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Review
. 2014 Dec 29;4(4):140-58.
eCollection 2014.

Neddylation and deneddylation in cardiac biology

Sridhar Kandala  1 , Il-Man Kim  1 , Huabo Su  2
Affiliations
Review

Neddylation and deneddylation in cardiac biology

Sridhar Kandala et al. Am J Cardiovasc Dis. .

Abstract

Neddylation is a post-translational protein modification that conjugates a ubiquitin-like protein NEDD8 to target proteins. Similar to ubiquitination, neddylation is mediated by a cascade of three NEDD8 specific enzymes, an E1 activating enzyme, an E2 conjugating enzyme and one of the several E3 ligases. Neddylation is countered by the action of deneddylases via a process termed deneddylation. By altering the substrate's conformation, stability, subcellular localization or binding affinity to DNA or proteins, neddylation regulates diverse cellular processes including the ubiquitin-proteasome system-mediated protein degradation, protein transcription, cell signaling etc. Dysregulation of neddylation has been linked to cancer, neurodegenerative disorders, and more recently, cardiac disease. Here we comprehensively overview the biochemistry, the proteome and the biological function of neddylation. We also summarize the recent progress in revealing the physiological and pathological role of neddylation and deneddylation in the heart.

Keywords: NEDD8; Post-translational modification; cardiac disease; deneddylation; neddylation.

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Figures

Figure 1
Figure 1
NEDD8 is a ubiquitin-like protein highly conserved among species. A. The amino acid sequences of human ubiquitin and NEDD8 are aligned. B. The amino acid sequences of NEDD8 precursor from various species are aligned. The conserved amino acids and the amino acids with identical properties, as well as those with weakly similar properties, are represented in light blue, dark red and yellow, respectively. Arrow points to the site cleaved by NEDD8 protease. The exposed C-terminal glycine is to be fused with the lysine residue of the substrate. A. thaliana, Arabidopsis thaliana; S. cerevisiae, Saccharomyces cerevisiae; C. elegans, Caenorhabditis elegans; D. melanogaster, Drosophila melanogaster; R. norvegicus, Rattus norvegicus; M. musculus, Mus musculus; H. sapiens, Homo sapiens.
Figure 2
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.
Figure 3
Figure 3
Regulation of cullin-RING ubiquitin ligase (CRL) activity by neddylation and deneddylation. CRL consists of a scaffold protein cullin, a RING protein Rbx1 that recruits ubiquitin E2, an adaptor protein Skp1 that interacts with a F-box protein, and a substrate (Subs)-recognizing F-box protein. NAE-Ubc12-DCN1-mediated neddylation of cullin changes the conformation of cullin, which prevents the binding of a CRL inhibitory protein CAND1 to cullin but allows the recruitment of Skp1 and Rbx1. The assembly of a functional CRL brings ubiquitin charged E2 and the substrate to the proximity, allowing the transfer of ubiquitin to the substrate. After ubiquitination, the deneddylase CSN removes NEDD8 from cullin, leading to the disassembly of CRL. The released cullin is then ready to recruit another ubiquitin charged E2 for next round of ubiquitination. Dynamic cycling of neddylation and deneddylation is essential for optimal CRL activity.
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References

    1. Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82:373–428. - PubMed
    1. Grabbe C, Husnjak K, Dikic I. The spatial and temporal organization of ubiquitin networks. Nat Rev Mol Cell Biol. 2011;12:295–307. - PMC - PubMed
    1. Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20:1242–1253. - PubMed
    1. Schulman BA, Harper JW. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol. 2009;10:319–331. - PMC - PubMed
    1. Kumar S, Yoshida Y, Noda M. Cloning of a cDNA which encodes a novel ubiquitin-like protein. Biochem Biophys Res Commun. 1993;195:393–399. - PubMed

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