NEDD8

Summary

NEDD8 (NEDD8 ubiquitin like modifier, HGNC:7732) is a protein-coding gene on chromosome 14q12, encoding Ubiquitin-like protein NEDD8 (Q15843). Ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis via its conjugation to a limited number of cellular proteins, such as cullins or p53/TP53. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

Enables ubiquitin protein ligase binding activity. Acts upstream of or within protein neddylation. Located in cytosol and nucleoplasm. Biomarker of Parkinson’s disease and malignant astrocytoma.

Source: NCBI Gene 4738 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_006156

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7732
Approved symbol	NEDD8
Name	NEDD8 ubiquitin like modifier
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	Nedd-8
Ensembl gene	ENSG00000129559
Ensembl biotype	protein_coding
OMIM	603171
Entrez	4738

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000250495, ENST00000396828, ENST00000524927, ENST00000526430, ENST00000527046, ENST00000531430, ENST00000533242, ENST00000560427, ENST00000895442, ENST00000939190, ENST00000939191, ENST00000939192

RefSeq mRNA: 1 — MANE Select: NM_006156 NM_006156

CCDS: CCDS9621

Canonical transcript exons

ENST00000250495 — 4 exons

Exon	Start	End
ENSE00001101093	24232250	24232367
ENSE00001549615	24216857	24217223
ENSE00003473952	24218384	24218431
ENSE00003627654	24218133	24218215

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 127.2698 / max 1883.5826, expressed in 1826 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142556	127.2698	1826

Top tissues by expression

134 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	99.39	gold quality
superior frontal gyrus	UBERON:0002661	99.39	gold quality
frontal cortex	UBERON:0001870	99.36	gold quality
right frontal lobe	UBERON:0002810	99.33	gold quality
anterior cingulate cortex	UBERON:0009835	99.33	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.32	gold quality
cerebral cortex	UBERON:0000956	99.30	gold quality
nucleus accumbens	UBERON:0001882	99.30	gold quality
primary visual cortex	UBERON:0002436	99.29	gold quality
apex of heart	UBERON:0002098	99.28	gold quality
hypothalamus	UBERON:0001898	99.27	gold quality
caudate nucleus	UBERON:0001873	99.26	gold quality
putamen	UBERON:0001874	99.26	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.22	gold quality
right adrenal gland	UBERON:0001233	99.21	gold quality
left adrenal gland	UBERON:0001234	99.21	gold quality
temporal lobe	UBERON:0001871	99.20	gold quality
amygdala	UBERON:0001876	99.20	gold quality
left adrenal gland cortex	UBERON:0035825	99.18	gold quality
islet of Langerhans	UBERON:0000006	99.17	gold quality
substantia nigra	UBERON:0002038	99.17	gold quality
right adrenal gland cortex	UBERON:0035827	99.17	gold quality
brain	UBERON:0000955	99.15	gold quality
Ammon’s horn	UBERON:0001954	99.12	gold quality
heart left ventricle	UBERON:0002084	99.12	gold quality
stromal cell of endometrium	CL:0002255	99.11	gold quality
granulocyte	CL:0000094	99.09	gold quality
adrenal gland	UBERON:0002369	99.06	gold quality
metanephros cortex	UBERON:0010533	99.03	gold quality
heart	UBERON:0000948	99.02	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7606	no	243.91
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT3B, EPAS1, HIF1A

miRNA regulators (miRDB)

31 targeting NEDD8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-3945	98.68	64.21	553
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-4482-5P	97.53	65.68	598
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-1288-3P	96.86	66.95	536
HSA-MIR-500B-3P	96.49	65.40	1087
HSA-MIR-6858-3P	96.37	64.41	771
HSA-MIR-3657	96.33	66.29	608
HSA-MIR-6805-5P	95.79	64.86	670
HSA-MIR-5586-3P	95.51	67.00	805
HSA-MIR-4693-3P	95.23	65.92	735
HSA-MIR-3679-5P	94.75	66.46	862
HSA-MIR-1185-5P	94.47	65.95	725

