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

The Cereblon – CRL4-CRBN E3 ubiquitin ligase complex is a multi-subunit enzyme complex that plays a pivotal role in the ubiquitin-proteasome system by mediating the polyubiquitination of specific substrate proteins for degradation (UniProt: Q96SW2). The complex is composed of the substrate receptor Cereblon (CRBN), the scaffold protein Cullin-4A or 4B (CUL4A/B), the adaptor protein DNA damage-binding protein 1 (DDB1), and the RING-finger protein RBX1 (Fischer et al., Nature, 2014). CRBN is the primary molecular target of immunomodulatory imide drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, which bind to its tri-thallium pocket (Ito et al., Science, 2010). This binding event reconfigures the surface of CRBN, enabling it to recruit and degrade non-native "neo-substrates" like the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for the survival of multiple myeloma cells (Kronke et al., Science, 2014). Beyond its role in cancer therapy, the CRL4-CRBN complex is a cornerstone of Targeted Protein Degradation (TPD) technology, serving as the E3 ligase component for numerous Proteolysis Targeting Chimeras (PROTACs). However, the drug-induced degradation of the transcription factor SALL4 by this complex is the primary mechanism underlying the severe teratogenic effects associated with thalidomide (Matyskiela et al., Nature, 2018). Consequently, while it is a highly effective therapeutic target in hematology, its modulation requires strict safety protocols to prevent developmental toxicity.

Other names

CRBNCereblonCRL4-CRBN complexCullin-RING ligase 4-Cereblon complexDDB1-CUL4-RBX1-CRBN complex

IMiDs and CELMoDs act as molecular glues that bind to the CRBN subunit, creating a new surface that recruits neo-substrates like IKZF1 and IKZF3 for ubiquitination and degradation (Kronke et al., Science, 2014). Additionally, the complex is recruited by PROTACs to induce the degradation of specific target proteins (Fischer et al., Nature, 2014).