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

The Cullin-RING E3 ubiquitin ligase 4-Cereblon (CRL4-CRBN) complex is a multi-protein assembly composed of the scaffold protein Cullin 4 (CUL4A or CUL4B), the RING-finger protein RBX1, the adaptor protein DDB1, and the substrate receptor Cereblon (CRBN) (Source: UniProt Q96SW2; PMCID: PMC4277123). Its primary biological function is to catalyze the transfer of ubiquitin to specific target proteins, marking them for degradation by the 26S proteasome, which is essential for maintaining cellular protein homeostasis and regulating the cell cycle (Source: PubMed: 24445239). The complex is the primary therapeutic target for immunomodulatory imide drugs (IMiDs) like thalidomide and lenalidomide, which act as 'molecular glues' by binding to the CRBN subunit and altering its substrate specificity to include 'neo-substrates' such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) (Source: NIH/NCI). This degradation leads to potent anti-tumor and immunomodulatory effects, particularly in hematologic malignancies like multiple myeloma. Furthermore, CRBN is extensively utilized in the development of Proteolysis Targeting Chimeras (PROTACs) to selectively degrade diverse pathogenic proteins (Source: PubMed: 31235123). Mutations in the CRBN subunit have been linked to autosomal recessive intellectual disability, while its downregulation is a known mechanism of resistance to IMiD therapy (Source: Wikipedia; PubMed: 20223982).

Other names

CRL4(CRBN) E3 ubiquitin ligaseCereblon E3 ligase complexCUL4-DDB1-RBX1-CRBN complexCRBN-CRL4 complex

Molecular glue (reprogramming substrate specificity to induce degradation of neo-substrates); E3 ligase recruitment for Proteolysis Targeting Chimeras (PROTACs)