ID NEDD8_HUMAN Reviewed; 81 AA. AC Q15843; Q3SXN8; Q6LES6; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 11-NOV-2015, entry version 146. DE RecName: Full=NEDD8; DE AltName: Full=Neddylin; DE AltName: Full=Neural precursor cell expressed developmentally down-regulated protein 8; DE Short=NEDD-8; DE AltName: Full=Ubiquitin-like protein Nedd8; DE Flags: Precursor; GN Name=NEDD8; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBUNIT. RC TISSUE=Fibrosarcoma; RX PubMed=9694792; DOI=10.1101/gad.12.15.2263; RA Osaka F., Kawasaki H., Aida N., Saeki M., Chiba T., Kawashima S., RA Tanaka K., Kato S.; RT "A new NEDD8-ligating system for cullin-4A."; RL Genes Dev. 12:2263-2268(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP PROTEIN SEQUENCE OF 1-21, FUNCTION, AND SUBUNIT. RX PubMed=10318914; DOI=10.1073/pnas.96.10.5510; RA Liakopoulos D., Buesgen T., Brychzy A., Jentsch S., Pause A.; RT "Conjugation of the ubiquitin-like protein NEDD8 to cullin-2 is linked RT to von Hippel-Lindau tumor suppressor function."; RL Proc. Natl. Acad. Sci. U.S.A. 96:5510-5515(1999). RN [5] RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND CLEAVAGE SITE. RX PubMed=9353319; DOI=10.1074/jbc.272.45.28557; RA Kamitani T., Kito K., Nguyen H.P., Yeh E.T.H.; RT "Characterization of NEDD8, a developmentally down-regulated RT ubiquitin-like protein."; RL J. Biol. Chem. 272:28557-28562(1997). RN [6] RP CLEAVAGE BY UCHL3. RX PubMed=9790970; DOI=10.1006/bbrc.1998.9532; RA Wada H., Kito K., Caskey L.S., Yeh E.T.H., Kamitani T.; RT "Cleavage of the C-terminus of NEDD8 by UCH-L3."; RL Biochem. Biophys. Res. Commun. 251:688-692(1998). RN [7] RP FUNCTION, SUBUNIT, AND TISSUE SPECIFICITY. RX PubMed=10597293; DOI=10.1038/sj.onc.1203093; RA Hori T., Osaka F., Chiba T., Miyamoto C., Okabayashi K., Shimbara N., RA Kato S., Tanaka K.; RT "Covalent modification of all members of human cullin family proteins RT by NEDD8."; RL Oncogene 18:6829-6834(1999). RN [8] RP INTERACTION WITH NUB1. RX PubMed=11259415; DOI=10.1074/jbc.M100920200; RA Kito K., Yeh E.T.H., Kamitani T.; RT "NUB1, a NEDD8-interacting protein, is induced by interferon and down- RT regulates the NEDD8 expression."; RL J. Biol. Chem. 276:20603-20609(2001). RN [9] RP FUNCTION. RX PubMed=11953428; DOI=10.1074/jbc.M200967200; RA Amir R.E., Iwai K., Ciechanover A.; RT "The NEDD8 pathway is essential for SCF(beta -TrCP)-mediated RT ubiquitination and processing of the NF-kappa B precursor p105."; RL J. Biol. Chem. 277:23253-23259(2002). RN [10] RP INTERACTION WITH AHR. RX PubMed=12215427; DOI=10.1074/jbc.M202413200; RA Antenos M., Casper R.F., Brown T.J.; RT "Interaction with Nedd8, a ubiquitin-like protein, enhances the RT transcriptional activity of the aryl hydrocarbon receptor."; RL J. Biol. Chem. 277:44028-44034(2002). RN [11] RP CLEAVAGE BY SENP8. RX PubMed=12730221; DOI=10.1074/jbc.M212948200; RA Mendoza H.M., Shen L.