Cullin-RING E3 ubiquitin ligase 4 complex (CRL4)

The Cullin-RING E3 ubiquitin ligase 4 (CRL4) complex is a modular multi-protein assembly essential for the selective ubiquitination and subsequent proteasomal degradation of various cellular proteins (Sang et al., 2015, Oncotarget). It is composed of a Cullin 4 scaffold (either CUL4A or CUL4B), the RING-finger protein RBX1, the adaptor protein DNA damage-binding protein 1 (DDB1), and a substrate-specific receptor known as a DDB1- and CUL4-associated factor (DCAF) (Fischer et al., 2014, Nature). The complex is a central regulator of diverse biological processes, including the DNA damage response (specifically nucleotide excision repair), cell cycle control, and chromatin remodeling (Higa et al., 2006, Nat Cell Biol). In clinical medicine, the CRL4 complex—specifically the CRL4-CRBN (Cereblon) subtype—is the primary target of immunomodulatory drugs (IMiDs) like lenalidomide and pomalidomide (Ito et al., 2010, Science). These drugs act as molecular glues, altering the substrate specificity of the ligase to induce the degradation of neo-substrates such as IKZF1 and IKZF3, which is therapeutic in hematological malignancies like multiple myeloma (Kronke et al., 2014, Science). Additionally, the CRL4 complex is a foundational component in the development of Proteolysis Targeting Chimeras (PROTACs), which harness the ligase's activity to degrade previously undruggable targets (Wang et al., 2024, ResearchGate).

Other names

CRL4 complexCUL4-DDB1 complexCullin 4-RING ligaseCUL4-RING ubiquitin ligaseDDB1-CUL4-RBX1 complexDDB1-CUL4-ROC1 complex

Molecular glue (reprogramming substrate specificity), Targeted protein degradation (TPD), Inhibition of complex activation via neddylation inhibition, and Disruption of complex assembly.