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

Cereblon (CRBN) is the substrate recognition component of the Cullin-RING E3 ubiquitin ligase 4 (CRL4^CRBN) complex, which also comprises Cullin-4A (CUL4A) or Cullin-4B (CUL4B), DNA damage-binding protein 1 (DDB1), and Ring-box protein 1 (RBX1) [1, 3]. In its native biological role, CRBN acts as a molecular chaperone and E3 ligase subunit involved in brain development and the regulation of large-conductance calcium-activated potassium channels [1, 5]. The complex is the primary therapeutic target for immunomodulatory imide drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, which bind to the thalidomide-binding domain (TBD) of CRBN [2, 4]. Upon binding to IMiDs, the CRL4^CRBN complex undergoes a gain-of-function conformational change that redefines its substrate specificity, enabling the recruitment and subsequent proteasomal degradation of "neo-substrates" such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) [2, 4]. This mechanism is highly effective in treating hematologic malignancies like multiple myeloma, where the degradation of these substrates leads to the downregulation of IRF4 and subsequent tumor cell apoptosis [2]. Beyond its role as a target for molecular glues, CRBN is the most frequently utilized E3 ligase for the development of Proteolysis Targeting Chimeras (PROTACs), serving as a recruitment site to induce the degradation of diverse pathogenic proteins [3, 6]. Citations: [1] Ito, T., et al. (2010) Science; [2] Lu, G., et al. (2014) Science; [3] Fischer, E. S., et al. (2014) Nature; [4] Chamberlain, P. P., et al. (2014) Nat Struct Mol Biol; [5] UniProt Q96SW2; [6] Bondeson, D. P., et al. (2015) Nat Chem Biol.

Other names

CRBNCereblonMCNMRT2ACRL4-CRBNCullin-RING E3 ubiquitin ligase 4-Cereblon complex

Molecular glue degradation; the drug binds to the thalidomide-binding domain of CRBN to facilitate the recruitment, ubiquitination, and proteasomal degradation of specific neo-substrate proteins.