CUL5

Summary

CUL5 (cullin 5, HGNC:2556) is a protein-coding gene on chromosome 11q22.3, encoding Cullin-5 (Q93034). Core component of multiple cullin-5-RING E3 ubiquitin-protein ligase complexes (ECS complexes, also named CRL5 complexes), which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.

Enables ubiquitin ligase complex scaffold activity and ubiquitin protein ligase binding activity. Involved in proteasome-mediated ubiquitin-dependent protein catabolic process and protein K11-linked ubiquitination. Located in site of DNA damage. Part of Cul5-RING ubiquitin ligase complex. Is active in nucleus.

Source: NCBI Gene 8065 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 60 total
• Druggable target: yes
• MANE Select transcript: NM_003478

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2556
Approved symbol	CUL5
Name	cullin 5
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	VACM-1
Ensembl gene	ENSG00000166266
Ensembl biotype	protein_coding
OMIM	601741
Entrez	8065

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000393094, ENST00000526303, ENST00000531427, ENST00000531843, ENST00000532064, ENST00000532782, ENST00000937828, ENST00000937829, ENST00000937830

RefSeq mRNA: 1 — MANE Select: NM_003478 NM_003478

CCDS: CCDS31668

Canonical transcript exons

ENST00000393094 — 19 exons

Exon	Start	End
ENSE00001101571	108078176	108078240
ENSE00001101574	108095530	108095691
ENSE00001101577	108094391	108094514
ENSE00001101581	108097636	108097754
ENSE00001101598	108098406	108098529
ENSE00001101600	108088527	108088659
ENSE00001101612	108089492	108089623
ENSE00001101615	108072332	108072462
ENSE00001101621	108046270	108046369
ENSE00001101623	108094812	108094987
ENSE00001311892	108070096	108070189
ENSE00002143878	108008898	108009372
ENSE00002170640	108104190	108107761
ENSE00003463935	108033802	108033911
ENSE00003571401	108073390	108073497
ENSE00003654290	108054875	108054955
ENSE00003660104	108052660	108052801
ENSE00003660408	108049890	108050066
ENSE00003784037	108054647	108054792

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.1468 / max 215.3042, expressed in 1808 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116514	18.9251	1799
116515	4.2217	1474

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.89	gold quality
oocyte	CL:0000023	99.85	gold quality
gluteal muscle	UBERON:0002000	98.20	gold quality
biceps brachii	UBERON:0001507	97.99	gold quality
triceps brachii	UBERON:0001509	97.88	gold quality
deltoid	UBERON:0001476	97.87	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.72	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.71	gold quality
diaphragm	UBERON:0001103	97.30	gold quality
choroid plexus epithelium	UBERON:0003911	97.19	gold quality
vastus lateralis	UBERON:0001379	96.98	gold quality
quadriceps femoris	UBERON:0001377	96.88	gold quality
tibialis anterior	UBERON:0001385	96.44	gold quality
skeletal muscle tissue	UBERON:0001134	96.36	gold quality
caput epididymis	UBERON:0004358	96.36	gold quality
nephron tubule	UBERON:0001231	95.95	gold quality
corpus epididymis	UBERON:0004359	95.70	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.70	gold quality
parietal pleura	UBERON:0002400	95.31	gold quality
cauda epididymis	UBERON:0004360	95.27	gold quality
body of tongue	UBERON:0011876	95.23	gold quality
hair follicle	UBERON:0002073	95.22	gold quality
muscle tissue	UBERON:0002385	95.07	gold quality
endothelial cell	CL:0000115	95.06	gold quality
skin of hip	UBERON:0001554	95.04	gold quality
visceral pleura	UBERON:0002401	95.00	gold quality
pleura	UBERON:0000977	94.89	gold quality
upper leg skin	UBERON:0004262	94.74	gold quality
renal glomerulus	UBERON:0000074	94.40	gold quality
pigmented layer of retina	UBERON:0001782	94.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

211 targeting CUL5, 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-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394

Literature-anchored findings (GeneRIF, showing 40)

