NEDD8 is a protein that in humans is encoded by the NEDD8 gene.[1][2] (In Saccharomyces cerevisiae this protein is known as Rub1.) This ubiquitin-like protein (ULP), which becomes covalently conjugated to a limited number of cellular proteins in a manner analogous to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The only known substrates of NEDD8 modification are the cullin subunits of SCF ubiquitin E3 ligases. The NEDDylation of cullins is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.
As with ubiquitin and SUMO, NEDD8 is conjugated to cellular proteins after its C-terminal tail is processed. The NEDD8 activating E1 enzyme is a heterodimer composed of APPBP1 and UBA3 subunits. The APPBP1/UBA3 enzyme has homology to the N- and C-terminal halves of the ubiquitin E1 enzyme, respectively. The UBA3 subunit contains the catalytic center and activates NEDD8 in an ATP-dependent reaction by forming a high-energy thiolester intermediate. The activated NEDD8 is subsequently transferred to the UbcH12 E2 enzyme, and is then conjugated to specific substrates in the presence of the appropriate E3 ligases. There are several different proteases which can remove NEDD8 from protein conjugates. UCHL1, UCHL3 and USP21 proteases have dual specificity for NEDD8 and ubiquitin. Proteases specific for NEDD8 removal are the COP9 signalosome which removes NEDD8 from the CUL1 subunit of SCF ubiquitin ligases, and NEDP1 (or DEN1, SENP8).[3]
Interactions [link]
NEDD8 has been shown to interact with UBE2M,[4] UBE1C,[4] NUB1,[5][6] Aryl hydrocarbon receptor[7] and UCHL3.[8]
References [link]
- ^ Kamitani T, Kito K, Nguyen HP, Yeh ET (Dec 1997). "Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein". J Biol Chem 272 (45): 28557–62. DOI:10.1074/jbc.272.45.28557. PMID 9353319.
- ^ "Entrez Gene: NEDD8 neural precursor cell expressed, developmentally down-regulated 8". https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&dopt=default&list_uids=4738&rn=1.
- ^ "Boston Biochem NEDD8 Reagents Overview". Archived from the original on 2008-05-02. https://web.archive.org/web/20080502050138/https://www.bostonbiochem.com/overview.php?prod=nedd8. Retrieved 2008-04-29.
- ^ a b Gong, L; Yeh E T (Apr. 1999). "Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway". J. Biol. Chem. (UNITED STATES) 274 (17): 12036–42. DOI:10.1074/jbc.274.17.12036. ISSN 0021-9258. PMID 10207026.
- ^ Hipp, Mark Steffen; Raasi Shahri, Groettrup Marcus, Schmidtke Gunter (Apr. 2004). "NEDD8 ultimate buster-1L interacts with the ubiquitin-like protein FAT10 and accelerates its degradation". J. Biol. Chem. (United States) 279 (16): 16503–10. DOI:10.1074/jbc.M310114200. ISSN 0021-9258. PMID 14757770.
- ^ Kamitani, T; Kito K, Fukuda-Kamitani T, Yeh E T (Dec. 2001). "Targeting of NEDD8 and its conjugates for proteasomal degradation by NUB1". J. Biol. Chem. (United States) 276 (49): 46655–60. DOI:10.1074/jbc.M108636200. ISSN 0021-9258. PMID 11585840.
- ^ Antenos, Monica; Casper Robert F, Brown Theodore J (Nov. 2002). "Interaction with Nedd8, a ubiquitin-like protein, enhances the transcriptional activity of the aryl hydrocarbon receptor". J. Biol. Chem. (United States) 277 (46): 44028–34. DOI:10.1074/jbc.M202413200. ISSN 0021-9258. PMID 12215427.
- ^ Wada, H; Kito K, Caskey L S, Yeh E T, Kamitani T (Oct. 1998). "Cleavage of the C-terminus of NEDD8 by UCH-L3". Biochem. Biophys. Res. Commun. (UNITED STATES) 251 (3): 688–92. DOI:10.1006/bbrc.1998.9532. ISSN 0006-291X. PMID 9790970.
Further reading [link]
- Kumar S, Tomooka Y, Noda M (1992). "Identification of a set of genes with developmentally down-regulated expression in the mouse brain.". Biochem. Biophys. Res. Commun. 185 (3): 1155–61. DOI:10.1016/0006-291X(92)91747-E. PMID 1378265.
- Kumar S, Yoshida Y, Noda M (1993). "Cloning of a cDNA which encodes a novel ubiquitin-like protein.". Biochem. Biophys. Res. Commun. 195 (1): 393–9. DOI:10.1006/bbrc.1993.2056. PMID 8395831.
- Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery.". Genome Res. 6 (9): 791–806. DOI:10.1101/gr.6.9.791. PMID 8889548.
- Osaka F, Kawasaki H, Aida N, et al. (1998). "A new NEDD8-ligating system for cullin-4A.". Genes Dev. 12 (15): 2263–8. DOI:10.1101/gad.12.15.2263. PMC 317039. PMID 9694792. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=317039.
- Wada H, Kito K, Caskey LS, et al. (1998). "Cleavage of the C-terminus of NEDD8 by UCH-L3.". Biochem. Biophys. Res. Commun. 251 (3): 688–92. DOI:10.1006/bbrc.1998.9532. PMID 9790970.
- Whitby FG, Xia G, Pickart CM, Hill CP (1999). "Crystal structure of the human ubiquitin-like protein NEDD8 and interactions with ubiquitin pathway enzymes.". J. Biol. Chem. 273 (52): 34983–91. DOI:10.1074/jbc.273.52.34983. PMID 9857030.
- Gong L, Yeh ET (1999). "Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway.". J. Biol. Chem. 274 (17): 12036–42. DOI:10.1074/jbc.274.17.12036. PMID 10207026.
- Gong L, Li B, Millas S, Yeh ET (1999). "Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex.". FEBS Lett. 448 (1): 185–9. DOI:10.1016/S0014-5793(99)00367-1. PMID 10217437.
- Liakopoulos D, Büsgen T, Brychzy A, et al. (1999). "Conjugation of the ubiquitin-like protein NEDD8 to cullin-2 is linked to von Hippel-Lindau tumor suppressor function.". Proc. Natl. Acad. Sci. U.S.A. 96 (10): 5510–5. DOI:10.1073/pnas.96.10.5510. PMC 21890. PMID 10318914. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=21890.
- Singer JD, Gurian-West M, Clurman B, Roberts JM (1999). "Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells.". Genes Dev. 13 (18): 2375–87. DOI:10.1101/gad.13.18.2375. PMC 317026. PMID 10500095. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=317026.
- Simeoni S, Mancini MA, Stenoien DL, et al. (2000). "Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract.". Hum. Mol. Genet. 9 (1): 133–44. DOI:10.1093/hmg/9.1.133. PMID 10587588.
- Hori T, Osaka F, Chiba T, et al. (2000). "Covalent modification of all members of human cullin family proteins by NEDD8.". Oncogene 18 (48): 6829–34. DOI:10.1038/sj.onc.1203093. PMID 10597293.
- Read MA, Brownell JE, Gladysheva TB, et al. (2000). "Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha.". Mol. Cell. Biol. 20 (7): 2326–33. DOI:10.1128/MCB.20.7.2326-2333.2000. PMC 85397. PMID 10713156. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=85397.
- Morimoto M, Nishida T, Honda R, Yasuda H (2000). "Modification of cullin-1 by ubiquitin-like protein Nedd8 enhances the activity of SCF(skp2) toward p27(kip1).". Biochem. Biophys. Res. Commun. 270 (3): 1093–6. DOI:10.1006/bbrc.2000.2576. PMID 10772955.
- Wada H, Yeh ET, Kamitani T (2000). "A dominant-negative UBC12 mutant sequesters NEDD8 and inhibits NEDD8 conjugation in vivo.". J. Biol. Chem. 275 (22): 17008–15. DOI:10.1074/jbc.275.22.17008. PMID 10828074.
- Venter JC, Adams MD, Myers EW, et al. (2001). "The sequence of the human genome.". Science 291 (5507): 1304–51. DOI:10.1126/science.1058040. PMID 11181995.
- Kito K, Yeh ET, Kamitani T (2001). "NUB1, a NEDD8-interacting protein, is induced by interferon and down-regulates the NEDD8 expression.". J. Biol. Chem. 276 (23): 20603–9. DOI:10.1074/jbc.M100920200. PMID 11259415.
- Kamitani T, Kito K, Fukuda-Kamitani T, Yeh ET (2002). "Targeting of NEDD8 and its conjugates for proteasomal degradation by NUB1.". J. Biol. Chem. 276 (49): 46655–60. DOI:10.1074/jbc.M108636200. PMID 11585840.
- Wu K, Chen A, Tan P, Pan ZQ (2002). "The Nedd8-conjugated ROC1-CUL1 core ubiquitin ligase utilizes Nedd8 charged surface residues for efficient polyubiquitin chain assembly catalyzed by Cdc34.". J. Biol. Chem. 277 (1): 516–27. DOI:10.1074/jbc.M108008200. PMID 11675391.
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