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

The Cereblon-Cullin-4-RING E3 ubiquitin ligase complex (CRL4-CRBN) is a multi-subunit enzyme assembly that plays a pivotal role in protein homeostasis by tagging specific substrates with ubiquitin for proteasomal degradation (Fischer et al., 2014 [2]). The complex is composed of the substrate receptor Cereblon (CRBN), the adaptor protein DNA damage-binding protein 1 (DDB1), a scaffold protein (Cullin-4A or 4B), and the RING-finger protein RBX1 (Ito et al., 2010 [1]). CRL4-CRBN is the primary molecular target of immunomodulatory imide drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide, which act as "molecular glues" to redirect the ligase's activity toward neomorphic substrates such as IKZF1 (Ikaros) and IKZF3 (Aiolos) (Gandhi et al., 2014 [4]). This targeted degradation is highly effective in treating hematologic malignancies, particularly multiple myeloma and 5q-deletion myelodysplastic syndrome (Petzold et al., 2016 [3]). Beyond its role in cancer therapy, the complex is a foundational tool in the development of Proteolysis Targeting Chimeras (PROTACs), where it is recruited to degrade a wide array of previously "undruggable" proteins (Matyskiela et al., 2018 [5]). Mutations in the CRBN component of the complex have also been linked to autosomal recessive non-syndromic intellectual disability, highlighting its importance in neurological development (Higgins et al., 2004 [6]). However, the drug-induced degradation of the transcription factor SALL4 by this complex is responsible for the severe teratogenic effects associated with thalidomide (Matyskiela et al., 2018 [5]). Current research focuses on developing next-generation Cereblon E3 Ligase Modulators (CELMoDs) with improved potency and substrate specificity to overcome resistance in refractory cancers.

Other names

CRL4(CRBN)CRBN-DDB1-CUL4-RBX1 complexCereblon E3 ligase complexCullin-4A-RING E3 ubiquitin ligase complex

Molecular glue degradation and targeted protein degradation via E3 ligase recruitment (Fischer et al., 2014 [2])