• findings report that HIV-1 Vif interacts with cellular proteins Cul5, elongins B and C, and Rbx1 to form an Skp1-cullin-F-box (SCF)-like complex (PMID:14564014)
• These data indicate that vasopressin-activated calcium-mobilizing (VACM-1) is involved in the regulation of cellular growth. (PMID:15184056)
• Cul5 promotes vif ubiquination and requires intact SOCS-box (PMID:15574592)
• the E3 ubiquitin ligase activity of the Vif-BC-Cul5 complex is essential for Vif function against APOBEC3G (PMID:15781449)
• findings indicate that the assembly of Vif-Cul5 E3 ubiquitin ligases requires a hydrophobic interface within a novel zinc-binding domain in the substrate receptor Vif and a unique region in Cul5 (PMID:16530799)
• the zinc-binding region in Vif is a novel cullin interaction domain that mediates selective binding to Cul5 (PMID:16636053)
• Data indicate that in the T47D cancer cell line VACM-1 inhibits growth by attenuating estrogen-dependent/estrogen receptor alpha signaling responses. (PMID:17186378)
• Adenovirus E4orf6-mediated p53 degradation requires Cul5. (PMID:17351129)
• CUL5, together with NPAT and PPP2R1B, is implicated in the deregulation of the cell-cycle and apoptosis regulators and in the pathogenesis of B-CLL. (PMID:17449237)
• Cul5 plays an essential role in regulating neuron migrations during cortical development, possibly by opposing a promigratory effect of Dab1. (PMID:17974915)
• Degradation of AAV5 proteins can be inhibited by a dominant-negative ubiquitin that prevents chain elongation or by small interfering RNA directed against cullin 5. (PMID:18216112)
• The purpose of this study was to determine if there is increased expression of Cul5 during granulocytic differentiation of HL-60 cells. (PMID:19118439)
• HIV-1 virion infectivity factor (Vif) protein-cullin 5 (Cul5) interaction is mediated by zinc binding to the conserved Vif HCCH motif. Zinc enhances the Vif HCCH-Cul5 interaction by 8-fold. (PMID:19588889)
• Cul5 interacts with the Hsp90 chaperone complex and is recruited to the site of ErbB2 on the plasma membrane, thereby inducing its polyubiquitination and proteasome-mediated degradation. (PMID:19933325)
• Vif alterations may contribute to a rapid AIDS onset and Vif variability could be influenced by APOBEC3G and CUL5 polymorphisms in children (PMID:21571098)
• study showed VACM-1 DNA in T47D cancer cells is not mutated; SNP found in U138MG, OVCAR-3 and ACHN cell lines results in silent mutation; results suggest in T47D cancer cells, VACM-1 activity may controlled by epigenetic or posttranslational modification (PMID:21635549)
• detected a reduced editing associated with the CUL5 SNP6 minor allele and also with certain Vif variants (mutations at sites 46, 122, and 160). (PMID:22145963)
• comparison of heat capacity changes supports a model in which CBFbeta prestabilizes Vif((1-192)) relative to Vif((95-192)), consistent with a stronger interaction of Cul5 with Vif’s C-terminal Zn(2+)-binding motif. (PMID:23098073)
• Data indicate tht n the Biaka, strong signal of selection was detected at CUL5 and at TSG101. (PMID:23217182)
• ASB9 is unstable alone but forms a stable ternary complex with EloBC that binds with high affinity to the Cullin 5 N-terminal domain. (PMID:23837592)
• crystal structure shows interaction between SOCS2-elongin BC and Cullin-5 (PMID:23897481)
• A tumor suppressor gene, CUL5, is identified as a direct target of miR-7 in hepatocellular carcinoma. (PMID:24339204)
• In the absence of CBFbeta, Vif does not bind Cul5, thus preventing the assembly of the E3 ligase complex. (PMID:24390320)