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• NEDDylation is required for conjugation and processing of p105 by SCF(beta-TrCP) following phosphorylation of the molecule (PMID:11953428)
• p120(CAND1) selectively binds to unneddylated CUL1 and is dissociated by CUL1 neddylation (PMID:12504025)
• Disruptions in the NEDD8 pathway provide a mechanism by which breast cancer cells acquire antiestrogen resistance while retaining expression of ERalpha. (PMID:12554766)
• structure and mutational analysis of human APPBP1-UBA3, the heterodimeric E1 enzyme for NEDD8 (PMID:12646924)
• Conservation in the mechanism of Nedd8 activation by the AppBp1-Uba3 heterodimer. (PMID:12740388)
• results suggest a unique role for NEDD8-specific protease 1(DEN1) in regulating the modification of cullin 1 by Nedd8 protein (PMID:12759363)
• An analysis of the NEDD8 modification on beta-TrCP ubiquitin ligase was made. (PMID:14676825)
• Data report the structure of the quaternary complex between human APPBP1-UBA3, a heterodimeric E1, its ubl NEDD8, and ATP. (PMID:14690597)
• crystal structure of a complex between the C-terminal domain from NEDD8’s heterodimeric E1 (APPBP1-UBA3) and the catalytic core domain of NEDD8’s E2 (Ubc12) (PMID:15694336)
• ubiquitin ligase of EGFR, namely c-Cbl, also mediates receptor modification with the ubiquitin-like molecule Nedd8 (PMID:16735510)
• Results describe the regulation of neddylation and deneddylation of cullin1 by Nedd8 in SCFSkp2 ubiquitin ligase by F-box protein and substrate. (PMID:16861300)
• Data show that NEDD8 and ubiquitin have similar conformational fluctuation in the evolutionary conserved enzyme-binding region and contain a structurally similar locally disordered conformer (I) in equilibrium with the basic folded conformer (N). (PMID:16979187)
• FBXO11 promotes the Neddylation (NEDD8) of p53 and inhibits its transcriptional activity (PMID:17098746)
• NEDD8 and ubiquitin function in a redundant manner in controlling receptor endocytic pathways. (PMID:17119158)
• NEDD8 modification of Cul2 has a role in the sequential activation of the ECV E3 ubiquitin ligase complex (PMID:17132228)
• Up-regulation of the NEDD8 conjugation is associated with oral squamous cell carcinoma (PMID:17660949)
• A new molecular interaction between wild-type ataxin-3 and NEDD8, using in vitro and in situ approaches, is reported. (PMID:17935801)
• These results illustrate the regulatory mechanisms by which AICD transcriptional activity might be regulated via covalent conjugation with Nedd8. (PMID:18096514)
• The basis for Ubiquitin-like proteins (UBL) selection by UBL conjugating enzyme 12 (Ubc12), which is specific for the neural precursor cell expressed, developmentally down-regulated protein 8 (NEDD8). (PMID:18264111)
• These studies identify a novel and specific role of the NEDD8 pathway in protecting a subset of ribosomal proteins from destabilization. (PMID:18274552)
• NEDD8 acts as a ‘molecular switch’ defining the functional selectivity of VHL. (PMID:18323857)
• X-ray crystallographic analysis of APPBP1-UBA3-NEDD8 shows that APPBP1-UBA3’s preference for NEDD8’s Ala72 appears to be indirect, due to proper positioning of UBA3’s Arg190. (PMID:18652489)
• SCF may be subject to autoinhibitory regulation, in which Nedd8 conjugation acts as a molecular switch to drive the E3 into an active state by diminishing the inhibitory ECTD x ROC1 interaction (PMID:18723677)
