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

Cereblon (CRBN) is a 442-amino acid protein that functions as the substrate recognition component of the Cullin-4-RING E3 ubiquitin ligase (CRL4) complex, which also includes Cullin-4 (CUL4A or CUL4B), DNA damage-binding protein 1 (DDB1), and Ring-box protein 1 (RBX1) (UniProt Q96SW2). This complex is responsible for the polyubiquitination of specific proteins, marking them for degradation by the 26S proteasome, and plays critical roles in limb development and the regulation of ion channels (Ito et al., 2010, Science). CRBN is the primary molecular target of immunomodulatory imide drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide (Chamberlain et al., 2014, Nature Structural & Molecular Biology). Upon binding to these drugs, CRBN undergoes a conformational change that allows it to recruit "neo-substrates"—proteins not normally targeted by the ligase—such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) (Kronke et al., 2014, Science). The degradation of these neo-substrates is particularly effective in treating hematologic malignancies like multiple myeloma and myelodysplastic syndromes (Lu et al., 2014, Science). Beyond its role in cancer therapy, CRBN is involved in the teratogenic effects of thalidomide and has been linked to autosomal recessive nonsyndromic intellectual disability (Ito et al., 2010, Science).

Other names

CRBNCereblonCRL4(CRBN)CRL4-CRBN E3 ligaseCUL4-RBX1-DDB1-CRBN complex

The CRL4-CRBN complex acts as an E3 ubiquitin ligase where CRBN serves as the substrate recognition subunit. Drugs such as immunomodulatory imide drugs (IMiDs) bind to the thalidomide-binding domain of CRBN, acting as molecular glues that reprogram the ligase's specificity to recruit and ubiquitinate neo-substrates (e.g., IKZF1, IKZF3, CK1α) for proteasomal degradation.