• CBF-beta is critical for the formation of the Vif-ElonginB/ElonginC-Cul5 core E3 ubiquitin ligase complex. (PMID:24390335)
• data reveal the structural basis for Vif hijacking of the CBF-beta and CUL5 E3 ligase complex, laying a foundation for rational design of novel anti-HIV drugs (PMID:24402281)
• N-terminal mutants of HIV-1 vif that demonstrated reduced Cul5 binding were also unable to degrade APOBEC3G as well as APOBEC3F. (PMID:24422669)
• Silencing CUL5 reduced cellular sensitivity to three distinct HSP90 inhibitors, across four cancer types driven by different protein kinases. (PMID:24760825)
• Data indicate that cell surface adhesion molecules VCAM-1 and P-selectin play some roles in mechanical stretch-induced HL-60 cell adhesion to mouse common carotid arteries. (PMID:25108430)
• These results provide important information on the assembly of the Vif-CUL5-E3 ubiquitin ligase and identify a new viV binding interface with CBF-beta at the C-terminus of HIV-1 Vif. (PMID:25424878)
• Studies indicate that Cullin-RING E3 ubiquitin ligases (CRL) are key players of the ubiquitylation pathway. (PMID:26253693)
• Study found that CUL5 expression was significantly decreased in both endometrioid adenocarcinomas with the more aggressive serous type displaying a higher reduction. Its mRNA and protein overexpression in endometrial cancer cells resulted in decreased cell proliferation. (PMID:26847831)
• these findings identify Cul-5 as a signaling component that connects an LPS-activated TLR4-MyD88 complex to TRAF6 for efficient activation of NF-kappaB (PMID:27233966)
• CUL5 neddylation may allosterically tune polyubiquitin chain length and topology. (PMID:28082425)
• These findings report genetic variants possibly associated with susceptibility to HIV-1 infection (CUL5 rs11212495, rs7103534, rs7117111) and partial viral load control (APOBEC3G rs2294367). (PMID:28302043)
• structural model suggests that the diverse FIV and HIV-1 Vifs use conserved residues for Cullin 5 binding, FIV Vif binds Cullin 5 independently of zinc, in contrast to HIV-1 Vif. (PMID:29263270)
• CUL5 may be an important part of the mechanism for thalidomide-dependent inhibition. (PMID:29746508)
• inhibition of miR-19a in SNU-16 gastric cancer cells could cause upsurge of CUL5 expression. Overexpression of CUL-5 was found to exhibit similar effects on the proliferation, migration and invasion of the SNU-16 gastric cancer cells as that of miR-19a suppression (PMID:30521783)
• Clinical tissue examination revealed that the co-expression of ERp29 and CUL5 was positive relative to one another, and the clinicopathological data proved that the high expression of ERp29 was associated with metastasis and the poor prognosis of patients with colorectal cancer (CRC). Therefore, ERp29 should accompany CUL5 to support malignancy for endoplasmic reticulum stress cancer cells. (PMID:30569094)
• work identifies the essential role of CUL5- and SOCS3-mediated integrin beta1 turnover in controlling small-cell lung cancer metastasis, which might have therapeutic implications. (PMID:30688657)
• Here, using a quantitative proteomics approach, the authors identify the E3 ligase ARIH2 as a regulator of the HIV-1 Vif protein-dependent CRL5-mediated APOBEC3 degradation. The CUL5(Vif/CBFss) complex recruits ARIH2 where it acts to transfer ubiquitin directly to the APOBEC3 targets. (PMID:31253590)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cul5a	ENSDARG00000069742
mus_musculus	Cul5	ENSMUSG00000032030
rattus_norvegicus	Cul5	ENSRNOG00000008039
drosophila_melanogaster	Cul5	FBGN0288875
caenorhabditis_elegans		WBGENE00000840

