Figure 2.

Protein modification by NEDD8. NEDD8 is translated into a precursor form that has to be processed by NEDD8 protease such as NEDP1 before NEDD8 can be attached to target proteins. Mature NEDD8 is conjugated to target proteins in an ATP-dependent manner by a serial reactions catalyzed by E1 (NAE), E2 (Ubc12) and E3 sequentially. With the help of these enzymes, the C-terminal glycine of NEDD8 forms an isopeptide bond with the lysine of target protein. An adenosine sulfamate analogue MLN4924 binds to the ATP-binding site in NAE and forms an irreversible MLN4924-NAE adduct, thus inhibiting the activation of neddylation. Deneddylases such as CSN and NEDP1 deconjugate NEDD8 from the neddylated proteins, freeing the substrate and NEDD8. NUB1L can specifically bind to and direct NEDD8 to the proteasome for degradation.