NEDD8 is a ubiquitin (Ub)-like molecule that shares 80% homology with ubiquitin, a protein known to modify and target various proteins for proteolytic degradation. NEDD8 and the corresponding yeast homolog RUB1 are activated by the E1 ubiquitin activating enzyme UBA2, which forms isopeptide linkages between thio esters. Similar to the Ub-mediated proteolytic pathway, NEDD8 is covalently coupled to an E3 Ub ligase by the E2 conjugating enzyme, UBC12. NEDD8 preferentially associates with the CUL-2 protein in the E3 ligase complex CBCVHL, which consists of cullin proteins associating with elongin B/C and the tumor suppressor F-box protein von Hippel Lindau (VHL). NEDD8 is predominantly localized to the nucleus and is highly expressed in adult heart and skeletal muscle. In vitro studies indicate that NEDD8 tetramers are also able to bind to the 26S proteasome, and that they assemble into complexes with conserved Ub-like moieties, suggesting that NEDD8 may regulate proteolysis of intracellular proteins similar to other Ub-mediated pathways.