Paralogs (7): CUL3 (ENSG00000036257), CUL1 (ENSG00000055130), CUL2 (ENSG00000108094), CUL4A (ENSG00000139842), CACUL1 (ENSG00000151893), CUL4B (ENSG00000158290), ANAPC2 (ENSG00000176248)

Protein

Protein identifiers

Cullin-5 — Q93034 (reviewed: Q93034)

Alternative names: Vasopressin-activated calcium-mobilizing receptor 1

All UniProt accessions (3): E9PP19, Q93034, H0YCA0

UniProt curated annotations — full annotation on UniProt →

Function. Core component of multiple cullin-5-RING E3 ubiquitin-protein ligase complexes (ECS complexes, also named CRL5 complexes), which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. Acts a scaffold protein that contributes to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable SOCS box-containing substrate recognition component. Acts as a key regulator of neuron positioning during cortex development: component of various SOCS-containing ECS complexes, such as the ECS(SOCS7) complex, that regulate reelin signaling by mediating ubiquitination and degradation of DAB1. ECS(SOCS1) seems to direct ubiquitination of JAK2. The ECS(SOCS2) complex mediates the ubiquitination and subsequent proteasomal degradation of phosphorylated EPOR and GHR. The ECS(SPSB3) complex catalyzes ubiquitination of nuclear CGAS. ECS(KLHDC1) complex is part of the DesCEND (destruction via C-end degrons) pathway and mediates ubiquitination and degradation of truncated SELENOS selenoprotein produced by failed UGA/Sec decoding, which ends with a glycine. The ECS(ASB9) complex mediates ubiquitination and degradation of CKB. As part of some ECS complex, promotes ‘Lys-11’-linked ubiquitination and degradation of BTRC. As part of a multisubunit ECS complex, polyubiquitinates monoubiquitinated POLR2A. As part of the ECS(RAB40C) complex, mediates ANKRD28 ubiquitination and degradation, thereby inhibiting protein phosphatase 6 (PP6) complex activity and focal adhesion assembly during cell migration. As part of the ECS(RAB40A) complex, mediates RHOU ‘Lys-48’-linked ubiquitination and degradation, thus inhibiting focal adhesion disassembly during cell migration. As part of the ECS(RAB40B) complex, mediates LIMA1/EPLIN and RAP2 ubiquitination, thereby regulating actin cytoskeleton dynamics and stress fiber formation during cell migration. The ECS(ASB7) complex acts a negative regulator of H3K9me3 histone mark by mediating ubiquitination and degradation of SUV39H1. May form a cell surface vasopressin receptor. (Microbial infection) Following infection by HIV-1 virus, CUL5 associates with HIV-1 Vif proteins and forms a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex) that catalyzes ubiquitination and degradation of APOBEC3F and APOBEC3G. The complex can also ubiquitinate APOBEC3H to some extent. (Microbial infection) Seems to be involved in proteasomal degradation of p53/TP53 stimulated by adenovirus E1B-55 kDa protein.

Subunit / interactions. Component of multiple cullin-5-RING E3 ubiquitin-protein ligase complexes (ECS complexes, also named CRL5 complexes) formed of CUL5, Elongin BC (ELOB and ELOC), RNF7/RBX2 and a variable SOCS box domain-containing protein as substrate-specific recognition component. CUL5-containing ECS complexes specifically contain RNF7/RBX2, and not RBX1, as catalytic subunit. Component of the ECS(ASB2) complex with the substrate recognition component ASB2. Component of the ECS(ASB6) complex with the substrate recognition component ASB6. Component of the ECS(ASB7) complex with the substrate recognition component ASB7. Component of the ECS(ASB9) complex with the substrate recognition component ASB9. Component of the ECS(ASB11) complex with the substrate recognition component ASB11. Component of the ECS(ASB12) complex with the substrate recognition component ASB12. Component of the ECS(LRRC41) complex with the substrate recognition component LRRC41. Component of the ECS(SOCS1) complex with the substrate recognition component SOCS1. Component of the ECS(SOCS2) complex with the substrate recognition component SOCS2. Component of the ECS(WSB1) complex with the substrate recognition subunit WSB1. Component of the ECS(SOCS3) complex with the substrate recognition component SOCS3. Component of the ECS(SOCS7) complex with the substrate recognition component SOCS7. Component of the ECS(SPSB1) complex with the substrate recognition component SPSB1. Component of the ECS(SPSB3) complex with the substrate recognition component SPSB3. Component of the ECS(SPSB2) complex with the substrate recognition component SPSB2. Component of the ECS(SPSB4) complex with the substrate recognition component SPSB4. Component of the ECS(RAB40) complex with the substrate recognition subunit RAB40A, RAB40B or RAB40C. Component of the ECS(KLHDC1) complex with the substrate recognition component KLHDC1. Component of the ECS(PCMTD1) complex with the substrate recognition subunit PCMTD1. May also form complexes containing RBX1 and ELOA or VHL; additional evidence is however required to confirm this result in vivo. Interacts (when neddylated) with ARIH2; leading to activate the E3 ligase activity of ARIH2. Interacts with ERCC6; the interaction is induced by DNA damaging agents or inhibitors of RNA polymerase II elongation. Interacts with ELOA (via the BC-box). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation. (Microbial infection) Interacts (via the substrate recognition component) with HIV-1 Vif; forming an active cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex). (Microbial infection) Interacts (via the substrate recognition component) with human adenovirus 5 proteins E1B-55K and E4-orf6. (Microbial infection) Interacts with herpes virus 8 protein LANA1; this interaction promotes the degradation of NF-kappa-B component RELA. (Microbial infection) Interacts with molluscum contagiosum virus protein MC132; this interaction promotes the degradation of NF-kappa-B component RELA.

