The reference OMIM entry for this protein is 603171

Neural precursor cell expressed, developmentally downregulated 8; nedd8

CLONING

Kumar et al. (1992) identified Nedd8 as 1 of a group of mouse genes that show developmentally regulated expression in embryonic brain. Kumar et al. (1993) found that mouse Nedd8 encodes a small protein with sequence similarity to ubiquitin (191339). Kamitani et al. (1997) reported that the sequences of the predicted 81-amino acid human, mouse, and rat NEDD8 proteins are nearly identical. Human NEDD8 and ubiquitin share 60% amino acid sequence identity. By Western blot analysis of human cell line lysates, NEDD8 migrated as a 6-kD protein. Immunofluorescence studies showed that NEDD8 is expressed primarily in the nucleus. As with ubiquitin and sentrin (601912), NEDD8 is conjugated to other cellular proteins after its C-terminal tail is processed. Northern blot analysis detected NEDD8 expression predominantly in heart and skeletal muscle.

GENE FUNCTION

Ubiquitin is covalently attached to target proteins by a multienzymatic system consisting of E1 (ubiquitin-activating), E2 (ubiquitin-conjugating), and E3 (ubiquitin-ligating) enzymes. Osaka et al. (1998) demonstrated that NEDD8 is activated by an E1-like complex, consisting of beta-amyloid precursor protein-binding protein-1 (APPBP1; 603385) and UBA3 (603172), and then linked to the E2-like enzyme, UBC12 (603173). They found that the major target protein modified by NEDD8 is cullin-4A (603137). Using confocal and time-lapse microscopy in C. elegans, Kurz et al. (2002) showed that Nedd8 conjugation negatively regulates contractility of the microfilament-rich cell cortex during pronuclear migration and during cytokinesis. They found that worms with an embryonic lethal mutation in the Rfl1 gene, the worm homolog of the ubiquitin-activating enzyme UBA3, had prominent defects in microfilament- and microtubule-mediated processes during mitosis. In C. elegans, the Mei1 and Mei2 genes encode a meiosis-specific katanin (see 606696) heterodimer that localizes to the meiotic spindle and chromosomes and has microtubule-severing activity. The authors found that worms with mutant Rfl1 and Mei1 genes did not show microtubule instability. Kurz et al. (2002) suggested that the Nedd8 pathway in C. elegans requires an intact spindle to be active during mitosis and, after meiosis, targets either Mei1 or Mei2 for ubiquitin-mediated degradation. COP9 signalosome cleaves the ubiquitin-like protein NEDD8 from the CUL1 (603134) subunit of SCF ubiquitin ligases. Cope et al. (2002) found that the JAB1/MPN domain metalloenzyme (JAMM) motif in the JAB1/COPS5 (604850) subunit underlies the COP9 signalosome's NEDD8 isopeptidase activity. The JAMM motif consists of a his-X-his-X(10)-asp motif (where X indicates any residue) accompanied by an upstream glutamate. The JAMM motif is found in proteins from archaea, bacteria, and eukaryotes, including the RPN11 subunit of the 26S proteasome. Metal chelators and point mutations within the JAMM motif abolished COP9 signalosome-dependent cleavage of NEDD8 from CUL1, yet had little effect on COP9 signalosome complex assembly. Cope et al. (2002) proposed that JAMM isopeptidases play important roles in a variety of physiologic pathways. Xirodimas et al. (2004) showed that MDM2 (164785) can promote NEDD8 modification of p53 (191170). They found that MDM2 is itself modified with NEDD8 with similar characteristics to the autoubiquitination activity of MDM2. Using a cell line with a temperature-sensitive mutation in the NEDD8 conjugation pathway and a p53 mu ... More on the omim web site

Subscribe to this protein entry history

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 603171 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).