Cereblon (CRBN) E3 ubiquitin ligase complex (CRL4-CRBN)

The Cereblon (CRBN) E3 ubiquitin ligase complex is a multi-subunit enzyme assembly comprising the substrate receptor CRBN, DNA damage-binding protein 1 (DDB1), Cullin-4A or 4B (CUL4A/B), and Regulator of Cullins 1 (ROC1) [1, 3]. Within this Cullin-RING ligase 4 (CRL4) framework, CRBN acts as the substrate recognition component responsible for identifying and binding proteins destined for polyubiquitination and subsequent degradation by the 26S proteasome [2]. This complex is the primary molecular target for immunomodulatory imide drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, which bind to a specific tri-tryptophan pocket in the CRBN protein [2, 4]. Drug binding alters the substrate specificity of the ligase, enabling the recruitment of "neo-substrates" such as the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), leading to their depletion and resulting in anti-proliferative and immunomodulatory effects [4, 5]. Consequently, the CRL4-CRBN complex plays a pivotal role in the treatment of hematologic malignancies, particularly multiple myeloma and myelodysplastic syndromes [5]. Furthermore, CRBN is the most widely utilized E3 ligase in the design of Proteolysis-Targeting Chimeras (PROTACs) to achieve targeted degradation of diverse oncogenic or pathogenic proteins [6]. (Citations: [1] UniProt Q96SW2; [2] Ito et al., Science 2010; [3] Fischer et al., Nature 2014; [4] Chamberlain et al., Nat Struct Mol Biol 2014; [5] Kronke et al., Science 2014; [6] Bondeson et al., Nat Chem Biol 2015).

Other names

CRL4-CRBN complexCRL4(CRBN)CRBN-DDB1-CUL4A-ROC1 complexCereblon-Cullin-4A-DDB1-ROC1 complex

Molecular glue degradation of neo-substrates; Targeted protein degradation (TPD) via PROTAC recruitment