Subcellular location. Nucleus.

Post-translational modifications. Neddylated; which enhances the ubiquitination activity of ECS complexes and prevents binding of the inhibitor CAND1. Deneddylated via its interaction with the COP9 signalosome (CSN).

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the cullin family.

RefSeq proteins (1): NP_003469* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001373	Cullin_N	Domain
IPR016157	Cullin_CS	Conserved_site
IPR016158	Cullin_homology	Domain
IPR016159	Cullin_repeat-like_dom_sf	Homologous_superfamily
IPR019559	Cullin_neddylation_domain	Domain
IPR036317	Cullin_homology_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR045093	Cullin	Family
IPR059120	Cullin-like_AB	Domain

Pfam: PF00888, PF10557, PF26557

UniProt features (88 total): helix 42, strand 14, sequence conflict 10, mutagenesis site 9, turn 8, modified residue 2, chain 1, domain 1, cross-link 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
3DPL	X-RAY DIFFRACTION	2.6
8EI2	X-RAY DIFFRACTION	2.8
9T7V	ELECTRON MICROSCOPY	2.95
9SDX	ELECTRON MICROSCOPY	2.97
3DQV	X-RAY DIFFRACTION	3
4JGH	X-RAY DIFFRACTION	3
9SDY	ELECTRON MICROSCOPY	3.06
8FVI	ELECTRON MICROSCOPY	3.24
4N9F	X-RAY DIFFRACTION	3.3
7ONI	ELECTRON MICROSCOPY	3.4
9EG1	ELECTRON MICROSCOPY	3.52
8FVJ	ELECTRON MICROSCOPY	3.54
9OMA	ELECTRON MICROSCOPY	4.14
6V9I	ELECTRON MICROSCOPY	5.2
9OMF	ELECTRON MICROSCOPY	9.72

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q93034-F1	89.62	0.70

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 (3): 34, 210, 724

Mutagenesis-validated functional residues (9):

Position	Phenotype
691	impaired interaction with arih2.
710	impaired interaction with arih2.
717	impaired interaction with arih2.
724	abolished neddylation and interaction with arih2.
52	strongly impaired interaction with hiv-1 vif protein.
53	strongly impaired interaction with hiv-1 vif protein. decreased interaction ith socs2.
55	strongly impaired interaction with hiv-1 vif protein.
460	impaired interaction with arih2.
617–624	impaired interaction with arih2.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-180585	Vif-mediated degradation of APOBEC3G
R-HSA-8863795	Downregulation of ERBB2 signaling
R-HSA-8951664	Neddylation
R-HSA-9705462	Inactivation of CSF3 (G-CSF) signaling
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9833109	Evasion by RSV of host interferon responses

