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Review
. 2008 Oct;9(10):969-76.
doi: 10.1038/embor.2008.183. Epub 2008 Sep 19.

Function and Regulation of Protein Neddylation. 'Protein Modifications: Beyond the Usual Suspects' Review Series

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Free PMC article
Review

Function and Regulation of Protein Neddylation. 'Protein Modifications: Beyond the Usual Suspects' Review Series

Gwénaël Rabut et al. EMBO Rep. .
Free PMC article

Abstract

Neddylation is the post-translational protein modification that is most closely related to ubiquitination. However, ubiquitination is known to regulate a myriad of processes in eukaryotic cells, whereas only a limited number of neddylation substrates have been described to date. Here, we review the principles of protein neddylation and highlight the mechanisms that ensure the specificity of neddylation over ubiquitination. As numerous neddylation substrates probably remain to be discovered, we propose some criteria that could be used as guidelines for the characterization of neddylated proteins.

Figures

Figure 1
Figure 1
Neddylation pathway. Schematic representation of the main steps of the neddylation pathway, including NEDD8 precursor processing, activation by the E1 (UBA3–APPBP1 heterodimer), loading onto the E2 (Ubc12), conjugation to a substrate by an E3 and recycling of NEDD8 by an isopeptidase. APPBP1, APP binding protein 1; NEDD8, neural precursor cell expressed developmentally downregulated protein 8; UBA3, ubiquitin-like modifier activating enzyme 3; Ubc, ubiquitin-conjugating.
Figure 2
Figure 2
Direct effects of neddylation. By remodelling the three-dimensional surface of its substrates, neddylation can achieve the following: (A) induce conformational changes (for example, neddylation of cullins allows their C-terminal domain and Rbx1 to adopt catalytically active conformations); (B) preclude association with certain partners or compete with other posttranslational modifications (for example, cullin neddylation is incompatible with CAND1 interaction); and (C) provide a novel binding surface to recruit new partners (for example, neddylated EGFR might recruit endocytic proteins such as Eps15 or Hrs). CAND1, cullin-associated and neddylation-dissociated 1; EGFR, epidermal growth factor receptor; Eps15, EGFR pathway substrate 15; Hrs, hepatocyte growth factor–regulated tyrosine kinase substrate; Rbx1, RING box.
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Gwénaël Rabut (left) & Matthias Peter

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