DCUN1D2

Summary

DCUN1D2 (defective in cullin neddylation 1 domain containing 2, HGNC:20328) is a protein-coding gene on chromosome 13q34, encoding DCN1-like protein 2 (Q6PH85). Contributes to the neddylation of all cullins by transferring NEDD8 from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes and plays an essential role in the regulation of SCF (SKP1-CUL1-F-box protein)-type complexes activit….

Enables cullin family protein binding activity. Involved in positive regulation of protein neddylation. Located in cytoplasm and nucleus.

Source: NCBI Gene 55208 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 58 total
• Druggable target: yes
• MANE Select transcript: NM_001014283

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20328
Approved symbol	DCUN1D2
Name	defective in cullin neddylation 1 domain containing 2
Location	13q34
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10704, FLJ20092
Ensembl gene	ENSG00000150401
Ensembl biotype	protein_coding
Entrez	55208

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000332592, ENST00000375403, ENST00000438545, ENST00000439909, ENST00000460318, ENST00000465710, ENST00000465938, ENST00000478244, ENST00000482038, ENST00000491647, ENST00000496873, ENST00000941882

RefSeq mRNA: 1 — MANE Select: NM_001014283 NM_001014283

CCDS: CCDS32013

Canonical transcript exons

ENST00000478244 — 7 exons

Exon	Start	End
ENSE00000994742	113483840	113484056
ENSE00001132460	113480575	113480743
ENSE00001881489	113490667	113490711
ENSE00003530859	113459312	113459408
ENSE00003576389	113461054	113461136
ENSE00003597959	113455819	113458108
ENSE00003650813	113474124	113474254

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 94.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.5461 / max 57.4145, expressed in 1443 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138359	2.1645	1132
138361	0.9518	535
138358	0.2353	88
138360	0.1944	65

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	94.75	gold quality
heart left ventricle	UBERON:0002084	94.66	gold quality
cardiac ventricle	UBERON:0002082	94.49	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.41	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.24	gold quality
gastrocnemius	UBERON:0001388	93.78	gold quality
muscle of leg	UBERON:0001383	93.64	gold quality
cerebellar hemisphere	UBERON:0002245	93.60	gold quality
cerebellar cortex	UBERON:0002129	93.56	gold quality
right atrium auricular region	UBERON:0006631	93.40	gold quality
muscle organ	UBERON:0001630	93.23	gold quality
gluteal muscle	UBERON:0002000	93.01	gold quality
cardiac atrium	UBERON:0002081	93.00	gold quality
triceps brachii	UBERON:0001509	92.86	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.86	gold quality
cerebellum	UBERON:0002037	92.76	gold quality
heart	UBERON:0000948	92.57	gold quality
vastus lateralis	UBERON:0001379	92.50	gold quality
skeletal muscle tissue	UBERON:0001134	92.42	gold quality
quadriceps femoris	UBERON:0001377	91.94	gold quality
muscle tissue	UBERON:0002385	91.38	gold quality
biceps brachii	UBERON:0001507	91.27	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.13	gold quality
myocardium	UBERON:0002349	91.12	gold quality
left ventricle myocardium	UBERON:0006566	89.69	gold quality
deltoid	UBERON:0001476	89.44	gold quality
heart right ventricle	UBERON:0002080	89.21	gold quality
cardiac muscle of right atrium	UBERON:0003379	88.80	gold quality
tendon of biceps brachii	UBERON:0008188	88.34	gold quality
tibia	UBERON:0000979	88.01	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	38.52
E-HCAD-8	no	370.68
E-ANND-3	no	2.94

Regulation

Is transcription factor: no

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	dcun1d2a	ENSDARG00000040838
danio_rerio	dcun1d2b	ENSDARG00000041592
mus_musculus	Dcun1d2	ENSMUSG00000038506
rattus_norvegicus	Dcun1d2	ENSRNOG00000019473
drosophila_melanogaster	SCCRO	FBGN0036510
drosophila_melanogaster	SCCRO4	FBGN0036967
caenorhabditis_elegans		WBGENE00010428

Paralogs (4): DCUN1D1 (ENSG00000043093), DCUN1D4 (ENSG00000109184), DCUN1D5 (ENSG00000137692), DCUN1D3 (ENSG00000188215)

Protein

Protein identifiers

DCN1-like protein 2 — Q6PH85 (reviewed: Q6PH85)

Alternative names: DCUN1 domain-containing protein 2, Defective in cullin neddylation protein 1-like protein 2

All UniProt accessions (7): Q6PH85, A0A0C4DFQ9, C9J2J1, C9J2J3, C9JAV2, C9JRE2, H7C216

UniProt curated annotations — full annotation on UniProt →

Function. Contributes to the neddylation of all cullins by transferring NEDD8 from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes and plays an essential role in the regulation of SCF (SKP1-CUL1-F-box protein)-type complexes activity.