• Study reports striking conformational rearrangements in the crystal structure of NEDD8Cul5(ctd)-Rbx1 and SAXS analysis of NEDD8Cul1(ctd)-Rbx1 relative to their unmodified counterparts. (PMID:18805092)
• SCCRO recruits Ubc12 approximately NEDD8 to the CAND1-Cul1-ROC1 complex but that this is not sufficient to dissociate or overcome the inhibitory effects of CAND1 on cullin neddylation (PMID:18826954)
• diverse effects of Nedd8 conjugation underscore the complexity of cullin-RING ubiquitin ligase regulation and suggest that modification of other ubiquitin ligases with ubiquitin or ubiquitin-like proteins may likewise have major functional consequences (PMID:18851830)
• The mechanism of poly-NEDD8 chain formation on Cullin-1 using a complete in vitro reconstituted NEDD8 conjugation system was shown. (PMID:19245792)
• NEDD8 expression level is higher in the peripheral blood of HIV patients developing lipodystrophy (PMID:19281774)
• identify NEDD8 as a crucial regulator of L11 RP signalling to p53. A decrease in L11 NEDDylation during nucleolar stress causes relocalization of L11 from the nucleolus to the nucleoplasm. (PMID:19713960)
• Data show that the stability of MDM2 is regulated by NEDD8 pathway and identify NEDP1 that deneddylates MDM2, resulting in MDM2 destabilization concomitant with p53 activation. (PMID:19784069)
• the Nedd8 pathway plays an important role in regulating the actin cytoskeleton and cellular morphology. (PMID:20603103)
• CHBP is an inhibitor of the ubiquitination pathway; it deamidated Gln40 in ubiquitin and ubiquitin-like protein NEDD8 in vitro and during Burkholderia infection; Cif deamidated NEDD8, abolishing activity of neddylated Cullin-RING ubiquitin ligases (PMID:20688984)
• EPEC Cif interacts with NEDD8 and interferes with SCF (Skp1-Cullin1-F-box protein) complex ubiquitin ligase function. (PMID:20850415)
• The steady-state repertoire of human SCF ubiquitin ligase complexes does not require ongoing Nedd8 conjugation (PMID:21169563)
• NEDD8 is an ancillary player to regulate the stability of HIF-1alpha (PMID:21193393)
• review the NEDD8 conjugation cascade derived from functional studies in genetic model organisms, structural insights from crystallographic studies, biochemical studies identifying a growing list of NEDD8 substrates with oncogenic implications (PMID:21316600)
• Study report that USP21 cleaves Ub polymers, and with reduced activity also targets ISG15, but is inactive against NEDD8. (PMID:21399617)
• findings suggest that TRIM40 inhibits NF-kappaB activity via neddylation of inhibitor of nuclear factor kappaB kinase subunit gamma and that TRIM40 prevents inflammation-associated carcinogenesis in the gastrointestinal tract (PMID:21474709)
• In cells, NEDD8 overexpression leads to this type of NEDDylation by increasing the concentration of NEDD8, whereas proteasome inhibition has the same effect by depleting free ubiquitin. (PMID:22004789)
• E1-E2 interactions in ubiquitin and Nedd8 ligation pathways (PMID:22069333)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nedd8	ENSDARG00000007989
danio_rerio	nedd8l	ENSDARG00000103472
mus_musculus	Nedd8	ENSMUSG00000010376
rattus_norvegicus	Nedd8	ENSRNOG00000019895
drosophila_melanogaster	Nedd8	FBGN0032725
caenorhabditis_elegans	ned-8	WBGENE00003587

