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Description

Protein cereblon (UniProt Q96SW2) is encoded by the CRBN (also known as AD-006, MRT2A) gene (Gene ID 51185) in human. Originally identified as a genetic cause of inherited autosomal recessive mental retardation, the human CRBN gene encodes a substrate receptor of a ubiquitin E3 cullin 4-RING ligase (CRL4) complex. A cullin-4 (CULT4) protein provides a scaffold for assembling RING box-domain protein (​,RBX1) and the adaptor protein damaged ​,DNA-binding protein 1 (​,DDB1) to form a CRL4 E3 complex, where ​,RBX1 serves as the docking site for the activated E2 protein, and ​,DDB1 recruits substrate-specificity receptors or DCAFs (DDB1-cullin 4-associated factors) to form the substrate-presenting side of the CRL4 complex. Thalidomide and its analogs (lenalidomide, pomalidomide and apremilast) are immunomodulatory drugs (IMiDs) that exert their antiproliferative effects on multiple myeloma (MM) cells and immunomodulatory effects on T cells by directly binding cereblon and promoting recruitment of the hematopoietic zinc-finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), leading to their ubiquitination and proteasomal degradation. Human cereblon is a 442-amino acid protein composed of a ​,Lon protease-like scaffold (a.a. 80-317) with a helical insertion that mediates ​,DDB1 binding and a thalidomide-binding domain (TBD, a.a. 339-442).