24284190, 24445239].