Paralogs (10): UBL4A (ENSG00000102178), RPS27A (ENSG00000143947), UBC (ENSG00000150991), UBB (ENSG00000170315), ZFAND4 (ENSG00000172671), UBL4B (ENSG00000186150), ISG15 (ENSG00000187608), ANKUB1 (ENSG00000206199), UBD (ENSG00000213886), UBA52 (ENSG00000221983)

Protein

Protein identifiers

Ubiquitin-like protein NEDD8 — Q15843 (reviewed: Q15843)

Alternative names: Neddylin, Neural precursor cell expressed developmentally down-regulated protein 8

All UniProt accessions (2): Q15843, F8VSA6

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin-like protein which plays an important role in cell cycle control and embryogenesis via its conjugation to a limited number of cellular proteins, such as cullins or p53/TP53. Attachment of NEDD8 to cullins is critical for the recruitment of E2 to the cullin-RING-based E3 ubiquitin-protein ligase complex, thus facilitating polyubiquitination and proteasomal degradation of cyclins and other regulatory proteins. Attachment of NEDD8 to p53/TP53 inhibits p53/TP53 transcriptional activity. Covalent attachment to its substrates requires prior activation by the E1 complex UBE1C-APPBP1 and linkage to the E2 enzyme UBE2M.

Subunit / interactions. Interacts with AHR; interaction is direct. Interacts with NUB1; interaction is direct. Interacts with ESR1.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in heart, skeletal muscle, spleen, thymus, prostate, testis, ovary, colon and leukocytes.

Post-translational modifications. Cleavage of precursor form by UCHL3 or SENP8 is necessary for function. (Microbial infection) Deamidated at Gln-40 by bacterial cyclomodulin Cif produced by enteropathogenic E.coli, Y.pseudotuberculosis or B.pseudomallei, leading to impair NEDD8 ability to activate cullin-RING-based E3 ubiquitin-protein ligase complexes (CRL complexes). Deamidation occurs on NEDD8-modified cullins. NEDD8 deamidation prevents switching from the inactive to active state by maintaining the ‘closed’ structure of the CRL complexes. Deamidation may also impair its deconjugation by the COP9 signalosome; However this result needs additional evidences.

Similarity. Belongs to the ubiquitin family.

RefSeq proteins (1): NP_006147* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR019954	Ubiquitin_CS	Conserved_site
IPR019956	Ubiquitin_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR038738	Nedd8-like	Domain
IPR050158	Ubiquitin_ubiquitin-like	Family

Pfam: PF00240

UniProt features (25 total): strand 7, mutagenesis site 6, helix 3, site 2, modified residue 2, chain 1, propeptide 1, sequence conflict 1, region of interest 1, cross-link 1

Structure

Experimental structures (PDB)

44 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1NDD	X-RAY DIFFRACTION	1.6
4FBJ	X-RAY DIFFRACTION	1.6
8WZN	X-RAY DIFFRACTION	1.8
2BKR	X-RAY DIFFRACTION	1.9
4F8C	X-RAY DIFFRACTION	1.95
1XT9	X-RAY DIFFRACTION	2.2
8WZO	X-RAY DIFFRACTION	2.25
4HCP	X-RAY DIFFRACTION	2.52
8CAF	X-RAY DIFFRACTION	2.66
2NVU	X-RAY DIFFRACTION	2.8
3DBH	X-RAY DIFFRACTION	2.85
3DBL	X-RAY DIFFRACTION	2.9
9T7V	ELECTRON MICROSCOPY	2.95
9EFQ	ELECTRON MICROSCOPY	2.96
9SDX	ELECTRON MICROSCOPY	2.97
1R4M	X-RAY DIFFRACTION	3
3DQV	X-RAY DIFFRACTION	3
3GZN	X-RAY DIFFRACTION	3
9EFV	ELECTRON MICROSCOPY	3.03
3DBR	X-RAY DIFFRACTION	3.05
4P5O	X-RAY DIFFRACTION	3.11
9EFM	ELECTRON MICROSCOPY	3.16
9QO1	ELECTRON MICROSCOPY	3.23
9QO0	ELECTRON MICROSCOPY	3.26
9E77	ELECTRON MICROSCOPY	3.3
9EG8	ELECTRON MICROSCOPY	3.39
7ONI	ELECTRON MICROSCOPY	3.4
8B3I	ELECTRON MICROSCOPY	3.5
9EG1	ELECTRON MICROSCOPY	3.52
8WQC	ELECTRON MICROSCOPY	3.54

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15843-F1	90.56	0.87

Antibody-complex structures (SAbDab): 1 — 8CAF

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 8 (interaction with ube1c); 44 (interaction with ube1c)

Post-translational modifications (3): 40, 48, 76

Mutagenesis-validated functional residues (6):