Subunit / interactions. Interacts (via the DCUN1 domain) with the unneddylated cullins: interacts with CUL1, CUL2, CUL3, CUL4A, CUL4B and CUL5; these interactions promote the cullin neddylation and the identity of the cullin dictates the affinity of the interaction. May also interact with regulators or subunits of cullin-RING ligases such as RBX1, RNF7, ELOB and DDB1; these interactions are bridged by cullins. Interacts with CAND1; this interaction is bridged by cullins such as CUL3 and strongly inhibits the neddylation of CUL3. These CAND-cullin-DCNL complexes can only be neddylated in the presence of a substrate adapter. Interacts (via DCUN1 domain) with the N-terminally acetylated form of UBE2M and UBE2F.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Mostly expressed in liver, kidney and brain.

Domain organisation. The DCUN1 domain, also known as PONY domain, mediates the interaction with different cullins. The DCUN1 domain mediates the interaction with the N-terminally acetylated NEDD8-conjugating E2s enzyme leading to the NEDD8 transfer from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes; the neddylation efficiency correlates with the DCUN1D5-cullin and DCUN1D5-E2 interaction affinities.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6PH85-1	1	yes
Q6PH85-2	2

RefSeq proteins (1): NP_001014305* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005176	PONY_dom	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR014764	DCN-prot	Family
IPR042460	DCN1-like_PONY	Homologous_superfamily

Pfam: PF03556, PF14555

UniProt features (24 total): helix 12, mutagenesis site 3, domain 2, strand 2, splice variant 2, chain 1, turn 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4GAO	X-RAY DIFFRACTION	3.28

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PH85-F1	93.86	0.90

Functional residue map

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

Post-translational modifications (1): 55

Mutagenesis-validated functional residues (3):

Position	Phenotype
211	loss of interaction with cul1, cul2, cul3, cula4, cula5 cand1 and rbx1; when associated with r-235 and a-241. does not a
235	loss of interaction with cul1, cul2, cul3, cula4, cula5 cand1 and rbx1; when associated with a-211 and a-241. does not a
241	loss of interaction with cul1, cul2, cul3, cula4, cula5 cand1 and rbx1; when associated with a-211 and r-235. does not a

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 114 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_PROTEIN_NEDDYLATION, chr13q34, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOCC_TRANSFERASE_COMPLEX, TCCCRNNRTGC_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEIN_MODIFICATION_PROCESS, GOMF_UBIQUITIN_LIKE_PROTEIN_BINDING, GOCC_UBIQUITIN_LIGASE_COMPLEX, GOMF_UBIQUITIN_LIKE_PROTEIN_CONJUGATING_ENZYME_BINDING, GOMF_CULLIN_FAMILY_PROTEIN_BINDING, GAZDA_DIAMOND_BLACKFAN_ANEMIA_ERYTHROID_DN, GOBP_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (3): protein neddylation (GO:0045116), regulation of protein neddylation (GO:2000434), positive regulation of protein neddylation (GO:2000436)

GO Molecular Function (4): ubiquitin conjugating enzyme binding (GO:0031624), ubiquitin-like protein binding (GO:0032182), cullin family protein binding (GO:0097602), protein binding (GO:0005515)

GO Cellular Component (3): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein neddylation	2
protein binding	2
protein modification by small protein conjugation	1
regulation of protein modification by small protein conjugation or removal	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of protein neddylation	1
ubiquitin-like protein conjugating enzyme binding	1
binding	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

537 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DCUN1D2	CUL3	Q13618	633
DCUN1D2	GRTP1	Q5TC63	544
DCUN1D2	UBE2F	Q969M7	537
DCUN1D2	UBA3	Q8TBC4	527
DCUN1D2	UBE2M	P61081	523
DCUN1D2	SLC9D1	Q6UWJ1	479
DCUN1D2	OR5D14	Q8NGL3	478
DCUN1D2	FEM1A	Q9BSK4	474
DCUN1D2	NEDD8	Q15843	471
DCUN1D2	FEM1C	Q96JP0	455
DCUN1D2	PLEKHA2	Q9HB19	439
DCUN1D2	SENP8	Q96LD8	433
DCUN1D2	ADPRHL1	Q8NDY3	430
DCUN1D2	ZDHHC16	Q969W1	411
DCUN1D2	NAE1	Q13564	403

