# NEDD8

## Overview
NEDD8 (neural precursor cell expressed, developmentally down-regulated 8) is a gene that encodes the ubiquitin-like protein NEDD8, which is involved in the post-translational modification of proteins through a process known as neddylation. Similar to ubiquitination, neddylation modifies cellular proteins to regulate their activity, stability, and localization, primarily impacting protein degradation pathways. The NEDD8 protein is particularly crucial for the activation of cullin-RING E3 ubiquitin ligases (CRLs), which play a significant role in various cellular processes including cell cycle control, signal transduction, and DNA repair. The dysregulation of NEDD8 pathways has been implicated in several diseases, including cancer, making it a potential target for therapeutic intervention (Pan2004Nedd8; Enchev2014Protein).

## Structure
NEDD8 is a ubiquitin-like protein that shares approximately 57% sequence identity with ubiquitin and possesses a similar molecular structure, including the conserved I44 hydrophobic patch (Stuber2021Structural). The primary structure of NEDD8 consists of 81 amino acids, with a notable C-terminal tail that undergoes significant reorientation during interactions with specific enzymes such as the E1 activating enzyme (Kitahara2006Evolutionally). 

The secondary structure of NEDD8 includes alpha helices and beta sheets, which are typical of the ubiquitin-like protein family (Santonico2020Old). These elements contribute to the β-grasp fold, a common feature among ubiquitin-like proteins, which is crucial for their function in protein modification processes. 

In terms of tertiary structure, NEDD8 and ubiquitin exhibit almost identical folded structures with a root mean square deviation (RMSD) of approximately 0.6 Å between the main chain atoms of the two proteins, indicating highly similar three-dimensional conformations (Kitahara2006Evolutionally).

Information on the quaternary structure of NEDD8, involving its interaction or assembly with other protein molecules, is not detailed in the provided excerpts. Similarly, specific domains beyond the general ubiquitin-like fold and post-translational modifications such as phosphorylation at serine 65, which affects the structural dynamics and function of NEDD8, are mentioned (Stuber2021Structural). However, details on splice variant isoforms are not provided in the context.

## Function
NEDD8 (neural precursor cell expressed, developmentally down-regulated 8) is a ubiquitin-like protein that plays a critical role in the regulation of protein degradation within cells. This process, known as neddylation, involves the conjugation of NEDD8 to specific lysine residues on target proteins, primarily cullin proteins, which are part of the cullin-RING E3 ubiquitin ligases (CRLs). Neddylation enhances the activity of these ligases, promoting the ubiquitination and subsequent degradation of various substrates involved in cell cycle regulation, DNA repair, and other critical cellular processes (Pan2004Nedd8; Enchev2014Protein).

NEDD8 modifies its substrates by covalently attaching to them, influencing their activity and stability. This modification is mediated by a series of enzymes including E1 (activating), E2 (conjugating), and E3 (ligating) enzymes (Enchev2014Protein). The neddylation pathway is crucial for several biological processes including cell division, signal transduction, and development. Defects in neddylation, such as mutations in components of the NEDD8 pathway or in the cullin proteins themselves, can lead to stabilization of SCF substrates and subsequent cellular dysfunctions, as observed in various model organisms (Pan2004Nedd8).

In addition to its role with CRLs, NEDD8 has been implicated in other biological functions as recent studies suggest the existence of non-cullin neddylation targets. However, the validation of these targets is complicated by the fact that overexpression of NEDD8 can lead to its conjugation through the ubiquitylation machinery, a process not typically associated with normal cellular function (Enchev2014Protein).

## Clinical Significance
NEDD8 has been implicated in various cancers, where its dysregulation plays a critical role in disease progression and prognosis. In nasopharyngeal carcinoma (NPC), elevated expression of NEDD8 correlates with poor patient outcomes, including lower overall survival and disease-free survival rates. High NEDD8 levels are associated with increased risk of death and lymph node metastasis, suggesting its potential as a therapeutic target (Xie2017Promoting). Similarly, in bladder cancer, overexpression of NEDD8 is linked to worse overall survival, advanced tumor stages, distant metastasis, and vascular invasion, indicating its role in tumor progression (Tian2018Neural). Breast cancer studies also show that NEDD8 and its activating enzymes are overexpressed, correlating with poor prognosis and suggesting a mechanism where NEDD8 contributes to tumorigenesis by facilitating the downregulation of tumor suppressive proteins (Naik2020NEDDylation). Furthermore, in colorectal cancer, NEDD8 activation of the Smurf1 ubiquitin ligase is essential for tumorigenesis, with high expression levels of NEDD8 correlating with cancer progression (Xie2014The). These findings across different cancer types underscore the clinical significance of NEDD8 as a potential marker for prognosis and a target for therapeutic intervention.

## Interactions
NEDD8 interacts with a variety of proteins through neddylation, a process analogous to ubiquitination. It modifies the activity, location, or stability of these proteins, notably the cullin components of Cullin-RING E3 ubiquitin ligases (CRLs). Neddylation of cullins, facilitated by E1, E2, and E3 enzymes, enhances their ability to ubiquitinate substrates, affecting various cellular processes including cell cycle and signal transduction (Watson2011NEDD8; Rabut2008Function).