-N., Botting C., Lewis A., Chen J., Ink B., RA Hay R.T.; RT "NEDP1, a highly conserved cysteine protease that deneddylates RT cullins."; RL J. Biol. Chem. 278:25637-25643(2003). RN [12] RP CLEAVAGE BY SENP8. RX PubMed=12759363; DOI=10.1074/jbc.M302888200; RA Wu K., Yamoah K., Dolios G., Gan-Erdene T., Tan P., Chen A., RA Lee C.-G., Wei N., Wilkinson K.D., Wang R., Pan Z.-Q.; RT "DEN1 is a dual function protease capable of processing the C-terminus RT of Nedd8 and deconjugating hyper-neddylated CUL1."; RL J. Biol. Chem. 278:28882-28891(2003). RN [13] RP SUBUNIT. RX PubMed=15242646; DOI=10.1016/j.cell.2004.06.016; RA Xirodimas D.P., Saville M.K., Bourdon J.-C., Hay R.T., Lane D.P.; RT "Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional RT activity."; RL Cell 118:83-97(2004). RN [14] RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS). RX PubMed=9857030; DOI=10.1074/jbc.273.52.34983; RA Whitby F.G., Xia G., Pickart C.M., Hill C.P.; RT "Crystal structure of the human ubiquitin-like protein NEDD8 and RT interactions with ubiquitin pathway enzymes."; RL J. Biol. Chem. 273:34983-34991(1998). RN [15] RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 1-76 IN COMPLEX WITH UBE1C; RP APPBP1 AND ATP, AND MUTAGENESIS OF ALA-72. RX PubMed=14690597; DOI=10.1016/S1097-2765(03)00452-0; RA Walden H., Podgorski M.S., Huang D.T., Miller D.W., Howard R.J., RA Minor D.L. Jr., Holton J.M., Schulman B.A.; RT "The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis RT for selective ubiquitin-like protein activation by an E1."; RL Mol. Cell 12:1427-1437(2003). RN [16] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-76 IN COMPLEX WITH SENP8. RX PubMed=15567417; DOI=10.1016/j.jmb.2004.10.022; RA Reverter D., Wu K., Erdene T.G., Pan Z.-Q., Wilkinson K.D., Lima C.D.; RT "Structure of a complex between Nedd8 and the Ulp/Senp protease family RT member Den1."; RL J. Mol. Biol. 345:141-151(2005). CC -!- FUNCTION: Ubiquitin-like protein which plays an important role in CC cell cycle control and embryogenesis. Covalent attachment to its CC substrates requires prior activation by the E1 complex UBE1C- CC APPBP1 and linkage to the E2 enzyme UBE2M. Attachment of NEDD8 to CC cullins activates their associated E3 ubiquitin ligase activity, CC and thus promotes polyubiquitination and proteasomal degradation CC of cyclins and other regulatory proteins. CC {ECO:0000269|PubMed:10318914, ECO:0000269|PubMed:10597293, CC ECO:0000269|PubMed:11953428}. CC -!- SUBUNIT: Directly interacts with NUB1 and AHR. Covalently attached CC to cullins and p53. {ECO:0000269|PubMed:10318914, CC ECO:0000269|PubMed:10597293, ECO:0000269|PubMed:11259415, CC ECO:0000269|PubMed:12215427, ECO:0000269|PubMed:14690597, CC ECO:0000269|PubMed:15242646, ECO:0000269|PubMed:15567417, CC ECO:0000269|PubMed:9694792}. CC -!