CUL3

Summary

CUL3 (cullin 3, HGNC:2553) is a protein-coding gene on chromosome 2q36.2, encoding Cullin-3 (Q13618). Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. In precision oncology, NFE2L2 Mutation OR KEAP1 Mutation OR CUL3 Mutation is associated with resistance to Platinum Doublet in Lung Non-small Cell Carcinoma (CIViC Level B). It is a selective cancer dependency (DepMap: 55.8% of cell lines).

This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation. Mutations in this gene are a cause of type 2E pseudohypoaldosteronism. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 8452 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pseudohypoaldosteronism type 2E (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 680 total — 64 pathogenic, 38 likely-pathogenic
• Phenotypes (HPO): 30
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types
• Cancer dependency (DepMap): dependent in 55.8% of screened cell lines
• MANE Select transcript: NM_003590

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2553
Approved symbol	CUL3
Name	cullin 3
Location	2q36.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000036257
Ensembl biotype	protein_coding
OMIM	603136
Entrez	8452

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 18 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000264414, ENST00000344951, ENST00000409096, ENST00000409777, ENST00000432260, ENST00000436172, ENST00000451538, ENST00000454323, ENST00000481135, ENST00000484081, ENST00000487558, ENST00000497715, ENST00000536702, ENST00000541548, ENST00000546102, ENST00000907241, ENST00000907242, ENST00000927034, ENST00000927035, ENST00000927036, ENST00000927037, ENST00000967310, ENST00000967311, ENST00000967312, ENST00000967313, ENST00000967314, ENST00000967315

RefSeq mRNA: 3 — MANE Select: NM_003590 NM_001257197, NM_001257198, NM_003590

CCDS: CCDS2462, CCDS58751

Canonical transcript exons

ENST00000264414 — 16 exons

Exon	Start	End
ENSE00000786384	224502965	224503072
ENSE00000786385	224503652	224503822
ENSE00000786388	224511354	224511582
ENSE00000965147	224505956	224506132
ENSE00000965148	224500363	224500487
ENSE00000965150	224495832	224495966
ENSE00001831638	224584944	224585363
ENSE00001926503	224470150	224474376
ENSE00003491945	224497753	224497849
ENSE00003521548	224557659	224557856
ENSE00003524390	224514612	224514772
ENSE00003585264	224506858	224507003
ENSE00003606176	224513524	224513638
ENSE00003608357	224481892	224482078
ENSE00003658141	224478200	224478345
ENSE00003693740	224535528	224535641

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 99.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.9289 / max 803.2397, expressed in 1819 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34245	14.8089	1805
34247	11.7221	1789
34246	7.1610	1750
34249	1.3417	755
34248	0.9159	580
34243	0.6452	221
34240	0.4165	166
34238	0.3656	156
34251	0.2818	96
34250	0.1720	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.94	gold quality
male germ cell	CL:0000015	99.78	gold quality
left testis	UBERON:0004533	99.28	gold quality
right testis	UBERON:0004534	99.25	gold quality
amniotic fluid	UBERON:0000173	99.14	gold quality
testis	UBERON:0000473	98.46	gold quality
epithelium of nasopharynx	UBERON:0001951	98.42	gold quality
adult organism	UBERON:0007023	98.25	gold quality
gluteal muscle	UBERON:0002000	98.22	gold quality
cervix squamous epithelium	UBERON:0006922	98.22	gold quality
calcaneal tendon	UBERON:0003701	98.04	gold quality
squamous epithelium	UBERON:0006914	98.04	gold quality
oral cavity	UBERON:0000167	98.03	gold quality
parotid gland	UBERON:0001831	98.03	gold quality
esophagus squamous epithelium	UBERON:0006920	98.01	gold quality
palpebral conjunctiva	UBERON:0001812	98.00	gold quality
tongue squamous epithelium	UBERON:0006919	97.97	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.95	gold quality
biceps brachii	UBERON:0001507	97.90	gold quality
gingival epithelium	UBERON:0001949	97.90	gold quality
gingiva	UBERON:0001828	97.86	gold quality
ventricular zone	UBERON:0003053	97.85	gold quality
upper leg skin	UBERON:0004262	97.85	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.84	gold quality
triceps brachii	UBERON:0001509	97.59	gold quality
cervix epithelium	UBERON:0004801	97.58	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.58	gold quality
cartilage tissue	UBERON:0002418	97.51	gold quality
epithelium of esophagus	UBERON:0001976	97.46	gold quality
ganglionic eminence	UBERON:0004023	97.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.33

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NANOG, NFE2L2

miRNA regulators (miRDB)

306 targeting CUL3, 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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
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