IntAct

8 interactions, top by confidence:

A	B	Type	Score
UBE2M	DCUN1D2	psi-mi:“MI:0915”(physical association)	0.400
DCUN1D2	ECE1	psi-mi:“MI:0915”(physical association)	0.370
DCUN1D2	CUL1	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	KLHL18	psi-mi:“MI:0914”(association)	0.350
DCUN1D2	INPPL1	psi-mi:“MI:0914”(association)	0.350
DCUN1D2	UBA1	psi-mi:“MI:0220”(ubiquitination reaction)	0.000

BioGRID (67): CUL1 (Biochemical Activity), CUL2 (Biochemical Activity), CUL3 (Biochemical Activity), CUL4A (Biochemical Activity), CUL4B (Biochemical Activity), CUL5 (Biochemical Activity), DCUN1D2 (Biochemical Activity), CUL1 (Affinity Capture-MS), CUL2 (Affinity Capture-MS), CUL3 (Affinity Capture-MS), CUL4A (Affinity Capture-MS), CUL4B (Affinity Capture-MS), CUL5 (Affinity Capture-MS), CAND1 (Affinity Capture-MS), RBX1 (Affinity Capture-MS)

ESM2 similar proteins: A2VE01, A4F4L4, O70133, O88761, O94973, O96015, P17427, P18484, P19803, P35615, P38024, P48444, P52565, P53619, P62495, P62496, P62497, P62498, Q08211, Q0VCK5, Q0VCX5, Q1W375, Q28141, Q32KN5, Q3TXS7, Q4R4J0, Q4R7R3, Q5F418, Q5R4C7, Q5R5S4, Q5R874, Q5RA77, Q5U2Q7, Q5XI73, Q5XJY5, Q5ZJL4, Q5ZL57, Q66H80, Q68FK8, Q6NRT5

Diamond homologs: A4IHK8, Q1RMX9, Q4V8B2, Q54GP1, Q5ADL9, Q5E9V1, Q5PPL2, Q5R9G1, Q5RDF9, Q5RHX6, Q5ZKU1, Q60YT5, Q6C0B6, Q6DFA1, Q6PH85, Q86JM4, Q8BZJ7, Q8CCA0, Q8IWE4, Q8K0V2, Q8T8S1, Q92564, Q96GG9, Q9BTE7, Q9CXV9, Q9QZ73, Q9U3C8, Q9VUQ8, Q9VWB1, P0CN06, P0CN07, Q9MBG8, Q4PF67, Q5AWS1, Q8WZK4, Q12395, Q750Y3, Q6FJR2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1894 predictions. Top by Δscore:

Variant	Effect	Δscore
13:113459304:T:TA	donor_gain	1.0000
13:113480568:GACTT:G	donor_loss	1.0000
13:113480569:ACTT:A	donor_loss	1.0000
13:113480570:CTTA:C	donor_loss	1.0000
13:113480571:TTA:T	donor_loss	1.0000
13:113480572:TACCC:T	donor_loss	1.0000
13:113480573:A:AC	donor_gain	1.0000
13:113480573:AC:A	donor_gain	1.0000
13:113480573:ACC:A	donor_gain	1.0000
13:113480574:C:A	donor_loss	1.0000
13:113480574:C:CC	donor_gain	1.0000
13:113480574:CC:C	donor_gain	1.0000
13:113480574:CCC:C	donor_gain	1.0000
13:113480574:CCCA:C	donor_gain	1.0000
13:113480574:CCCAA:C	donor_gain	1.0000
13:113480742:ATCTG:A	acceptor_loss	1.0000
13:113480744:C:CA	acceptor_loss	1.0000
13:113480744:C:CC	acceptor_gain	1.0000
13:113480750:T:TC	acceptor_gain	1.0000
13:113480757:C:CT	acceptor_gain	1.0000
13:113480758:A:T	acceptor_gain	1.0000
13:113483836:TTAC:T	donor_loss	1.0000
13:113483837:TA:T	donor_loss	1.0000
13:113483838:ACC:A	donor_loss	1.0000
13:113483839:C:CG	donor_loss	1.0000
13:113459404:TGTTC:T	acceptor_gain	0.9900
13:113459408:CCTAA:C	acceptor_gain	0.9900
13:113459414:A:C	acceptor_gain	0.9900
13:113474116:ATAC:A	donor_loss	0.9900
13:113474117:TACT:T	donor_loss	0.9900

