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

The Cullin-RING ligase 4-Cereblon (CRL4-CRBN) E3 ubiquitin ligase complex is a multi-subunit enzyme responsible for the polyubiquitination and subsequent proteasomal degradation of specific protein substrates (UniProt Q96SW2). The complex consists of the scaffold protein Cullin 4 (CUL4A or CUL4B), the RING finger protein RBX1, the adaptor protein DDB1, and the substrate receptor Cereblon (CRBN) (Ito et al., 2010, Science). CRBN acts as the substrate recognition component, determining which proteins are targeted for degradation. This complex gained significant clinical importance when it was identified as the primary molecular target for immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide (Chamberlain et al., 2014, Nature). Upon binding to IMiDs, the CRL4-CRBN complex undergoes a conformational change that allows it to recruit "neo-substrates"—proteins it does not normally target—such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) (Kronke et al., 2014, Science). The degradation of these neo-substrates leads to the potent anti-tumor and immunomodulatory effects observed in the treatment of multiple myeloma and other hematologic malignancies. Beyond IMiDs, the CRL4-CRBN complex is a cornerstone of targeted protein degradation (TPD) technology, serving as the E3 ligase recruiter for many Proteolysis Targeting Chimeras (PROTACs) designed to eliminate disease-causing proteins (Bondeson et al., 2015, Nature Chemical Biology).

Other names

CRBN-CRL4Cereblon-CRL4 complexCRL4(CRBN)Cullin-4A-RING E3 ubiquitin ligase complexDDB1-CUL4-RBX1-CRBN complex

Molecular glue-mediated neo-substrate degradation (e.g., IKZF1, IKZF3, CK1α) and targeted protein degradation via Proteolysis Targeting Chimeras (PROTACs) (Petzold et al., 2016, Nature; Bondeson et al., 2015, Nature Chemical Biology).