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 55.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Data show that Keap1 associates with the N-terminal region of Cullin 3 through the IVR domain and promotes the ubiquitination of Nrf2 in cooperation with the Cullin 3-Roc1 complex. (PMID:15282312)
• Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome (PMID:15601839)
• Here, we report that the E3 ubiquitin ligase consisting of SPOP and CULLIN3 is able to ubiquitinate the Polycomb group protein BMI1. (PMID:15897469)
• SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis (PMID:16524876)
• Cul1 and Cul3, as well as their associated substrate recognition subunits Skp2 and Keap1, respectively, homooligomerize in intact cells, suggesting that cullin-based ligases are dimeric. (PMID:17254749)
• Cul3-based E3 ubiquitin-ligase is required to maintain SAC signaling in human cells. (PMID:18075312)
• define a novel mechanism whereby the phosphoinositide phosphatidylinositol 5-phosphate leads to stimulation of Cul3-SPOP ubiquitin ligase activity (PMID:18218622)
• Findings suggest that the ectromelia virus-encoded BTB/kelch proteins, EVM150 and EVM167, interact with cullin-3 potentially functioning to recruit unidentified substrates for ubiquitination. (PMID:18221766)
• Cys151 adduction confers a critical alkylation sensor function upon Keap1, making Keap1 unique among CUL3 adapter proteins (PMID:18251510)
• KLHL12 specifically interacts with the D4 polymorphism, thereby building up a Cul3-E3 ligase complex with substrate specificity toward the D4 receptor (PMID:18303015)
• provides in vivo validation of the two-site substrate recognition model for Nrf2 activation by the Keap1-Cul3-based E3 ligase (PMID:18757741)
• Cul3-deficient cells or Ctb9/KLHDC5-deficient cells show an increase in p60/katanin levels, indicating that Cul3/Ctb9/KLHDC5 is required for efficient p60/katanin removal (PMID:19261606)
• The ubiquitin-binding protein p62/sequestosome-1 promoted aggregation of CUL3-modified caspase-8 within p62-dependent foci, leading to full activation and processing of the enzyme and driving commitment to cell death. (PMID:19427028)
• Modification of Cys(151) of human Keap1, by mutation to a tryptophan, relieves the repression by Keap1 and allows activation of the antioxidant response element by Nrf2. (PMID:19489739)
• Data show that the PEST sequences of a short-lived protein called HSF2 interact with Cullin3, a subunit of a Cullin-RING E3 ubiquitin ligase, and that this interaction mediates the Cul3-dependent ubiquitination and degradation of HSF2. (PMID:19768582)
• Cullin-3 mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement. (PMID:19782033)
• The study provides a molecular understanding of how SPOP and other MATH-BTB proteins recruit substrates to Cul3 and how their dimerization and conformational variability may facilitate avid interactions with diverse substrates. (PMID:19818708)
• KLHL21 localizes to midzone microtubules in anaphase & recruits aurora B & Cul3 to this region; results suggest that different Cul3 adaptors nonredundantly regulate aurora B during mitosis, possibly by ubiquitinating different pools of aurora B (PMID:19995937)
• KLHL20-Cul3-ROC1 is an E3 ligase for DAPK ubiquitination (PMID:20389280)
• Nrf2 regulates Cul3-Rbx1 by controlling regulation of expression and induction of Cul3-Rbx1 (PMID:20452971)
• KLHL7 forms a dimer, assembles with Cul3 through its BTB and BACK domains, and exerts E3 activity. (PMID:21828050)
• These results suggest that the novel regulatory mechanism of BRMS1 by Cul3-SPOP complex is important for breast cancer progression. (PMID:22085717)
• Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response (PMID:22147914)
• These results suggest a crucial role of Cul3 in regulating late steps in the endolysosomal trafficking pathway. (PMID:22219362)
• fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis (PMID:22266938)
• these results demonstrate that KBTBD13 is a putative substrate adaptor for Cul3-RL that functions as a muscle specific ubiquitin ligase, and thereby implicate the ubiquitin proteasome pathway in the pathogenesis of KBTBD13-associated NEM. (PMID:22542517)
• Adaptor protein self-assembly provides a graded level of regulation of the SPOP/Cul3 E3 ligase toward its multiple protein substrates. (PMID:22632832)
• Cul3 modulated the aggressive phenotype of cancer cells by modifying the expression of cytoskeleton proteins involved in bladder cancer aggressiveness. (PMID:23308193)
• analysis of crystal structures of the BTB-BACK domains of KLHL11 both alone and in complex with Cul3 (PMID:23349464)
• Somatic mutation in CUL3 gene is associated with sporadic form of papillary renal cell carcinoma. (PMID:23365135)
• The CUL3-KLHL3 E3 ligase complex mutated in Gordon’s hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. (PMID:23387299)
• changes in conformation rather than dissociation from Cul3 inactivate the repressor function of Keap1 leading to Nrf2 stabilization (PMID:23454126)
• Disease causing mutations in human KLHL3 disrupt the interaction with CUL3, a crystallographic study. (PMID:23573258)
• CUL3 and KLHL3 have roles in in electrolyte homeostasis and in Pseudohypoaldosteronism type II (PMID:23576762)
• genetic analysis to detect the CUL3 mutation and to enable intervention early in the disease course would be beneficial for infants with suspected pseudohypoaldosteronism type II (PMID:23689903)
• Co-expression of KLHL2 and Cullin3 decreases the abundance of WNK1, WNK3 and WNK4 within HEK293T cells. (PMID:23838290)
• In a patient with pseudohypoaldosteronism type III, the Cullin 3 gene showed abnormal splicing caused by modification of exon 9. (PMID:23902721)
• analysis of how mutations of KLHL3 show less ability to ubiquitinate WNK4 because of KLHL3’s low stability and/or decreased binding to CUL3 or WNK4 (PMID:23962426)
• REVIEW: latest advances in basic research on the biology of Cul3 and how it could help to direct drug discovery efforts on this target (PMID:24024173)
• CUL3/KLHL22 may contact two distinct motifs within PLK1 protein, consistent with the bivalent mode of substrate targeting. (PMID:24067371)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cul3a	ENSDARG00000038967
danio_rerio	cul3b	ENSDARG00000100108
mus_musculus	Cul3	ENSMUSG00000004364
rattus_norvegicus	Cul3	ENSRNOG00000015633
drosophila_melanogaster	Cul3	FBGN0261268
caenorhabditis_elegans		WBGENE00000838

Paralogs (7): CUL1 (ENSG00000055130), CUL2 (ENSG00000108094), CUL4A (ENSG00000139842), CACUL1 (ENSG00000151893), CUL4B (ENSG00000158290), CUL5 (ENSG00000166266), ANAPC2 (ENSG00000176248)