NEDD8 also forms a thioester bond with the NEDD8-conjugating enzyme UBE2F, which is charged by the NEDD8-specific E1 enzyme complex NAE1-UBA3. This interaction is crucial for the activation of cullin-based ubiquitin ligases (Huang2009E2-RING). Additionally, NEDD8 competes with ubiquitin for lysine residues on substrates like EGFR, affecting protein stability and function (Rabut2008Function).

In the context of protein degradation, NEDD8 is involved in the regulation of the 26 S proteasome through its interaction with the adaptor protein NUB1, which links NEDD8 conjugates to the proteasome, facilitating their degradation (Kamitani2001Targeting). This interaction highlights the role of NEDD8 not only in protein modification but also in the targeted degradation of proteins, integrating NEDD8 into broader cellular regulatory networks.


## References


[1. (Stuber2021Structural) Katrin Stuber, Tobias Schneider, Jill Werner, Michael Kovermann, Andreas Marx, and Martin Scheffner. Structural and functional consequences of nedd8 phosphorylation. Nature Communications, October 2021. URL: http://dx.doi.org/10.1038/s41467-021-26189-9, doi:10.1038/s41467-021-26189-9. (17 citations) 10.1038/s41467-021-26189-9](https://doi.org/10.1038/s41467-021-26189-9)

[2. (Xie2017Promoting) Ping Xie, Jun-Ping Yang, Yun Cao, Li-Xia Peng, Li-Sheng Zheng, Rui Sun, Dong-Fang Meng, Meng-Yao Wang, Yan Mei, Yuan-Yuan Qiang, Li Cao, Yan-Qun Xiang, Dong-Hua Luo, Jing-Ping Yun, Bi-Jun Huang, Li-Jun Jia, and Chao-Nan Qian. Promoting tumorigenesis in nasopharyngeal carcinoma, nedd8 serves as a potential theranostic target. Cell Death & Disease, 8(6):e2834–e2834, June 2017. URL: http://dx.doi.org/10.1038/cddis.2017.195, doi:10.1038/cddis.2017.195. (45 citations) 10.1038/cddis.2017.195](https://doi.org/10.1038/cddis.2017.195)

[3. (Xie2014The) Ping Xie, Minghua Zhang, Shan He, Kefeng Lu, Yuhan Chen, Guichun Xing, Yiming Lu, Ping Liu, Yang Li, Shaoxia Wang, Nan Chai, Jiawei Wu, Haiteng Deng, Hong-Rui Wang, Yu Cao, Fei Zhao, Yu Cui, Jian Wang, Fuchu He, and Lingqiang Zhang. The covalent modifier nedd8 is critical for the activation of smurf1 ubiquitin ligase in tumorigenesis. Nature Communications, May 2014. URL: http://dx.doi.org/10.1038/ncomms4733, doi:10.1038/ncomms4733. (189 citations) 10.1038/ncomms4733](https://doi.org/10.1038/ncomms4733)

[4. (Huang2009E2-RING) Danny T. Huang, Olivier Ayrault, Harold W. Hunt, Asad M. Taherbhoy, David M. Duda, Daniel C. Scott, Laura A. Borg, Geoffrey Neale, Peter J. Murray, Martine F. Roussel, and Brenda A. Schulman. E2-ring expansion of the nedd8 cascade confers specificity to cullin modification. Molecular Cell, 33(4):483–495, February 2009. URL: http://dx.doi.org/10.1016/j.molcel.2009.01.011, doi:10.1016/j.molcel.2009.01.011. (216 citations) 10.1016/j.molcel.2009.01.011](https://doi.org/10.1016/j.molcel.2009.01.011)

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[7. (Kitahara2006Evolutionally) Ryo Kitahara, Yoshiki Yamaguchi, Eri Sakata, Takeshi Kasuya, Keiji Tanaka, Koichi Kato, Shigeyuki Yokoyama, and Kazuyuki Akasaka. Evolutionally conserved intermediates between ubiquitin and nedd8. Journal of Molecular Biology, 363(2):395–404, October 2006. URL: http://dx.doi.org/10.1016/j.jmb.2006.07.074, doi:10.1016/j.jmb.2006.07.074. (37 citations) 10.1016/j.jmb.2006.07.074](https://doi.org/10.1016/j.jmb.2006.07.074)

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[13. (Kamitani2001Targeting) Tetsu Kamitani, Katsumi Kito, Taeko Fukuda-Kamitani, and Edward T.H. Yeh. Targeting of nedd8 and its conjugates for proteasomal degradation by nub1. Journal of Biological Chemistry, 276(49):46655–46660, December 2001. URL: http://dx.doi.org/10.1074/jbc.m108636200, doi:10.1074/jbc.m108636200. (115 citations) 10.1074/jbc.m108636200](https://doi.org/10.1074/jbc.m108636200)