DNA damage-binding protein 1–Cullin-4–RING-box protein 1 E3 ubiquitin ligase complex (CRL4)

The DNA damage-binding protein 1–Cullin-4–RING-box protein 1 (DDB1–CUL4–RBX1) E3 ubiquitin ligase complex, commonly known as Cullin-RING Ligase 4 (CRL4), is a multi-subunit enzyme assembly that facilitates the transfer of ubiquitin to specific substrate proteins, marking them for degradation by the 26S proteasome (UniProt: Q16531, P39900). The complex is composed of a Cullin-4 scaffold (either CUL4A or CUL4B), the adapter protein DDB1, and the RING-finger protein RBX1, which recruits the E2 ubiquitin-conjugating enzyme (Angers et al., Nature, 2006). CRL4 complexes are essential for various cellular processes, including DNA replication, DNA repair, and cell cycle progression, by regulating the stability of proteins like Cdt1 and p21 (Abbas and Dutta, Nature Reviews Cancer, 2009). This complex has gained significant therapeutic prominence as the primary target for immunomodulatory imide drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, which bind to the substrate receptor Cereblon (CRBN) associated with the CRL4 complex (Ito et al., Science, 2010). These drugs act as molecular glues, altering the substrate specificity of the CRL4-CRBN ligase to induce the degradation of non-physiological "neo-substrates" like IKZF1 and IKZF3, which is a key mechanism in treating multiple myeloma (Fischer et al., Nature, 2014). Beyond IMiDs, the CRL4 complex is also the foundation for many Proteolysis-Targeting Chimeras (PROTACs) that utilize CRBN as the E3 ligase recruitment module (Petzold et al., Nature, 2016).

Other names

CRL4 complexCUL4-DDB1-RBX1 complexCullin-RING ligase 4DDB1-CUL4-ROC1 complex

Molecular glue-mediated recruitment of neo-substrates for ubiquitination and proteasomal degradation