Protein

Protein identifiers

Cullin-3 — Q13618 (reviewed: Q13618)

All UniProt accessions (5): A0A087X1R9, Q13618, H7C1J0, H7C1L6, H7C399

UniProt curated annotations — full annotation on UniProt →

Function. Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. BCR complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the BCR complex depends on the BTB domain-containing protein as the substrate recognition component. BCR(KLHL42) is involved in ubiquitination of KATNA1. BCR(SPOP) is involved in ubiquitination of BMI1/PCGF4, BRMS1, MACROH2A1 and DAXX, GLI2 and GLI3. Can also form a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL; these complexes have lower ubiquitin ligase activity. BCR(KLHL9-KLHL13) controls the dynamic behavior of AURKB on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis. BCR(KLHL12) is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B). BCR(KLHL3) acts as a regulator of ion transport in the distal nephron; by mediating ubiquitination of WNK4. The BCR(KLHL20) E3 ubiquitin ligase complex is involved in interferon response and anterograde Golgi to endosome transport: it mediates both ubiquitination leading to degradation and ‘Lys-33’-linked ubiquitination. The BCR(KLHL21) E3 ubiquitin ligase complex regulates localization of the chromosomal passenger complex (CPC) from chromosomes to the spindle midzone in anaphase and mediates the ubiquitination of AURKB. The BCR(KLHL22) ubiquitin ligase complex mediates monoubiquitination of PLK1, leading to PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation. The BCR(KLHL22) ubiquitin ligase complex is also responsible for the amino acid-stimulated ‘Lys-48’ polyubiquitination and proteasomal degradation of DEPDC5. Through the degradation of DEPDC5, releases the GATOR1 complex-mediated inhibition of the TORC1 pathway. The BCR(KLHL25) ubiquitin ligase complex is involved in translational homeostasis by mediating ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1). The BCR(KLHL25) ubiquitin ligase complex is also involved in lipid synthesis by mediating ubiquitination and degradation of ACLY. The BCR(KBTBD8) complex acts by mediating monoubiquitination of NOLC1 and TCOF1, leading to remodel the translational program of differentiating cells in favor of neural crest specification. Involved in ubiquitination of cyclin E and of cyclin D1 (in vitro) thus involved in regulation of G1/S transition. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and RBX1, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. The BCR(KCTD17) E3 ubiquitin ligase complex mediates ubiquitination and degradation of TCHP, a down-regulator of cilium assembly, thereby inducing ciliogenesis. The BCR(KLHL24) E3 ubiquitin ligase complex mediates ubiquitination of KRT14, controls KRT14 levels during keratinocytes differentiation, and is essential for skin integrity. The BCR(KLHL18) E3 ubiquitin ligase complex mediates the ubiquitination of AURKA leading to its activation at the centrosome which is required for initiating mitotic entry. The BCR(KEAP1) E3 ubiquitin ligase complex acts as a key sensor of oxidative and electrophilic stress by mediating ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes. As part of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex functions mediates ‘Lys-48’ ubiquitination and proteasomal degradation of TIAM1. By controlling the ubiquitination of that RAC1 guanine exchange factors (GEF), regulates RAC1 signal transduction and downstream biological processes including the organization of the cytoskeleton, cell migration and cell proliferation. The BCR(KBTBD4) E3 ubiquitin ligase complex targets CoREST corepressor complex components RCOR1, KDM1A/LSD1 and HDAC2 for proteasomal degradation with RCOR1 likely to be the primary target while degradation of KDM1A and HDAC2 is likely due to their association with RCOR1. It also targets RCOR3, MIER2 and MIER3 for proteasomal degradation as well as associated proteins ZNF217 and RREB1 with degradation being dependent on the presence of an ELM2 domain in the target proteins. The BCR(ARMC5) complex mediates premature transcription termination of transcripts that are unfavorably configured for transcriptional elongation by mediating ubiquitination of Pol II subunit POLR2A. Required for ‘Lys-63’-linked ubiquitination of large ribosomal subunit protein MRPL12. Protects against human enterovirus D68 infection by mediating the ubiquitination and subsequent degradation of viral protein VP1.

