APPBP1/UBA3 is the heterodimeric E1 enzyme that conjugates Nedd8 to protein substrates.Nedd8 is conjugated onto the catalytic cysteine residue of UBA3 by formation of a thioester bond in an ATP-dependent reaction.The activated Nedd8 is then passed on to an E2 (Ubc12) to be finally attached to a substrate.Nedd8 is mainly conjugated on Cullins to increase the activity of the Cullin – RING E3 Ub ligases.