- INTERACTION: CC Q9Y297:BTRC; NbExp=2; IntAct=EBI-716247, EBI-307461; CC Q13616:CUL1; NbExp=8; IntAct=EBI-716247, EBI-359390; CC P62913:RPL11; NbExp=4; IntAct=EBI-716247, EBI-354380; CC P18124:RPL7; NbExp=2; IntAct=EBI-716247, EBI-350806; CC P60866:RPS20; NbExp=2; IntAct=EBI-716247, EBI-353105; CC P23396:RPS3; NbExp=2; IntAct=EBI-716247, EBI-351193; CC P62081:RPS7; NbExp=2; IntAct=EBI-716247, EBI-354360; CC Q8WXE9:STON2; NbExp=2; IntAct=EBI-716247, EBI-539742; CC P61081:UBE2M; NbExp=3; IntAct=EBI-716247, EBI-1041660; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:9353319}. CC Note=Mainly nuclear. CC -!- TISSUE SPECIFICITY: Highly expressed in heart, skeletal muscle, CC spleen, thymus, prostate, testis, ovary, colon and leukocytes. CC {ECO:0000269|PubMed:10597293, ECO:0000269|PubMed:9353319}. CC -!- PTM: Cleavage of precursor form by UCHL3 or SENP8 is necessary for CC function. CC -!- SIMILARITY: Belongs to the ubiquitin family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D23662; BAA04889.1; -; mRNA. DR EMBL; CR407662; CAG28590.1; -; mRNA. DR EMBL; BC104200; AAI04201.1; -; mRNA. DR EMBL; BC104201; AAI04202.1; -; mRNA. DR EMBL; BC104664; AAI04665.1; -; mRNA. DR CCDS; CCDS9621.1; -. DR RefSeq; NP_006147.1; NM_006156.2. DR UniGene; Hs.531064; -. DR PDB; 1NDD; X-ray; 1.60 A; A/B/C/D=1-76. DR PDB; 1R4M; X-ray; 3.00 A; I/J/K/L=1-76. DR PDB; 1R4N; X-ray; 3.60 A; I/J/K/L=1-76. DR PDB; 1XT9; X-ray; 2.20 A; B=1-76. DR PDB; 2BKR; X-ray; 1.90 A; B=1-76. DR PDB; 2KO3; NMR; -; A=1-76. DR PDB; 2NVU; X-ray; 2.80 A; I/J=1-76. DR PDB; 3DBH; X-ray; 2.85 A; I/J/K/L=1-76. DR PDB; 3DBL; X-ray; 2.90 A; I/J/K/L=1-76. DR PDB; 3DBR; X-ray; 3.05 A; I/J/K/L=1-76. DR PDB; 3DQV; X-ray; 3.00 A; A/B=1-76. DR PDB; 3GZN; X-ray; 3.00 A; I/J=1-76. DR PDB; 4F8C; X-ray; 1.95 A; B/D=1-81. DR PDB; 4FBJ; X-ray; 1.60 A; B=1-81. DR PDB; 4HCP; X-ray; 2.52 A; B=1-76. DR PDB; 4P5O; X-ray; 3.11 A; H/K=1-76. DR PDBsum; 1NDD; -. DR PDBsum; 1R4M; -. DR PDBsum; 1R4N; -. DR PDBsum; 1XT9; -. DR PDBsum; 2BKR; -. DR PDBsum; 2KO3; -. DR PDBsum; 2NVU; -. DR PDBsum; 3DBH; -. DR PDBsum; 3DBL; -. DR PDBsum; 3DBR; -. DR PDBsum; 3DQV; -. DR PDBsum; 3GZN; -. DR PDBsum; 4F8C; -. DR PDBsum; 4FBJ; -. DR PDBsum; 4HCP; -. DR PDBsum; 4P5O; -. DR ProteinModelPortal; Q15843; -. DR SMR; Q15843; 1-76. DR BioGrid; 110815; 245. DR DIP; DIP-29266N; -. DR IntAct; Q15843; 89. DR MINT; MINT-268324; -. DR STRING; 9606.ENSP00000250495; -. DR PhosphoSite; Q15843; -. DR BioMuta; NEDD8; -. DR DMDM; 2833270; -. DR MaxQB; Q15843; -. DR PaxDb; Q15843; -. DR PeptideAtlas; Q15843; -. DR PRIDE; Q15843; -. DR Ensembl; ENST00000250495; ENSP00000250495; ENSG00000129559. DR GeneID; 4738; -. DR KEGG; hsa:4738; -. DR UCSC; uc001wnn.2; human. DR CTD; 4738; -. DR GeneCards; NEDD8; -. DR HGNC; HGNC:7732; NEDD8. DR HPA; CAB004082; -. DR