Subunit / interactions. Forms neddylation-dependent homodimers. Component of multiple BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes formed of CUL3, RBX1 and a variable BTB domain-containing protein acting as both, adapter to cullin and substrate recognition subunit. The BCR complex may be active as a heterodimeric complex, in which NEDD8, covalently attached to one CUL3 molecule, binds to the C-terminus of a second CUL3 molecule. Interacts with RBX1, RNF7, CYCE and TIP120A/CAND1. Part of the BCR(SPOP) containing SPOP, and of BCR containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL. Part of the probable BCR(KLHL9-KLHL13) complex with BTB domain proteins KLHL9 and KLHL13. Part of the BCR(KLHL41) complex containing KLHL41. Component of the BCR(KLHL12) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL12 and RBX1. Component of the BCR(KLHL3) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL3 and RBX1. Part of the BCR(ENC1) complex containing ENC1. Part of a complex consisting of BMI1/PCGF4, CUL3 and SPOP. Part of a complex consisting of BRMS1, CUL3 and SPOP. Component of the BCR(KLHL21) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL21 and RBX1. Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1. Component of the BCR(KLHL25) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL25 and RBX1. Part of a complex consisting of MACROH2A1, CUL3 and SPOP. Component of the BCR(KLHL42) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL42. Interacts with KLHL42 (via the BTB domain). Interacts with KATNA1; the interaction is enhanced by KLHL42. Component of the BCR(KBTBD8) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD8 and RBX1. Interacts with KCTD5, KLHL9, KLHL11, KLHL13, GAN, ZBTB16, KLHL3, KLHL15, KLHL20, KLHL36, GMCL2, BTBD1. Part of a complex that contains CUL3, RBX1 and GAN. Interacts (via BTB domain) with KLHL17; the interaction regulates surface GRIK2 expression. Interacts with KCTD7. Part of the BCR(GAN) complex containing GAN. Part of the BCR(KEAP1) complex containing KEAP1. Interacts with KLHL10. Interacts with KAT5 and ATF2. Interacts with KCTD17 in the BCR(KCTD17) E3 ubiquitin ligase complex, at least composed of CUL3, KCTD17 and RBX1. Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1. Interacts with COPS9 isoform 2. Interacts with PPP2R5B; this interaction is indirect and mediated through KLHL15-binding and leads to PPP2R5B proteasomal degradation. Interacts with RBBP8/CtIP; this interaction is indirect and mediated through KLHL15-binding and leads to RBBP8 proteasomal degradation. Interacts with KLHL24 in the BCR(KLHL24) E3 ubiquitin ligase complex, composed of CUL3, RBX1 and KLHL24. Interacts with RHOBTB2. Interacts with AURKA and KLHL18 (via BTB domain). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation. Component of a BCR3 (BTB-CUL3-RBX1) E3 ubiquitin ligase complex, also named Cul3-RING ubiquitin ligase complex CUL3(KBTBD6/7), composed of CUL3, RBX1, KBTBD6 and KBTBD7. Component of the BCR(KBTBD2) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD2 and RBX1. Interacts with KBTBD2 (via the BTB domain). Component of the BCR(KBTBD4) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD4 and RBX1. Component of the BCR(ARMC5) E3 ubiquitin ligase complex, composed of CUL3, ARMC5 and RBX1. (Microbial infection) Interacts with vaccinia virus protein A55/KBTB1; this interaction may direct the CUL3-RING E3 ligase complex to degrade cellular/viral target proteins that are normally unaffected.

Subcellular location. Nucleus. Golgi apparatus. Cell projection. Cilium. Flagellum. Cytoplasm. Cytoskeleton. Spindle. Microtubule organizing center. Centrosome. Spindle pole.

Tissue specificity. Brain, spermatozoa, and testis (at protein level). Widely expressed.

Post-translational modifications. Neddylated. Attachment of NEDD8 is required for the E3 ubiquitin-protein ligase activity of the BCR complex. Deneddylated via its interaction with the COP9 signalosome (CSN) complex. (Microbial infection) Cleaved at Gln-681 by human enterovirus D68 protease 3C; leading to inhibition of CUL3-dependent ubiquitination activity.

Disease relevance. Pseudohypoaldosteronism 2E (PHA2E) [MIM:614496] An autosomal dominant disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with or without autism or seizures (NEDAUS) [MIM:619239] An autosomal dominant disorder manifesting in infancy and characterized by global developmental delay, variably impaired intellectual development, and speech delay. Some patients have seizures, others have autistic features or behavioral abnormalities. Additional variable features include cardiac defects, failure to thrive, or brain imaging anomalies. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. High-glucose conditions in renal tubular epithelial cells lead to up-regulation of CUL3 expression, significant increase in CUL3-mediated ubiquitination of MRPL12 and dysregulation of mitochondrial biosynthesis.

Similarity. Belongs to the cullin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13618-1	1, Cul-3 Long	yes
Q13618-2	2
Q13618-3	3, Cul-3 Short

RefSeq proteins (3): NP_001244126, NP_001244127, NP_003581* (*=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 (52 total): helix 23, sequence variant 8, sequence conflict 5, splice variant 2, region of interest 2, strand 2, turn 2, modified residue 2, initiator methionine 1, chain 1, domain 1, compositionally biased region 1, site 1, cross-link 1

Structure

Experimental structures (PDB)

30 structures.

PDB	Method	Resolution (Å)
6I2M	X-RAY DIFFRACTION	2.3
4EOZ	X-RAY DIFFRACTION	2.4
4AP2	X-RAY DIFFRACTION	2.8
8I79	ELECTRON MICROSCOPY	2.8
4APF	X-RAY DIFFRACTION	3.1
9RWZ	ELECTRON MICROSCOPY	3.1
5NLB	X-RAY DIFFRACTION	3.45
4HXI	X-RAY DIFFRACTION	3.51
8U80	ELECTRON MICROSCOPY	3.6
8KHP	ELECTRON MICROSCOPY	3.67
8H3Q	ELECTRON MICROSCOPY	3.76
8K8T	ELECTRON MICROSCOPY	3.8
8U81	ELECTRON MICROSCOPY	3.82
8U82	ELECTRON MICROSCOPY	3.84
8U84	ELECTRON MICROSCOPY	3.88
9EGL	ELECTRON MICROSCOPY	3.93
8GQ6	ELECTRON MICROSCOPY	3.96
8U83	ELECTRON MICROSCOPY	3.98
8K9I	ELECTRON MICROSCOPY	4.2
8H38	ELECTRON MICROSCOPY	4.25
8H36	ELECTRON MICROSCOPY	4.6
8H3R	ELECTRON MICROSCOPY	6.36
8H3F	ELECTRON MICROSCOPY	6.73
8H35	ELECTRON MICROSCOPY	7.41
8H3A	ELECTRON MICROSCOPY	7.51
8H37	ELECTRON MICROSCOPY	7.52
8H33	ELECTRON MICROSCOPY	7.86
8H34	ELECTRON MICROSCOPY	7.99
2MYL	SOLUTION NMR
2MYM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13618-F1	90.68	0.81

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 (1): 681–682 ((microbial infection) cleavage; by human enterovirus protease 3c)