Position	Phenotype
31	decreased interaction with b.pseudomallei cif protein, leading to slightly decreased deamidation.
40	impaired ability to activate cullin-ring-based e3 ubiquitin-protein ligase complexes.
68	decreased interaction with b.pseudomallei cif protein, leading to slightly decreased deamidation.
72	prevents adenylation by ube1c.
7–9	decreased interaction with b.pseudomallei cif protein, leading to decreased deamidation.
11	decreased interaction with b.pseudomallei cif protein, leading to decreased deamidation.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-5689603	UCH proteinases
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8951664	Neddylation
R-HSA-917937	Iron uptake and transport
R-HSA-162582	Signal Transduction
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-199991	Membrane Trafficking
R-HSA-382551	Transport of small molecules
R-HSA-392499	Metabolism of proteins
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5688426	Deubiquitination
R-HSA-597592	Post-translational protein modification
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 214 (showing top): MODULE_172, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, WANG_CLIM2_TARGETS_UP, MORF_MBD4, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_SYNAPSE_ASSEMBLY, ENK_UV_RESPONSE_KERATINOCYTE_UP, CMYB_01, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES, GOBP_PROTEIN_NEDDYLATION, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, REACTOME_MEMBRANE_TRAFFICKING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (11): regulation of transcription by RNA polymerase II (GO:0006357), proteolysis (GO:0006508), ubiquitin-dependent protein catabolic process (GO:0006511), intracellular protein localization (GO:0008104), anatomical structure morphogenesis (GO:0009653), modification-dependent protein catabolic process (GO:0019941), regulation of proteolysis (GO:0030162), protein modification process (GO:0036211), protein neddylation (GO:0045116), cellular response to camptothecin (GO:0072757), regulation of postsynapse assembly (GO:0150052)

GO Molecular Function (3): protein tag activity (GO:0031386), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Post-translational protein modification	2
Signaling by TGF-beta Receptor Complex	1
Deubiquitination	1
Clathrin-mediated endocytosis	1
Transport of small molecules	1
Signaling by TGFB family members	1
Vesicle-mediated transport	1
Metabolism of proteins	1
Membrane Trafficking	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein metabolic process	2
synapse	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
macromolecule localization	1
developmental process	1
anatomical structure development	1
protein catabolic process	1
protein modification process	1
modification-dependent macromolecule catabolic process	1
proteolysis	1
regulation of protein metabolic process	1
macromolecule modification	1
protein modification by small protein conjugation	1
cellular response to alkaloid	1
cellular response to alcohol	1
response to camptothecin	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
molecular tag activity	1
ubiquitin-like protein ligase binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

5136 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEDD8	NAE1	Q13564	998
NEDD8	UBA3	Q8TBC4	998
NEDD8	CUL1	Q13616	997
NEDD8	RBX1	P62877	996
NEDD8	UBE2M	P61081	995
NEDD8	ELOB	Q15370	980
NEDD8	CUL2	Q13617	975
NEDD8	ELOC	Q15369	974
NEDD8	CUL5	Q93034	963
NEDD8	SENP8	Q96LD8	961
NEDD8	DCUN1D1	Q96GG9	959
NEDD8	CUL4A	Q13619	956
NEDD8	RNF7	Q9UBF6	956
NEDD8	SUMO1	P55856	948
NEDD8	COPS5	Q92905	943

IntAct

183 interactions, top by confidence:

A	B	Type	Score
CUL1	RBX1	psi-mi:“MI:0915”(physical association)	0.980
CUL1	RBX1	psi-mi:“MI:0194”(cleavage reaction)	0.980
NEDD8	CUL1	psi-mi:“MI:0407”(direct interaction)	0.960
CUL1	NEDD8	psi-mi:“MI:0195”(covalent binding)	0.960
CUL1	NEDD8	psi-mi:“MI:0915”(physical association)	0.960
CUL1	NEDD8	psi-mi:“MI:0407”(direct interaction)	0.960
CAND1	CUL1	psi-mi:“MI:0914”(association)	0.960
NEDD8	CUL1	psi-mi:“MI:0915”(physical association)	0.960
NEDD8	CUL1	psi-mi:“MI:0914”(association)	0.960
UBE2M	NEDD8	psi-mi:“MI:0915”(physical association)	0.940
UBE2M	NEDD8	psi-mi:“MI:0407”(direct interaction)	0.940
NEDD8	UBE2M	psi-mi:“MI:0407”(direct interaction)	0.940
CUL2	VHL	psi-mi:“MI:0914”(association)	0.940
NEDD8	UBE2M	psi-mi:“MI:0914”(association)	0.940
GPS1	COPS2	psi-mi:“MI:0915”(physical association)	0.860
PRAME	CUL2	psi-mi:“MI:0914”(association)	0.830
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
CUL1	UBE2M	psi-mi:“MI:0567”(neddylation reaction)	0.790
CUL1	UBE2M	psi-mi:“MI:0915”(physical association)	0.790
KLHDC3	CUL2	psi-mi:“MI:0914”(association)	0.770
PDCD6	SEC31A	psi-mi:“MI:0914”(association)	0.740
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730