AlphaMissense

1740 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:113458103:A:G	W236R	0.999
13:113458103:A:T	W236R	0.999
13:113459375:A:G	W213R	0.999
13:113459375:A:T	W213R	0.999
13:113458080:A:C	F243L	0.998
13:113458080:A:T	F243L	0.998
13:113458082:A:G	F243L	0.998
13:113458101:C:A	W236C	0.998
13:113458101:C:G	W236C	0.998
13:113459368:A:G	L215P	0.998
13:113459373:C:A	W213C	0.998
13:113459373:C:G	W213C	0.998
13:113459380:T:G	D211A	0.998
13:113461060:G:C	F199L	0.998
13:113461060:G:T	F199L	0.998
13:113461062:A:G	F199L	0.998
13:113461071:A:G	W196R	0.998
13:113461071:A:T	W196R	0.998
13:113458100:G:A	P237S	0.997
13:113459374:C:G	W213S	0.997
13:113459379:G:C	D211E	0.997
13:113459379:G:T	D211E	0.997
13:113459380:T:A	D211V	0.997
13:113459380:T:C	D211G	0.997
13:113459381:C:G	D211H	0.997
13:113459389:A:T	I208N	0.997
13:113461070:C:G	W196S	0.997
13:113461113:A:G	W182R	0.997
13:113461113:A:T	W182R	0.997
13:113474158:G:C	F162L	0.997

dbSNP variants (sampled 300 via entrez): RS1000008684 (13:113470090 G>A,T), RS1000092381 (13:113468976 G>A,C), RS1000164886 (13:113470346 C>G), RS1000305322 (13:113485026 T>C), RS1000402464 (13:113490815 C>A,T), RS1000413911 (13:113490610 T>C), RS1000478464 (13:113479840 G>A), RS1000521520 (13:113464634 C>A,T), RS1000569476 (13:113473867 C>T), RS1000625112 (13:113473390 C>T), RS1000636145 (13:113484821 G>C), RS1000671439 (13:113479524 A>G), RS1000700931 (13:113479220 G>A,C), RS1000790772 (13:113455468 C>A), RS1000898292 (13:113474100 T>A,C)

Disease associations

OMIM: gene `` | disease phenotypes: MIM:616487

GenCC curated gene-disease

Mondo (1): epidermolysis bullosa simplex with nail dystrophy (MONDO:0014661)

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST008362_52	Birth weight	1.000000e-08
GCST90002394_475	Monocyte percentage of white cells	5.000000e-11
GCST90002398_215	Neutrophil count	4.000000e-23

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295866 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.18	Ki	66.19	nM	CHEMBL4592844
6.50	Ki	313.3	nM	CHEMBL4865016

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 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
4-(4-methylphenyl)-2-prop-2-ynylsulfanyl-6-(1,3-thiazol-2-ylsulfanyl)pyrimidine-5-carbonitrile	1599584: Binding affinity to N-terminal GST tagged recombinant DCN2 (unknown origin) (62 to 259 residues) expressed in Escherichia coli BL21(DE3) assessed as reduction in DCN1-FAM-labelled N-terminal acetylated UBE2M (1 to 21 residues) protein-protein interaction after 30 mins by HTRF assay	ki	0.0662	uM
5-(2-phenylphenyl)-3-[[5-(2-phenylphenyl)-1H-1,2,4-triazol-3-yl]disulfanyl]-1H-1,2,4-triazole	1758790: Inhibition of recombinant human GST-tagged DCN2 (62 to 259 residues) expressed in Escherichia coli BL21 (DE3) using MIKLFSLKQQKKEEESAGGTK-biotin as substrate incubated for 30 mins by HTRF assay	ki	0.3133	uM

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
beta-lapachone	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	decreases methylation	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	affects methylation, increases abundance	1
Doxorubicin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Nitrogen Dioxide	affects methylation, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	increases expression	1
Silicon Dioxide	decreases expression	1
Tretinoin	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Particulate Matter	affects methylation, increases abundance	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4222549	Binding	Inhibition of human DCN2-mediated cullin neddylation assessed as reduction in transfer of fluorescein-5-maleimide-tagged NEDD8 from N-terminally acetylated human UBE2M to CUL2-CTD at 12.5 and 50 uM measured for 10 sec by pulse-chase assay	Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation. — J Med Chem

Clinical trials (associated diseases)

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