Post-translational modifications (3): 2, 585, 712

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-4641258	Degradation of DVL
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-5658442	Regulation of RAS by GAPs
R-HSA-8951664	Neddylation
R-HSA-9013418	RHOBTB2 GTPase cycle
R-HSA-9013422	RHOBTB1 GTPase cycle
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9706019	RHOBTB3 ATPase cycle
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9929491	SPOP-mediated proteasomal degradation of PD-L1(CD274)

MSigDB gene sets: 558 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_CHROMOSOME_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, AAGCAAT_MIR137, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_GLAND_MORPHOGENESIS, GOBP_VESICLE_LOCALIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_INFLAMMATORY_RESPONSE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION

GO Biological Process (68): G1/S transition of mitotic cell cycle (GO:0000082), negative regulation of transcription by RNA polymerase II (GO:0000122), protein polyubiquitination (GO:0000209), kidney development (GO:0001822), trophectodermal cellular morphogenesis (GO:0001831), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), inflammatory response (GO:0006954), mitotic metaphase chromosome alignment (GO:0007080), integrin-mediated signaling pathway (GO:0007229), gastrulation (GO:0007369), positive regulation of cell population proliferation (GO:0008284), gene expression (GO:0010467), Wnt signaling pathway (GO:0016055), cell migration (GO:0016477), protein ubiquitination (GO:0016567), stem cell division (GO:0017145), cell projection organization (GO:0030030), anaphase-promoting complex-dependent catabolic process (GO:0031145), positive regulation of protein ubiquitination (GO:0031398), protein destabilization (GO:0031648), positive regulation of cytokinesis (GO:0032467), negative regulation of type I interferon production (GO:0032480), cellular response to oxidative stress (GO:0034599), negative regulation of Rho protein signal transduction (GO:0035024), embryonic cleavage (GO:0040016), stress fiber assembly (GO:0043149), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), fibroblast apoptotic process (GO:0044346), positive regulation of mitotic metaphase/anaphase transition (GO:0045842), COPII vesicle coat assembly (GO:0048208), protein autoubiquitination (GO:0051865), protein K48-linked ubiquitination (GO:0070936), cellular response to amino acid stimulus (GO:0071230), nuclear protein quality control by the ubiquitin-proteasome system (GO:0071630), liver morphogenesis (GO:0072576), intrinsic apoptotic signaling pathway (GO:0097193), regulation protein catabolic process at postsynapse (GO:0140252), regulation of cellular response to insulin stimulus (GO:1900076)

GO Molecular Function (9): Notch binding (GO:0005112), cyclin binding (GO:0030332), POZ domain binding (GO:0031208), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), ubiquitin ligase complex scaffold activity (GO:0160072), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515)

GO Cellular Component (22): spindle pole (GO:0000922), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), centrosome (GO:0005813), polar microtubule (GO:0005827), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), Cul3-RING ubiquitin ligase complex (GO:0031463), sperm flagellum (GO:0036126), extracellular exosome (GO:0070062), mitotic spindle (GO:0072686), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), spindle (GO:0005819), cytoskeleton (GO:0005856), cilium (GO:0005929), cullin-RING ubiquitin ligase complex (GO:0031461), motile cilium (GO:0031514), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
RHOBTB GTPase Cycle	2
TCF dependent signaling in response to WNT	1
Signaling by Hedgehog	1
RAF/MAP kinase cascade	1
Post-translational protein modification	1
SARS-CoV Infections	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Cellular response to chemical stress	1
Class I MHC mediated antigen processing & presentation	1
Regulation of PD-L1(CD274) Post-translational modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein ubiquitination	3
cytoplasm	3
mitotic cell cycle	2
embryonic morphogenesis	2
cell surface receptor signaling pathway	2
protein binding	2
spindle	2
intracellular membrane-bounded organelle	2
synapse	2
intracellular membraneless organelle	2
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
animal organ development	1
renal system development	1
cell morphogenesis	1
trophectodermal cell differentiation	1
modification-dependent protein catabolic process	1
intercellular transport	1
intracellular transport	1
Golgi vesicle transport	1
defense response	1
mitotic sister chromatid segregation	1
metaphase chromosome alignment	1
mitotic cell cycle process	1
ectoderm formation	1
endoderm formation	1
mesoderm formation	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
macromolecule biosynthetic process	1
cell motility	1
protein modification by small protein conjugation	1
cell division	1
cellular component organization	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1

Protein interactions and networks

STRING

4679 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CUL3	RBX1	P62877	999
CUL3	KEAP1	Q14145	998
CUL3	SPOP	O43791	997
CUL3	KLHL20	Q9Y2M5	995
CUL3	KLHL9	Q9P2J3	993
CUL3	CUL2	Q13617	983
CUL3	KLHL12	Q53G59	982
CUL3	SPOPL	Q6IQ16	982
CUL3	KLHL13	Q9P2N7	980
CUL3	KCTD5	Q9NXV2	977
CUL3	CUL1	Q13616	968
CUL3	KLHL3	Q9UH77	968
CUL3	CUL4A	Q13619	966
CUL3	RNF7	Q9UBF6	966
CUL3	CUL5	Q93034	959

IntAct

392 interactions, top by confidence:

A	B	Type	Score
CAND1	CUL1	psi-mi:“MI:0914”(association)	0.960
NEDD8	UBE2M	psi-mi:“MI:0914”(association)	0.940
KLHL12	CUL3	psi-mi:“MI:0915”(physical association)	0.920
CUL3	KLHL12	psi-mi:“MI:0915”(physical association)	0.920
CUL3	KLHL12	psi-mi:“MI:0914”(association)	0.920
KLHL2	CUL3	psi-mi:“MI:0915”(physical association)	0.880
CUL3	KLHL2	psi-mi:“MI:0915”(physical association)	0.880
CUL3	BTBD1	psi-mi:“MI:0915”(physical association)	0.880
CUL3	KCTD9	psi-mi:“MI:0915”(physical association)	0.870
CUL3	KCTD6	psi-mi:“MI:0915”(physical association)	0.870
CUL3	KCTD13	psi-mi:“MI:0915”(physical association)	0.870
KCTD6	CUL3	psi-mi:“MI:0915”(physical association)	0.870
KCTD13	CUL3	psi-mi:“MI:0915”(physical association)	0.870
KCTD6	CUL3	psi-mi:“MI:0407”(direct interaction)	0.870
KLHL9	CUL3	psi-mi:“MI:0915”(physical association)	0.860
KLHL9	CUL3	psi-mi:“MI:0914”(association)	0.860
CUL3	KLHL3	psi-mi:“MI:0915”(physical association)	0.850
KLHL3	CUL3	psi-mi:“MI:0915”(physical association)	0.850

BioGRID (4883): CUL3 (Affinity Capture-MS), CUL3 (Affinity Capture-MS), KLHL22 (Affinity Capture-Western), BTBD1 (Affinity Capture-Western), BTBD2 (Affinity Capture-Western), KCTD13 (Affinity Capture-Western), TNFAIP1 (Affinity Capture-Western), KLHL3 (Affinity Capture-Western), RBX1 (Reconstituted Complex), CUL3 (Affinity Capture-Western), UBE2D1 (Reconstituted Complex), CUL3 (Affinity Capture-Western), CUL3 (Affinity Capture-Western), CUL3 (Two-hybrid), KLHL2 (Two-hybrid)

ESM2 similar proteins: A4IHP4, B5DF89, B5DFC8, O13790, O14122, O43747, O60999, P0CH31, P22892, P34561, Q09760, Q12018, Q13617, Q13618, Q17389, Q17390, Q17391, Q17392, Q1MTP1, Q20938, Q21346, Q23639, Q24311, Q2TBL4, Q54NZ5, Q54XF7, Q5B3U7, Q5R5M2, Q5RAT8, Q5RCF3, Q5ZC88, Q6DE95, Q6GPF3, Q7SI58, Q8LGH4, Q8LPK4, Q8LPL6, Q8R1B4, Q8VWK0, Q94AH6

Diamond homologs: A2A432, A4IHP4, B5DF89, O13790, O14122, O60999, P0CH31, Q09760, Q13616, Q13618, Q13619, Q13620, Q17391, Q17392, Q24311, Q3TCH7, Q54CS2, Q54NZ5, Q54XF7, Q5R4G6, Q5ZC88, Q6DE95, Q6GPF3, Q8LGH4, Q94AH6, Q9C9L0, Q9JLV5, Q9SRZ0, Q9WTX6, Q9ZVH4, Q12018, Q13617, Q17389, Q17390, Q21346, Q5RCF3, Q9D4H8, Q9XZJ3, Q23639, Q5RB36

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
NAE	“up-regulates activity”	CUL3	neddylation
CUL3	“up-regulates activity”	TNFAIP1	binding
CUL3	“up-regulates activity”	KCTD13	binding
CUL3	“up-regulates activity”	KCTD10	binding
CUL3	“down-regulates quantity by destabilization”	RHOA	ubiquitination
CUL3	“up-regulates activity”	ARIH1	binding
SPOP	“up-regulates activity”	CUL3	binding
CUL3	“up-regulates activity”	LZTR1	binding
CUL3	“form complex”	“Cullin 3-RBX1-Skp1”	binding
CUL3	“form complex”	CUL3-RBX1-KEAP1	binding
CUL3	“down-regulates quantity by destabilization”	HSF2	ubiquitination
GAN	“up-regulates activity”	CUL3	binding
CUL3	“down-regulates quantity”	TBCB	ubiquitination
CUL3	“down-regulates quantity”	MAP1B	ubiquitination
CUL3	“down-regulates quantity”	MAP1S	ubiquitination
KEAP1	“up-regulates activity”	CUL3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 100 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	7	25.9×	1e-06
Iron uptake and transport	5	22.5×	9e-05
Neddylation	35	21.5×	5e-36
Formation of TC-NER Pre-Incision Complex	7	19.2×	7e-06
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	6	18.5×	3e-05
Vif-mediated degradation of APOBEC3G	5	16.5×	4e-04
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	5	16.1×	4e-04
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	5	16.1×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein neddylation	10	76.3×	6e-15
regulation of protein neddylation	7	71.2×	6e-10
extrinsic apoptotic signaling pathway via death domain receptors	5	21.8×	2e-04
proteasome-mediated ubiquitin-dependent protein catabolic process	25	14.2×	1e-19
protein ubiquitination	27	12.2×	1e-19
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	5	11.4×	3e-03
neurogenesis	5	11.3×	3e-03
protein K48-linked ubiquitination	6	11.0×	1e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — LUSC, PRCC, RCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	38
Uncertain significance	298
Likely benign	138
Benign	78

