Cereblon-containing E3 ubiquitin ligase (CRL4-CRBN)

The Cereblon-containing E3 ubiquitin ligase complex, specifically the CRL4-CRBN complex, is a multi-protein machinery responsible for the ubiquitination and subsequent proteasomal degradation of specific cellular proteins [1, 3, 4, 7, 8, 9, 10, 12, 13, 15, 18, 19]. It consists of the substrate receptor Cereblon (CRBN), the adapter protein DDB1, the scaffold protein Cullin-4 (CUL4A or CUL4B), and the RING-finger protein RBX1 [1, 3, 4, 5, 14, 15, 18, 19]. CRBN is the primary target of immunomodulatory imide drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide [1, 2, 3, 4, 5, 6, 8, 9, 12, 13, 14, 16, 18, 19, 20, 21]. These drugs act as molecular glues, altering the substrate specificity of the ligase to recruit and degrade neosubstrates such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are critical for the survival of multiple myeloma cells [4, 8, 9, 12, 13, 14, 18, 19, 20, 21]. Beyond cancer, CRBN plays roles in neuronal development, and its dysfunction is linked to autosomal recessive nonsyndromic mental retardation [1, 4, 12, 15]. The complex is also a cornerstone of Proteolysis-Targeting Chimera (PROTAC) technology, where it is hijacked to degrade a wide variety of disease-causing proteins [3, 7, 8, 10, 11, 12, 19, 20].

Other names

CRBNCereblonCullin-4 RING E3 ubiquitin ligase complexCRL4-CRBN E3 ubiquitin ligaseMRT2MRT2A

Molecular glue-mediated neosubstrate recruitment and targeted protein degradation