BioGRID (585): NEDD8 (Reconstituted Complex), NEDD8 (Reconstituted Complex), NEDD8 (Reconstituted Complex), NEDD8 (Affinity Capture-MS), NEDD8 (Biochemical Activity), NEDD8 (Reconstituted Complex), NEDD8 (Co-crystal Structure), HGS (Reconstituted Complex), NEDD8 (Biochemical Activity), UCHL3 (Reconstituted Complex), CUL3 (Two-hybrid), NEDD8 (Biochemical Activity), NEDD8 (Reconstituted Complex), NEDD8 (Biochemical Activity), NEDD8 (Affinity Capture-MS)

ESM2 similar proteins: A7WLI0, O02741, O14399, O65381, P05161, P05759, P0C016, P0C030, P0C031, P0C032, P0C073, P0C2F1, P0C8R3, P14797, P16709, P21899, P29595, P61282, P61955, P61956, P61957, P61958, P61959, P62865, P69061, Q03919, Q12306, Q15843, Q28H04, Q2PFW2, Q4PLJ0, Q54TK0, Q54XV3, Q5A109, Q5ZHQ1, Q5ZJM9, Q64339, Q6DHL4, Q6DI05, Q6DK72

Diamond homologs: A2VDN6, B9DHA6, G1SK22, O13900, O14399, O15042, P05759, P0C016, P0C030, P0C031, P0C032, P0C073, P0C8R3, P0CG71, P0CG73, P0CG81, P0CG82, P0CG83, P0CG84, P0CG85, P0CG86, P0CG87, P0CH04, P0CH05, P0CH10, P0CH11, P0CH27, P0CH32, P0CH33, P0CH34, P0CH35, P0DJ25, P12297, P14795, P14799, P15357, P19848, P23324, P23398, P27923

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
MAP3K8 (TPL2)-dependent MAPK1/3 activation	5	34.3×	1e-05
Regulation of NF-kappa B signaling	5	30.5×	1e-05
DNA Damage Recognition in GG-NER	11	30.2×	1e-11
Recognition of DNA damage by PCNA-containing replication complex	6	22.0×	1e-05
Inactivation of CSF3 (G-CSF) signaling	5	21.1×	7e-05
Formation of TC-NER Pre-Incision Complex	10	20.3×	8e-09
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	8	18.3×	1e-06
Formation of Incision Complex in GG-NER	7	17.1×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein neddylation	8	44.9×	1e-09
ubiquitin-dependent protein catabolic process via the C-end degron rule pathway	5	44.9×	6e-06
regulation of protein neddylation	5	37.5×	2e-05
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	8	24.0×	3e-07
post-translational protein modification	6	20.2×	4e-05
intrinsic apoptotic signaling pathway	7	20.1×	6e-06
positive regulation of protein ubiquitination	9	15.4×	1e-06
cellular response to UV	6	14.2×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

0 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1040 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24217145:T:TA	donor_gain	1.0000
14:24218131:A:AC	donor_gain	1.0000
14:24218132:C:CC	donor_gain	1.0000
14:24218132:CAT:C	donor_gain	1.0000
14:24217140:C:CT	donor_gain	0.9900
14:24217141:C:CT	donor_gain	0.9900
14:24217241:C:CT	acceptor_gain	0.9900
14:24217242:A:T	acceptor_gain	0.9900
14:24218069:G:A	donor_gain	0.9900
14:24218077:T:A	donor_gain	0.9900
14:24218088:T:C	donor_gain	0.9900
14:24218127:ACTC:A	donor_loss	0.9900
14:24218128:CTCA:C	donor_loss	0.9900
14:24218129:TCA:T	donor_loss	0.9900
14:24218130:CA:C	donor_loss	0.9900
14:24218132:C:CA	donor_loss	0.9900
14:24218141:G:A	donor_gain	0.9900
14:24218214:ACCT:A	acceptor_loss	0.9900
14:24218215:CC:C	acceptor_loss	0.9900
14:24218217:T:A	acceptor_loss	0.9900
14:24232177:C:A	donor_gain	0.9900
14:24232215:C:CT	donor_gain	0.9900
14:24232216:T:TT	donor_gain	0.9900
14:24232274:T:A	donor_gain	0.9900
14:24218120:A:AC	donor_gain	0.9800
14:24218121:C:CC	donor_gain	0.9800
14:24218126:AACT:A	donor_loss	0.9800
14:24218215:CCT:C	acceptor_loss	0.9800
14:24218216:C:A	acceptor_loss	0.9800
14:24218216:C:CC	acceptor_gain	0.9800

