Research Paper Volume 12, Issue 17 pp 17380—17392

Figure 1. Schematic overview of cullin-RING E3 ligases (CRLs) and the NEDD8 conjugation pathway. (A) Cullin (CUL) proteins form the scaffold of the CRL E3 ligase complexes. CRL1 and CRL7 use SKP1; CRL2 and CRL5 use both Elongin B and Elongin C; CRL4A and CRL4B use DDB1; and CRL3 uses BTB as substrate adaptors. CRL1 uses F-box proteins; CRL4A and CRL4B use DCAF; CRL2 and CRL5 use SOCSs; and CRL7 uses FBXW8 as substrate binding proteins. CRL1-3, 4A/B and 7 use Rbx1; and CRL5 uses Rbx2 as RING-finger proteins. (B) Conjugation of the Ub-like protein NEDD8 to a cullin protein is required for fully activation of the CRL. The conjugation of NEDD8 occurs in three steps: activation by the NEDD8 activation enzyme (NAE; E1^N), transference to the E2 enzyme (E2^N), and conjugation of NEDD8 to the cullin protein in the CRL. UBE2F is the major E2^N needed for NEDD8 conjugation to CRL5. MLN4924 (Pevonedistat) is a first-in-class inhibitor of E1^N that can prevent NEDD8 conjugation to CRLs. Abbreviations: Ub, ubiquitin; RING, really interesting new gene; DDB1, DNA damage-binding protein 1; DCAF, DDB1- and CUL4-associated factor; FBXW8, F-box and WD40 domain 8; BTB, broad-complex, tramtrack, and bric-à-brac; SOCS, suppressor of cytokine signaling.