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

The Cereblon-Cullin 4 E3 ubiquitin ligase complex (CRL4-CRBN) is a multi-subunit enzyme complex that plays a pivotal role in the ubiquitin-proteasome system by mediating the polyubiquitination of specific substrate proteins [1, 2]. The complex is composed of the substrate receptor Cereblon (CRBN), the adaptor protein DNA damage-binding protein 1 (DDB1), the scaffold protein Cullin 4 (CUL4A or CUL4B), and the RING-finger protein RBX1 [2, 3]. CRL4-CRBN gained significant clinical prominence as the primary molecular target of immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide [3, 4]. These drugs function as molecular glues, binding to the CRBN subunit and altering its surface to recruit "neo-substrates"—proteins not normally targeted by the ligase—such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) [4, 5]. The subsequent degradation of these factors is essential for the anti-proliferative and immunomodulatory effects observed in the treatment of multiple myeloma and myelodysplastic syndromes [5, 6]. Additionally, the CRL4-CRBN complex is a cornerstone of targeted protein degradation (TPD) technology, serving as the E3 ligase component for many Proteolysis-Targeting Chimeras (PROTACs) designed to eliminate diverse pathogenic proteins [7]. Beyond its role in cancer therapy, mutations in the CRBN subunit are associated with autosomal recessive intellectual disability, and its interaction with thalidomide is responsible for the drug's well-known teratogenic effects during limb development [1, 3, 9].

Other names

CRBN-CRL4 complexCullin-4A-DDB1-CRBN complexCRL4A-CRBNCereblon-containing E3 ubiquitin ligase

The complex acts as a scaffold for the E3 ubiquitin ligase machinery. Drugs like IMiDs act as molecular glues that bind the CRBN subunit, creating a new interface that recruits neo-substrates (e.g., IKZF1, IKZF3) for ubiquitination and degradation [4, 5]. PROTACs use the complex to recruit specific proteins of interest for targeted degradation [7].