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100515	NM_003590.5(CUL3):c.1207-12T>G	Pathogenic
100516	NM_003590.5(CUL3):c.1207-1G>A	Pathogenic
100517	NM_003590.5(CUL3):c.1207-26A>G	Pathogenic
100518	NM_003590.5(CUL3):c.1207-28T>G	Pathogenic
100519	NM_003590.5(CUL3):c.1207-3C>T	Pathogenic
100520	NM_003590.5(CUL3):c.1207-5T>A	Pathogenic
100521	NM_003590.5(CUL3):c.1236G>A (p.Leu412=)	Pathogenic
100522	NM_003590.5(CUL3):c.1376A>G (p.Lys459Arg)	Pathogenic
100523	NM_003590.5(CUL3):c.1376_1377+4del	Pathogenic
100524	NM_003590.5(CUL3):c.1377+1dup	Pathogenic
100525	NM_003590.5(CUL3):c.1377+1G>C	Pathogenic
1048101	NM_003590.5(CUL3):c.596C>G (p.Ser199Ter)	Pathogenic
1048102	NM_003590.5(CUL3):c.854T>C (p.Val285Ala)	Pathogenic
1048103	NM_003590.5(CUL3):c.137del (p.Arg46fs)	Pathogenic
1048104	NM_003590.5(CUL3):c.1239del (p.Asp413fs)	Pathogenic
1048105	NM_003590.5(CUL3):c.1758_1759insTG (p.Thr587Ter)	Pathogenic
1190331	NM_003590.5(CUL3):c.433_436del (p.Ile145fs)	Pathogenic
1449007	NM_003590.5(CUL3):c.883+1G>T	Pathogenic
1451655	NM_003590.5(CUL3):c.514dup (p.Glu172fs)	Pathogenic
1699112	NM_003590.5(CUL3):c.578T>G (p.Leu193Ter)	Pathogenic
1709001	NM_003590.5(CUL3):c.1035_1036dup (p.Leu346fs)	Pathogenic
1803956	NM_003590.5(CUL3):c.264+2T>G	Pathogenic
1805942	NM_003590.5(CUL3):c.652C>T (p.Gln218Ter)	Pathogenic
1810435	NM_003590.5(CUL3):c.268C>T (p.Arg90Ter)	Pathogenic
1925139	NM_003590.5(CUL3):c.1358del (p.Asn453fs)	Pathogenic
2013975	NM_003590.5(CUL3):c.1893dup (p.Gln632fs)	Pathogenic
2019327	NM_003590.5(CUL3):c.1630_1648dup (p.Leu550fs)	Pathogenic
2090420	NM_003590.5(CUL3):c.442C>T (p.Arg148Ter)	Pathogenic
2171740	NM_003590.5(CUL3):c.117_118del (p.Ala40fs)	Pathogenic
2445419	NM_003590.5(CUL3):c.1419_1425delinsTAAAC (p.Met473fs)	Pathogenic

SpliceAI

3184 predictions. Top by Δscore:

Variant	Effect	Δscore
2:224474190:T:TA	donor_gain	1.0000
2:224474257:T:C	donor_gain	1.0000
2:224474264:A:AC	donor_gain	1.0000
2:224474265:C:CC	donor_gain	1.0000
2:224478194:CCTCA:C	donor_loss	1.0000
2:224478195:CTCA:C	donor_loss	1.0000
2:224478196:TCA:T	donor_loss	1.0000
2:224478197:CACC:C	donor_loss	1.0000
2:224478198:ACC:A	donor_loss	1.0000
2:224478199:C:T	donor_loss	1.0000
2:224478199:CCT:C	donor_gain	1.0000
2:224478201:T:TA	donor_gain	1.0000
2:224478341:AGCAA:A	acceptor_gain	1.0000
2:224478342:GCAA:G	acceptor_gain	1.0000
2:224478343:CAA:C	acceptor_gain	1.0000
2:224478343:CAAC:C	acceptor_gain	1.0000
2:224478344:AA:A	acceptor_gain	1.0000
2:224478344:AACT:A	acceptor_gain	1.0000
2:224478345:ACTA:A	acceptor_gain	1.0000
2:224478345:ACTAA:A	acceptor_loss	1.0000
2:224478346:C:CC	acceptor_gain	1.0000
2:224478351:A:AC	acceptor_gain	1.0000
2:224481887:GATAC:G	donor_loss	1.0000
2:224481888:ATAC:A	donor_loss	1.0000
2:224481889:TA:T	donor_loss	1.0000
2:224481890:ACCTG:A	donor_loss	1.0000
2:224481891:C:CG	donor_loss	1.0000
2:224482075:TTTC:T	acceptor_gain	1.0000
2:224495978:T:C	acceptor_gain	1.0000
2:224495978:T:TC	acceptor_gain	1.0000

AlphaMissense

5123 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:224474256:A:C	Y766D	1.000
2:224474256:A:G	Y766H	1.000
2:224474262:A:C	Y764D	1.000
2:224474262:A:G	Y764H	1.000
2:224474289:C:G	A755P	1.000
2:224474291:A:C	L754W	1.000
2:224474291:A:G	L754S	1.000
2:224474294:T:C	Y753C	1.000
2:224474295:A:C	Y753D	1.000
2:224474295:A:G	Y753H	1.000
2:224474299:T:A	R751S	1.000
2:224474299:T:G	R751S	1.000
2:224474300:C:A	R751I	1.000
2:224474300:C:G	R751T	1.000
2:224474306:A:T	I749N	1.000
2:224474309:A:C	L748R	1.000
2:224474309:A:G	L748P	1.000
2:224474309:A:T	L748H	1.000
2:224474310:G:A	L748F	1.000
2:224474315:T:A	E746V	1.000
2:224474316:C:T	E746K	1.000
2:224474318:A:T	I745N	1.000
2:224474326:C:A	K742N	1.000
2:224474326:C:G	K742N	1.000
2:224474327:T:A	K742M	1.000
2:224474328:T:C	K742E	1.000
2:224474330:A:T	I741N	1.000
2:224474345:G:T	P736Q	1.000
2:224474350:G:C	F734L	1.000
2:224474350:G:T	F734L	1.000

dbSNP variants (sampled 300 via entrez): RS1000000232 (2:224490832 T>A,C), RS1000010327 (2:224580026 G>A,T), RS1000088084 (2:224570508 AAG>A), RS1000122014 (2:224499411 C>T), RS1000127473 (2:224523616 C>T), RS1000131080 (2:224556078 G>A), RS1000142756 (2:224539226 A>G), RS1000199143 (2:224525264 T>C), RS1000200276 (2:224508193 T>A), RS1000209209 (2:224565000 G>A,T), RS1000217834 (2:224493014 C>A,T), RS1000289069 (2:224533492 G>A,T), RS1000294544 (2:224493258 A>G), RS1000337199 (2:224586044 T>C), RS1000343758 (2:224527928 C>T)

