CRBN

CRBN (cereblon) is the substrate-recognition subunit of a CRL4 cullin-RING E3 ubiquitin ligase, the DCX/CRL4(CRBN) complex composed of DDB1, CUL4A or CUL4B, RBX1 and CRBN. Through an N-terminal Lon-protease-like domain it binds the adaptor DDB1, and through a C-terminal thalidomide-binding (CULT) domain that coordinates a structural Zn2+ ion it recruits substrate proteins for ubiquitination and subsequent proteasomal degradation. Endogenous substrates include MEIS2, glutamine synthetase (GLUL) and ILF2, and the complex is required for normal limb outgrowth and FGF8 expression in vertebrates. CRBN also regulates neuronal large-conductance Ca2+-activated potassium (BK) channels via interaction with KCNT1, contributing to presynaptic glutamate release, memory and learning; loss-of-function variants cause autosomal recessive intellectual developmental disorder. The CULT domain is the direct molecular target of thalidomide, lenalidomide and pomalidomide (IMiDs) and of newer molecular-glue and PROTAC degraders, which act as molecular glues that reprogram CRBN substrate specificity to recruit neosubstrates such as IKZF1, IKZF3, SALL4, CK1alpha and GSPT1 for degradation. CRBN is expressed widely and most highly in brain, and localizes to cytoplasm, nucleus and peripheral membranes.

Disorders

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