The modular architecture of Cullin-RING E3 Ligases (CRLs).

(A) CRL1 ubiquitin ligase complexes are perhaps the best known examples and bind their substrates via an F-box containing subunit. D'Angiolella and his laboratory discovered functions of cyclin F (FBXO1), the founding member of the F-box family of Cullin-RING ubiquitin ligases. (B) BTB-Kelch proteins assemble into CRL3 ubiquitin ligase complexes in which the BTB domain binds to Cullin3 and the Kelch domain forms the substrate recognition domain. (C) Some Cullin-RING ubiquitin ligase subunits, such as Cereblon are bound by “molecular glue” drugs (e.g. lenalidomide) that enable the recruitment of neo-substrates (e.g. Ikaros) for ubiquitylation. Similarly, bifunctional small molecule PROTAC drugs can bind to the E3 ligase VHL to recruit neo-substrates (e.g. oncoproteins) for ubiquitylation and degradation .