AlphaMissense

517 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24218201:C:A	K27N	0.999
14:24218201:C:G	K27N	0.999
14:24217167:A:G	L69P	0.998
14:24218142:C:A	G47V	0.997
14:24218154:A:G	L43P	0.997
14:24218156:C:A	R42S	0.997
14:24218156:C:G	R42S	0.997
14:24218159:C:A	Q41H	0.997
14:24218159:C:G	Q41H	0.997
14:24218160:T:G	Q41P	0.997
14:24217173:A:T	L67H	0.996
14:24218154:A:T	L43H	0.996
14:24218196:C:G	R29P	0.996
14:24218205:A:C	I26S	0.996
14:24218421:C:A	G10V	0.996
14:24218203:T:C	K27E	0.995
14:24218205:A:G	I26T	0.995
14:24218421:C:T	G10E	0.995
14:24217171:G:C	H68D	0.994
14:24218142:C:T	G47D	0.994
14:24218202:T:G	K27T	0.994
14:24218205:A:T	I26N	0.994
14:24218157:C:A	R42M	0.993
14:24232250:C:A	K6N	0.993
14:24232250:C:G	K6N	0.993
14:24218157:C:G	R42T	0.992
14:24218422:C:G	G10R	0.992
14:24218422:C:T	G10R	0.992
14:24217161:A:G	L71S	0.991
14:24217167:A:T	L69Q	0.991

dbSNP variants (sampled 300 via entrez): RS1000014354 (14:24228452 C>T), RS1000034305 (14:24231642 G>A), RS1000035965 (14:24218365 G>A), RS1000316790 (14:24231721 A>G), RS1000408551 (14:24218000 G>C,T), RS1000465965 (14:24223405 A>C), RS1000560321 (14:24219257 T>G), RS1000618473 (14:24229747 G>A,C), RS1000668709 (14:24231432 CA>C,CAA), RS1001052726 (14:24229970 T>A,C), RS1001082473 (14:24225524 A>G), RS1001443043 (14:24219264 C>G), RS1001500311 (14:24228316 C>A), RS1001834183 (14:24226990 G>A), RS1001953122 (14:24233434 T>C,G)

Disease associations

OMIM: gene MIM:603171 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003365_1	Systolic blood pressure (cigarette smoking interaction)	3.000000e-08
GCST006011_31	Mean corpuscular volume	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL4295831 (SINGLE PROTEIN), CHEMBL4523655 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523656 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,600 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL457547	MICAFUNGIN	4	120
CHEMBL1231160	PEVONEDISTAT	3	1,480

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 4 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.33	IC50	4.7	nM	PEVONEDISTAT

PubChem BioAssay actives

1 with measured affinity, of 31 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl sulfamate	1371347: Inhibition of NEDD8 (unknown origin) assessed as decrease in formation of E2-UBL thioester reaction product	ic50	0.0047	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
bisphenol F	affects cotreatment, increases expression	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
1,12-benzoperylene	increases expression	1
bisphenol A	affects expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
beryllium sulfate	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
bisphenol B	increases expression	1
N-butyrylglucosamine	increases expression	1
Arsenic Trioxide	decreases expression	1
Atrazine	decreases expression	1
Cadmium	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Quercetin	increases expression	1
Selenium	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	decreases expression	1
Vitamin E	affects cotreatment, increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

16 unique, capped per target: 16 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4185514	Binding	Inhibition of NEDD8 (unknown origin) assessed as decrease in formation of E2-UBL thioester reaction product	Interrogating the Roles of Post-Translational Modifications of Non-Histone Proteins. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F4BT	MDA-MB-231 NEDD8 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.