Neural precursor cell-expressed developmentally downregulated protein 8, also known as Rub1 in plants and yeast, is a member of the ubiquitin-like protein family. The covalent attachment of NEDD8 to target proteins, termed neddylation, is a reversible, multi-step process analogous to ubiquitination. NEDD8 is first synthesized in a precursor form with a carboxy-terminal extension peptide that is removed by either the UCH-L3 or NEDP1/DEN1 hydrolase protein to yield a mature NEDD8 protein. Mature NEDD8 is then covalently linked to target proteins via the carboxy-terminal glycine residue in a reaction catalyzed by the APP-BP1/Uba3 heterodimer complex and Ubc12 as the E1- and E2-like enzymes, respectively. An E3 ligase protein, Roc1/Rbx1, is also required for neddylation of the cullin proteins. Protein de-neddylation is catalyzed by a number of enzymes in the cell, including a "ubiquitin-specific" protease USP21, the NEDP1/DEN1 hydrolase and the COP9/signalosome. In contrast to the ubiquitin pathway, the NEDD8 modification system acts on only a few substrates and does not appear to target proteins for degradation. Neddylation of cullin proteins activates the SCF E3 ubiquitin ligase complex by promoting complex formation and enhancing the recruitment of the E2-ubiquitin intermediate. While NEDD8 modification of VHL is not required for ubiquitination of HIF1-α, it is required for fibronectin matrix assembly. Mdm2-dependent neddylation of p53 inhibits its transcriptional activity.
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