NEDD8

Template:PBB NEDD8 is a protein that in humans is encoded by the NEDD8 gene. (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 most substrates of NEDD8 modification are the Cullin subunits of Cullin-based E3 ubiquitin ligases, which are active only when neddylated. Their NEDDylation 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.

Activation and conjugation

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.

Removal

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).

Interactions

NEDD8 has been shown to interact with:

• Aryl hydrocarbon receptor,
• NUB1,
• UBE1C,
• UBE2M, and
• UCHL3.

Further reading

• Xirodimas DP (Oct 2008). "Novel substrates and functions for the ubiquitin-like molecule NEDD8". Biochemical Society Transactions. 36 (Pt 5): 802–6. doi:10.1042/BST0360802. PMID 18793140.
• Kumar S, Tomooka Y, Noda M (Jun 1992). "Identification of a set of genes with developmentally down-regulated expression in the mouse brain". Biochemical and Biophysical Research Communications. 185 (3): 1155–61. doi:10.1016/0006-291X(92)91747-E. PMID 1378265.
• Kumar S, Yoshida Y, Noda M (Aug 1993). "Cloning of a cDNA which encodes a novel ubiquitin-like protein". Biochemical and Biophysical Research Communications. 195 (1): 393–9. doi:10.1006/bbrc.1993.2056. PMID 8395831.
• Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Osaka F, Kawasaki H, Aida N, Saeki M, Chiba T, Kawashima S, Tanaka K, Kato S (Aug 1998). "A new NEDD8-ligating system for cullin-4A". Genes & Development. 12 (15): 2263–8. doi:10.1101/gad.12.15.2263. PMC 317039. PMID 9694792.
• Wada H, Kito K, Caskey LS, Yeh ET, Kamitani T (Oct 1998). "Cleavage of the C-terminus of NEDD8 by UCH-L3". Biochemical and Biophysical Research Communications. 251 (3): 688–92. doi:10.1006/bbrc.1998.9532. PMID 9790970.
• Whitby FG, Xia G, Pickart CM, Hill CP (Dec 1998). "Crystal structure of the human ubiquitin-like protein NEDD8 and interactions with ubiquitin pathway enzymes". The Journal of Biological Chemistry. 273 (52): 34983–91. doi:10.1074/jbc.273.52.34983. PMID 9857030.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Gong L, Yeh ET (Apr 1999). "Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway". The Journal of Biological Chemistry. 274 (17): 12036–42. doi:10.1074/jbc.274.17.12036. PMID 10207026.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Gong L, Li B, Millas S, Yeh ET (Apr 1999). "Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex". FEBS Letters. 448 (1): 185–9. doi:10.1016/S0014-5793(99)00367-1. PMID 10217437.
• Liakopoulos D, Büsgen T, Brychzy A, Jentsch S, Pause A (May 1999). "Conjugation of the ubiquitin-like protein NEDD8 to cullin-2 is linked to von Hippel-Lindau tumor suppressor function". Proceedings of the National Academy of Sciences of the United States of America. 96 (10): 5510–5. doi:10.1073/pnas.96.10.5510. PMC 21890. PMID 10318914.
• Singer JD, Gurian-West M, Clurman B, Roberts JM (Sep 1999). "Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells". Genes & Development. 13 (18): 2375–87. doi:10.1101/gad.13.18.2375. PMC 317026. PMID 10500095.
• Simeoni S, Mancini MA, Stenoien DL, Marcelli M, Weigel NL, Zanisi M, Martini L, Poletti A (Jan 2000). "Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract". Human Molecular Genetics. 9 (1): 133–44. doi:10.1093/hmg/9.1.133. PMID 10587588.
• Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S, Tanaka K (Nov 1999). "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, Hottelet M, Parent LA, Coggins MB, Pierce JW, Podust VN, Luo RS, Chau V, Palombella VJ (Apr 2000). "Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha". Molecular and Cellular Biology. 20 (7): 2326–33. doi:10.1128/MCB.20.7.2326-2333.2000. PMC 85397. PMID 10713156.
• Morimoto M, Nishida T, Honda R, Yasuda H (Apr 2000). "Modification of cullin-1 by ubiquitin-like protein Nedd8 enhances the activity of SCF(skp2) toward p27(kip1)". Biochemical and Biophysical Research Communications. 270 (3): 1093–6. doi:10.1006/bbrc.2000.2576. PMID 10772955.
• Wada H, Yeh ET, Kamitani T (Jun 2000). "A dominant-negative UBC12 mutant sequesters NEDD8 and inhibits NEDD8 conjugation in vivo". The Journal of Biological Chemistry. 275 (22): 17008–15. doi:10.1074/jbc.275.22.17008. PMID 10828074.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Kito K, Yeh ET, Kamitani T (Jun 2001). "NUB1, a NEDD8-interacting protein, is induced by interferon and down-regulates the NEDD8 expression". The Journal of Biological Chemistry. 276 (23): 20603–9. doi:10.1074/jbc.M100920200. PMID 11259415.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Kamitani T, Kito K, Fukuda-Kamitani T, Yeh ET (Dec 2001). "Targeting of NEDD8 and its conjugates for proteasomal degradation by NUB1". The Journal of Biological Chemistry. 276 (49): 46655–60. doi:10.1074/jbc.M108636200. PMID 11585840.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Wu K, Chen A, Tan P, Pan ZQ (Jan 2002). "The Nedd8-conjugated ROC1-CUL1 core ubiquitin ligase utilizes Nedd8 charged surface residues for efficient polyubiquitin chain assembly catalyzed by Cdc34". The Journal of Biological Chemistry. 277 (1): 516–27. doi:10.1074/jbc.M108008200. PMID 11675391.{{cite journal}}: CS1 maint: unflagged free DOI (link)