Disease associations

OMIM: gene MIM:603136 | disease phenotypes: MIM:145260, MIM:614496, MIM:619239, MIM:177735

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	Autosomal dominant
neurodevelopmental disorder with or without autism or seizures	Definitive	Autosomal dominant
pseudohypoaldosteronism type 2E	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
pseudohypoaldosteronism type 2E	Definitive	AD
complex neurodevelopmental disorder	Definitive	AD

Mondo (9): pseudohypoaldosteronism type 2A (MONDO:0007772), pseudohypoaldosteronism type 2E (MONDO:0013782), neurodevelopmental disorder with or without autism or seizures (MONDO:0030994), autism spectrum disorder (MONDO:0005258), neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038), autosomal dominant pseudohypoaldosteronism type 1 (MONDO:0008329), NK-cell enteropathy (MONDO:0016996), intellectual disability (MONDO:0001071)

Orphanet (9): Pseudohypoaldosteronism type 2E (Orphanet:300530), Pseudohypoaldosteronism type 2 (Orphanet:757), Pseudohypoaldosteronism type 2A (Orphanet:88938), Non-specific syndromic intellectual disability (Orphanet:528084), Renal pseudohypoaldosteronism type 1 (Orphanet:171871), Pseudohypoaldosteronism type 1 (Orphanet:756), NK-cell enteropathy (Orphanet:263665), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000252	Microcephaly
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000822	Hypertension
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001270	Motor delay
HP:0001508	Failure to thrive
HP:0001631	Atrial septal defect
HP:0001642	Pulmonic stenosis
HP:0001942	Metabolic acidosis
HP:0002153	Hyperkalemia
HP:0002188	Delayed CNS myelination
HP:0002521	Hypsarrhythmia
HP:0003593	Infantile onset
HP:0004918	Hyperchloremic metabolic acidosis
HP:0008242	Pseudohypoaldosteronism
HP:0009777	Absent thumb
HP:0010851	EEG with burst suppression
HP:0010864	Severe intellectual disability
HP:0011423	Hyperchloremia
HP:0011968	Feeding difficulties
HP:0012469	Infantile spasms
HP:0025336	Delayed ability to sit
HP:0031936	Delayed ability to walk
HP:0032792	Tonic seizure

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002539_43	Schizophrenia	1.000000e-08
GCST003806_1	Response to bupropion and depression	6.000000e-07
GCST003941_3	Acute graft versus host disease in bone marrow transplantation (recipient effect)	2.000000e-08
GCST004946_133	Schizophrenia	5.000000e-12
GCST005411_1	Thrombin-activatable fibrinolysis inhibitor activation peptide	6.000000e-07
GCST006803_76	Schizophrenia	4.000000e-09
GCST007201_315	Schizophrenia	1.000000e-08
GCST007201_88	Schizophrenia	4.000000e-11
GCST007325_297	General risk tolerance (MTAG)	3.000000e-16
GCST009310_31	Sensorimotor dexterity	6.000000e-07
GCST90000025_878	Appendicular lean mass	4.000000e-33
GCST90000047_83	Age at first sexual intercourse	1.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004599	acute graft vs. host disease
EFO:0008579	risk-taking behaviour
EFO:0008354	cognitive function measurement
EFO:0004980	appendicular lean mass
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL4296123 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296124 (PROTEIN-PROTEIN INTERACTION), CHEMBL6067538 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
NFE2L2 Mutation OR KEAP1 Mutation OR CUL3 Mutation	Platinum Doublet	Lung Non-small Cell Carcinoma	Resistance	CIViC B	EID12558

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.82	Kd	15.06	nM	CHEMBL3752910
7.72	ED50	19.09	nM	CHEMBL3752910
6.07	Kd	860.9	nM	CHEMBL5653589
5.96	ED50	1092	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 19 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-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148182: Binding affinity to human CUL3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0151	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148182: Binding affinity to human CUL3 incubated for 45 mins by Kinobead based pull down assay	kd	0.8609	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	6
bisphenol A	decreases methylation, increases expression, decreases expression	5
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	increases reaction, increases expression, affects binding	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
decabromobiphenyl ether	decreases expression	1
arsenite	increases reaction, affects binding	1
sulforaphane	affects binding, decreases reaction	1
solanesol	affects binding, decreases reaction	1
2-tert-butylhydroquinone	affects binding, decreases reaction	1
tetrabromobisphenol A	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
mercuric bromide	affects cotreatment, decreases expression	1
salvianolic acid B	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	affects binding, increases reaction	1
K 7174	increases expression	1
motexafin gadolinium	decreases expression, affects cotreatment	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4147530	Binding	Induction of Keap1/Cul3-mediated EGFP tagged Tau (unknown origin) degredation in human SH-SY5Y cells by Flow cytometry analysis	Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. — Eur J Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7WW	Abcam Raji CUL3 KO	Cancer cell line	Male
CVCL_B9XG	Abcam THP-1 CUL3 KO	Cancer cell line	Male
CVCL_C6ZC	Abcam PC-3 CUL3 KO	Cancer cell line	Male
CVCL_D8JM	Ubigene HCT 116 CUL3 KO	Cancer cell line	Male
CVCL_D9CQ	Ubigene HEK293 CUL3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder