Cereblon–DDB1–Cullin-4–ROC1 E3 ubiquitin ligase complex (CRL4-CRBN) (CRL4-CRBN)

The Cereblon–DDB1–Cullin-4–ROC1 E3 ubiquitin ligase complex (CRL4-CRBN) is a multi-subunit enzyme that plays a pivotal role in cellular proteostasis by tagging specific proteins with ubiquitin for degradation by the 26S proteasome (UniProt Q96SW2). The complex consists of the substrate receptor Cereblon (CRBN), the adapter protein Damage-specific DNA binding protein 1 (DDB1), a Cullin-4 scaffold (CUL4A or CUL4B), and the RING-finger protein ROC1 (Fischer et al., 2014, Nature). It is the primary therapeutic target for immunomodulatory imide drugs (IMiDs) like thalidomide and lenalidomide, which are used to treat multiple myeloma and other hematologic malignancies (Ito et al., 2010, Science). These drugs act as molecular glues, binding to the CRBN subunit and altering its surface to recruit "neo-substrates" such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) for degradation (Kronke et al., 2014, Science). This targeted degradation results in the inhibition of tumor cell proliferation and the stimulation of T-cell activity, though it is also responsible for the teratogenic effects associated with this class of drugs (Lu et al., 2014, Science). Beyond IMiDs, the CRL4-CRBN complex is a central component in the development of Proteolysis Targeting Chimeras (PROTACs), which utilize the complex to recruit the E3 ligase to degrade a wide variety of disease-causing proteins (Bondeson et al., 2015, Nature Chemical Biology). Mutations or decreased expression of the CRBN subunit are frequently associated with acquired resistance to IMiD therapy in clinical settings (Gandhi et al., 2014, British Journal of Haematology).

Other names

CRL4-CRBNCRBN-DDB1-CUL4-RBX1 complexCereblon E3 ligaseCullin-RING ligase 4-Cereblon

Molecular glue-mediated recruitment of neo-substrates for ubiquitination and proteasomal degradation; Targeted protein degradation (TPD) via E3 ligase recruitment.