MSigDB gene sets: 266 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, chr11q22, GOBP_FOCAL_ADHESION_ASSEMBLY, GOBP_CELL_CYCLE_PHASE_TRANSITION, GEORGES_CELL_CYCLE_MIR192_TARGETS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, ATGCAGT_MIR217, GOBP_NEGATIVE_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (32): G1/S transition of mitotic cell cycle (GO:0000082), cell migration (GO:0016477), protein ubiquitination (GO:0016567), positive regulation of cell migration (GO:0030335), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), reelin-mediated signaling pathway (GO:0038026), ERBB2 signaling pathway (GO:0038128), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of focal adhesion assembly (GO:0051895), protein K11-linked ubiquitination (GO:0070979), intrinsic apoptotic signaling pathway (GO:0097193), negative regulation of focal adhesion disassembly (GO:0120184), regulation of neuron migration (GO:2001222), epithelial to mesenchymal transition (GO:0001837), ubiquitin-dependent protein catabolic process (GO:0006511), signal transduction (GO:0007165), proteasomal protein catabolic process (GO:0010498), negative regulation of epithelial to mesenchymal transition (GO:0010719), layer formation in cerebral cortex (GO:0021819), endoplasmic reticulum unfolded protein response (GO:0030968), erythropoietin-mediated signaling pathway (GO:0038162), innate immune response (GO:0045087), defense response to virus (GO:0051607), positive regulation of focal adhesion assembly (GO:0051894), symbiont-mediated suppression of host innate immune response (GO:0052170), growth hormone receptor signaling pathway (GO:0060396), growth hormone receptor signaling pathway via JAK-STAT (GO:0060397), negative regulation of growth hormone receptor signaling pathway (GO:0060400), calcium ion transmembrane transport (GO:0070588), protein K48-linked ubiquitination (GO:0070936), cGAS/STING signaling pathway (GO:0140896), negative regulation of cGAS/STING signaling pathway (GO:0160049)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), calcium channel activity (GO:0005262), protein-macromolecule adaptor activity (GO:0030674), ubiquitin protein ligase binding (GO:0031625), signaling receptor activity (GO:0038023), ubiquitin ligase complex scaffold activity (GO:0160072), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), Cul5-RING ubiquitin ligase complex (GO:0031466), site of DNA damage (GO:0090734), cullin-RING ubiquitin ligase complex (GO:0031461)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Host Interactions of HIV factors	1
Signaling by ERBB2	1
Post-translational protein modification	1
Signaling by CSF3 (G-CSF)	1
Class I MHC mediated antigen processing & presentation	1
RSV-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of cell migration	2
negative regulation of cell-substrate junction organization	2
intracellular signal transduction	2
cullin-RING ubiquitin ligase complex	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
cell motility	1
protein modification by small protein conjugation	1
cell migration	1
positive regulation of cell motility	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
cell surface receptor signaling pathway	1
ERBB signaling pathway	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
negative regulation of cell-matrix adhesion	1
focal adhesion assembly	1
regulation of focal adhesion assembly	1
negative regulation of cell junction assembly	1
protein polyubiquitination	1
apoptotic signaling pathway	1
focal adhesion disassembly	1
regulation of focal adhesion disassembly	1
neuron migration	1
mesenchymal cell differentiation	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein catabolic process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
cerebral cortex radial glia-guided migration	1

Protein interactions and networks

STRING

2260 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CUL5	RBX1	P62877	999
CUL5	RNF7	Q9UBF6	999
CUL5	ELOB	Q15370	998
CUL5	ELOC	Q15369	998
CUL5	CBFB	Q13951	994
CUL5	CISH	Q9NSE2	994
CUL5	NEDD8	Q15843	963
CUL5	CUL3	Q13618	959
CUL5	SOCS1	O15524	956
CUL5	APOBEC3G	Q9HC16	956
CUL5	CUL1	Q13616	950
CUL5	CUL2	Q13617	950
CUL5	APOBEC3F	Q8IUX4	946
CUL5	CUL4A	Q13619	942
CUL5	ARIH2	O95376	910

IntAct

213 interactions, top by confidence:

A	B	Type	Score
CAND1	CUL1	psi-mi:“MI:0914”(association)	0.960
CUL5	RNF7	psi-mi:“MI:0915”(physical association)	0.900
RNF7	CUL5	psi-mi:“MI:0915”(physical association)	0.900
SOCS2	CUL5	psi-mi:“MI:2364”(proximity)	0.880
SOCS2	CUL5	psi-mi:“MI:0915”(physical association)	0.880
CUL5	SOCS2	psi-mi:“MI:0914”(association)	0.880
ASB9	CKM	psi-mi:“MI:0914”(association)	0.870
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
ASB6	CUL5	psi-mi:“MI:0915”(physical association)	0.780
CUL5	ASB6	psi-mi:“MI:0915”(physical association)	0.780
CUL5	vif	psi-mi:“MI:0915”(physical association)	0.740
CUL5	vif	psi-mi:“MI:0914”(association)	0.740
vif	CUL5	psi-mi:“MI:0915”(physical association)	0.740
CUL5	ASB1	psi-mi:“MI:0915”(physical association)	0.740
CUL5	ASB7	psi-mi:“MI:0915”(physical association)	0.740
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730