MIM; 603171; gene. DR neXtProt; NX_Q15843; -. DR PharmGKB; PA31537; -. DR eggNOG; KOG0005; Eukaryota. DR eggNOG; COG5272; LUCA. DR GeneTree; ENSGT00660000095622; -. DR HOGENOM; HOG000233942; -. DR HOVERGEN; HBG000057; -. DR InParanoid; Q15843; -. DR KO; K12158; -. DR OMA; KLAPPRH; -. DR OrthoDB; EOG7JDR1W; -. DR PhylomeDB; Q15843; -. DR TreeFam; TF300072; -. DR Reactome; R-HSA-2173789; TGF-beta receptor signaling activates SMADs. DR EvolutionaryTrace; Q15843; -. DR GeneWiki; NEDD8; -. DR GenomeRNAi; 4738; -. DR NextBio; 18272; -. DR PMAP-CutDB; Q15843; -. DR PRO; PR:Q15843; -. DR Proteomes; UP000005640; Chromosome 14. DR Bgee; Q15843; -. DR CleanEx; HS_NEDD8; -. DR ExpressionAtlas; Q15843; baseline and differential. DR Genevisible; Q15843; HS. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; TAS:ProtInc. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc. DR GO; GO:0006464; P:cellular protein modification process; TAS:ProtInc. DR GO; GO:0008104; P:protein localization; IEA:Ensembl. DR GO; GO:0045116; P:protein neddylation; IDA:MGI. DR GO; GO:0006508; P:proteolysis; TAS:ProtInc. DR GO; GO:0006357; P:regulation of transcription from RNA polymerase II promoter; IEA:Ensembl. DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc. DR InterPro; IPR019956; Ubiquitin. DR InterPro; IPR029071; Ubiquitin-rel_dom. DR InterPro; IPR019954; Ubiquitin_CS. DR InterPro; IPR000626; Ubiquitin_dom. DR Pfam; PF00240; ubiquitin; 1. DR PRINTS; PR00348; UBIQUITIN. DR SMART; SM00213; UBQ; 1. DR SUPFAM; SSF54236; SSF54236; 1. DR PROSITE; PS00299; UBIQUITIN_1; 1. DR PROSITE; PS50053; UBIQUITIN_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Complete proteome; KW Direct protein sequencing; Isopeptide bond; Nucleus; KW Reference proteome; Ubl conjugation pathway. FT CHAIN 1 76 NEDD8. FT /FTId=PRO_0000042767. FT PROPEP 77 81 FT /FTId=PRO_0000042768. FT REGION 70 72 Interaction with UBE1C. FT SITE 8 8 Interaction with UBE1C. FT SITE 44 44 Interaction with UBE1C. FT MOD_RES 48 48 N6-acetyllysine. FT {ECO:0000250|UniProtKB:P29595}. FT CROSSLNK 76 76 Glycyl lysine isopeptide (Gly-Lys) FT (interchain with K-? in acceptor FT proteins). FT MUTAGEN 72 72 A->R: Prevents adenylation by UBE1C. FT {ECO:0000269|PubMed:14690597}. FT CONFLICT 15 15 I -> V (in Ref. 2; CAG28590). FT {ECO:0000305}. FT STRAND 2 6 {ECO:0000244|PDB:1NDD}. FT STRAND 8 10 {ECO:0000244|PDB:4P5O}. FT STRAND 12 16 {ECO:0000244|PDB:1NDD}. FT HELIX 23 34 {ECO:0000244|PDB:1NDD}. FT HELIX 38 40 {ECO:0000244|PDB:1NDD}. FT STRAND 41 45 {ECO:0000244|PDB:1NDD}. FT STRAND 52 55 {ECO:0000244|PDB:2NVU}. FT HELIX 56 59 {ECO:0000244|PDB:1NDD}. FT STRAND 66 71 {ECO:0000244|PDB:1NDD}. FT STRAND 73 75 {ECO:0000244|PDB:1XT9}. SQ SEQUENCE 81 AA; 9072 MW; DC2FE102BE4725D2 CRC64; MLIKVKTLTG KEIEIDIEPT DKVERIKERV EEKEGIPPQQ QRLIYSGKQM NDEKTAADYK ILGGSVLHLV LALRGGGGLR Q //