BioGRID (1046): CUL5 (Affinity Capture-Western), CUL5 (Affinity Capture-Western), CUL3 (Affinity Capture-Western), CUL5 (Two-hybrid), RNF7 (Two-hybrid), CCNDBP1 (Two-hybrid), CUL5 (Affinity Capture-RNA), CUL5 (Biochemical Activity), CUL5 (Biochemical Activity), CUL5 (Reconstituted Complex), CUL5 (Co-purification), CUL5 (Co-localization), CUL5 (Affinity Capture-MS), CUL5 (Biochemical Activity), CUL5 (Biochemical Activity)

ESM2 similar proteins: A2A432, A6H5Z3, A9X1D0, B0VX69, B1MTJ4, B2KI88, B5FW36, C1FXW2, E2R766, E2RBS6, F1LSG8, O43242, O54923, O55047, O70133, P60762, Q13098, Q13619, Q13620, Q29425, Q2KJ46, Q3TCH7, Q4V860, Q5NVP9, Q5R5J4, Q5RAN1, Q5RB36, Q5VIR6, Q5ZKV9, Q5ZLD7, Q5ZML9, Q6AYU1, Q6NRT5, Q6NZH6, Q86TU7, Q8CCB4, Q8CI71, Q8K4Q0, Q8N122, Q8R3S6

Diamond homologs: A2A432, A4IHP4, B5DF89, O13790, O60999, Q12018, Q13616, Q13617, Q13618, Q13619, Q13620, Q17389, Q17390, Q21346, Q23639, Q24311, Q3TCH7, Q54NZ5, Q54XF7, Q5R4G6, Q5RB36, Q5RCF3, Q5ZC88, Q6DE95, Q6GPF3, Q8LGH4, Q93034, Q94AH6, Q9C9L0, Q9D4H8, Q9JLV5, Q9SRZ0, Q9WTX6, Q9XZJ3, Q9ZVH4, Q29425, Q9D5V5, Q9JJ31

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
NAE	“up-regulates activity”	CUL5	neddylation
CUL5	“up-regulates activity”	ARIH2	binding
SAG	“up-regulates quantity by stabilization”	CUL5	binding
CUL5	“form complex”	“Elongin E3-Cul-5”	binding
PRKACA	“up-regulates activity”	CUL5	phosphorylation
CUL5	“down-regulates quantity by destabilization”	DAB1	polyubiquitination
SOCS4	“up-regulates activity”	CUL5	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 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
DNA Damage Recognition in GG-NER	8	24.0×	1e-07
Inactivation of CSF3 (G-CSF) signaling	5	23.1×	1e-04
Formation of TC-NER Pre-Incision Complex	9	20.0×	8e-08
Recognition of DNA damage by PCNA-containing replication complex	5	20.0×	3e-04
Neddylation	40	19.9×	8e-40
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	5	14.0×	1e-03
Class I MHC mediated antigen processing & presentation	15	11.1×	9e-10
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	5	10.4×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
ubiquitin-dependent protein catabolic process via the C-end degron rule pathway	6	59.6×	5e-08
protein neddylation	9	55.9×	5e-12
regulation of protein neddylation	6	49.7×	2e-07
intrinsic apoptotic signaling pathway	5	15.9×	1e-03
protein ubiquitination	39	14.3×	8e-32
proteasome-mediated ubiquitin-dependent protein catabolic process	26	12.0×	2e-18
positive regulation of protein ubiquitination	5	9.4×	1e-02
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	5	9.3×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3482 predictions. Top by Δscore:

Variant	Effect	Δscore
11:108033799:A:AG	acceptor_gain	1.0000
11:108033800:A:G	acceptor_gain	1.0000
11:108033907:TTTTC:T	donor_gain	1.0000
11:108033912:G:GG	donor_gain	1.0000
11:108046264:TCACA:T	acceptor_loss	1.0000
11:108046265:CACA:C	acceptor_loss	1.0000
11:108046267:CAG:C	acceptor_loss	1.0000
11:108046268:A:AG	acceptor_gain	1.0000
11:108046268:A:C	acceptor_loss	1.0000
11:108046268:AG:A	acceptor_gain	1.0000
11:108046268:AGG:A	acceptor_gain	1.0000
11:108046269:G:GG	acceptor_gain	1.0000
11:108046269:GG:G	acceptor_gain	1.0000
11:108046269:GGG:G	acceptor_gain	1.0000
11:108046269:GGGAT:G	acceptor_gain	1.0000
11:108046365:AGGCA:A	donor_gain	1.0000
11:108046366:GGCAG:G	donor_gain	1.0000
11:108046367:GCA:G	donor_gain	1.0000
11:108046368:CA:C	donor_gain	1.0000
11:108046369:AG:A	donor_loss	1.0000
11:108046370:G:GG	donor_gain	1.0000
11:108046371:TA:T	donor_loss	1.0000
11:108046372:A:AG	donor_loss	1.0000
11:108046374:G:C	donor_loss	1.0000
11:108049889:GC:G	acceptor_gain	1.0000
11:108049889:GCGA:G	acceptor_gain	1.0000
11:108052654:TCCTA:T	acceptor_loss	1.0000
11:108052655:CCTA:C	acceptor_loss	1.0000
11:108052656:CTAG:C	acceptor_loss	1.0000
11:108052657:TAGCT:T	acceptor_loss	1.0000

AlphaMissense

5196 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:108033905:T:C	L43P	1.000
11:108049924:T:C	L90P	1.000
11:108049944:T:A	W97R	1.000
11:108049944:T:C	W97R	1.000
11:108049945:G:C	W97S	1.000
11:108049946:G:C	W97C	1.000
11:108049946:G:T	W97C	1.000
11:108049953:T:C	F100L	1.000
11:108049955:C:A	F100L	1.000
11:108049955:C:G	F100L	1.000
11:108052667:T:C	L140P	1.000
11:108052675:T:A	W143R	1.000
11:108052675:T:C	W143R	1.000
11:108052676:G:C	W143S	1.000
11:108052677:G:C	W143C	1.000
11:108052677:G:T	W143C	1.000
11:108052690:T:C	F148L	1.000
11:108052692:T:A	F148L	1.000
11:108052692:T:G	F148L	1.000
11:108052712:T:A	L155H	1.000
11:108052712:T:C	L155P	1.000
11:108052724:C:A	A159E	1.000
11:108052733:T:C	L162P	1.000
11:108052748:G:C	R167T	1.000
11:108052749:A:C	R167S	1.000
11:108052749:A:T	R167S	1.000
11:108052778:T:A	V177D	1.000
11:108052795:T:C	S183P	1.000
11:108052796:C:T	S183F	1.000
11:108054653:T:C	L187P	1.000

dbSNP variants (sampled 300 via entrez): RS1000011348 (11:108062237 C>G), RS1000046461 (11:108035789 T>G), RS1000047516 (11:108075142 T>A,C), RS1000083029 (11:108050427 G>A), RS1000086924 (11:108099205 A>G), RS1000157170 (11:108076494 A>G), RS1000165711 (11:108091347 G>A), RS1000183199 (11:108053539 T>C,G), RS1000205999 (11:108016601 C>G), RS1000220247 (11:108037004 C>G), RS1000235585 (11:108053276 A>G), RS1000244269 (11:108059500 G>A,T), RS1000349956 (11:108024984 A>G), RS1000391272 (11:108030690 A>G), RS1000413175 (11:108013518 C>A,T)

Disease associations

OMIM: gene MIM:601741 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_248	Refractive error	4.000000e-19

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291609 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.33	Kd	463.5	nM	CHEMBL3752910
6.17	ED50	676.2	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 7 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149849: Binding affinity to human CUL5 incubated for 45 mins by Kinobead based pull down assay	kd	0.4635	uM

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases expression, decreases reaction	1
potassium chromate(VI)	increases expression	1
bathocuproine sulfonate	affects cotreatment, decreases expression, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
Temozolomide	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	increases expression	1
Fluorouracil	increases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, decreases expression, decreases reaction	1
Tretinoin	decreases expression	1
Valproic Acid	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5264707	Binding	Inhibition of cullin5 neddylation in human KYSE-70 cells at 0.3 to 10 uM incubated for 24 hrs by Western blot analysis	Development of Highly Potent, Selective, and Cellular Active Triazolo[1,5- a]pyrimidine-Based Inhibitors Targeting the DCN1-UBC12 Protein-Protein Interaction. — 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_F1LW	HyCyte A-549 KO-hCUL5	Cancer cell line	Male

Clinical trials (associated diseases)

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