Protein / target
Cullin-4A
Protein at a glance
Biological role
Ubiquitin ligase complex scaffold activity
Primary system
Immune system
Strongest disease association
plasma cell myeloma
Therapeutic maturity
Clinically validated target
Druggability
Small molecule
Clinical development
3 approved · 1 in clinical development
Derived from structured UniProt, Open Targets and literature data on this page.
Protein profile
Canonical identity and biological annotation from UniProt.
Function
Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins (PubMed:14578910, PubMed:14739464, PubMed:15448697, PubMed:15548678, PubMed:15811626, PubMed:16678110, PubMed:17041588, PubMed:24209620, PubMed:30166453, PubMed:33854232, PubMed:33854239). As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme (PubMed:14578910, PubMed:14739464, PubMed:15448697, PubMed:15548678, PubMed:15811626, PubMed:16678110, PubMed:17041588, PubMed:24209620). 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 (PubMed:14578910, PubMed:14739464, PubMed:15448697, PubMed:15548678, PubMed:15811626, PubMed:16678110, PubMed:17041588, PubMed:24209620). The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component (PubMed:14578910, PubMed:14739464, PubMed:15448697, PubMed:15548678, PubMed:15811626, PubMed:16678110, PubMed:17041588, PubMed:24209620). DCX(DET1-COP1) directs ubiquitination of JUN (PubMed:14739464). DCX(DDB2) directs ubiquitination of XPC (PubMed:15811626). DCX(DDB2) ubiquitinates histones H3-H4 and is required for efficient histone deposition during replication-coupled (H3.1) and replication-independent (H3.3) nucleosome assembly, probably by facilitating the transfer of H3 from ASF1A/ASF1B to other chaperones involved in histone deposition (PubMed:16678110, PubMed:17041588, PubMed:24209620). DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of p53/TP53 in response to radiation-induced DNA damage and during DNA replication (PubMed:14578910, PubMed:15448697, PubMed:15548678). DCX(DTL) directs autoubiquitination of DTL (PubMed:23478445). In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip (PubMed:16537899). Is involved in ubiquitination of HOXA9 (PubMed:14609952). The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1 (PubMed:26431207). The DCX(ERCC8) complex (also named CSA complex) plays a role in transcription-coupled repair (TCR) (PubMed:12732143, PubMed:32355176, PubMed:38316879). A number of DCX complexes (containing either TRPC4AP or DCAF12 as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948). The DCX(AMBRA1) complex is a master regulator of the transition from G1 to S cell phase by mediating ubiquitination of phosphorylated cyclin-D (CCND1, CCND2 and CCND3) (PubMed:33854232, PubMed:33854239). The DCX(AMBRA1) complex also acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes (PubMed:30166453). With CUL4B, contributes to ribosome biogenesis (PubMed:26711351)
Domains and Gene Ontology detail (38)Hide
Domains & features
Gene Ontology
- CCul4-RING E3 ubiquitin ligase complex
- CCul4A-RING E3 ubiquitin ligase complex
- Ccytoplasm
- Cnucleoplasm
- Cnucleus
- Fubiquitin ligase complex scaffold activity
- Fubiquitin protein ligase activity
- Fubiquitin protein ligase binding
- Pcell population proliferation
- Pcellular response to UV
- PDNA damage response
- Pepigenetic regulation of gene expression
Biological roles
What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.
View supporting evidenceHide supporting evidence
Transcriptional regulation
- ·Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which…
- ·epigenetic regulation of gene expression
- ·Transcription-Coupled Nucleotide Excision Repair (TC-NER)
Immune signalling
- ·regulation of mitotic cytokinesis
- ·T cell activation
Apoptosis & cell death
- ·regulation of apoptotic process
View underlying pathways (10)Hide underlying pathways
Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.
Interaction neighbourhood
Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.
Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.
Drugs targeting this protein
Whether each drug engages this protein directly or through a complex, and how many other targets are recorded for it. Direct binders with few recorded targets are listed first.
CRL4(CRBN) E3 ubiquitin ligase inhibitor
Appears in clinical studies involving plasma cell myeloma, immune system disorder, prostate cancer, non-small cell lung carcinoma
CRL4(CRBN) E3 ubiquitin ligase inhibitor
Appears in clinical studies involving anemia, mantle cell lymphoma, myelodysplastic syndrome, plasma cell myeloma
ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.
Translational evidence
Why this target matters therapeutically — disease associations, drugs in development, tractability and safety, from Open Targets.
Highest-confidence therapeutic associations
Diseases where a drug acting on this target has already reached clinical development.
Highest overall evidence
Remaining associations by Open Targets' aggregated evidence score.
Show all associationsHide all associations
Open Targets ranks 498 associations for this target and we store the top 10 by aggregated score. The long tail is largely literature co-mention and RNA-expression evidence, not evidence that this target drives those diseases.
Known drugs · 4 total
plasma cell myeloma · sarcoidosis · systemic lupus erythematosus
plasma cell myeloma · systemic sclerosis · immune system disorder
anemia · mantle cell lymphoma · myelodysplastic syndrome
plasma cell myeloma · immune system disorder · prostate cancer
Tractability
Clinical trials
Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.
Show remaining trials (24)Hide
ClinicalTrials.gov via the drug-target graph.
Forefront confidence
Our own weighting of the evidence behind each disease association. Human genetics and clinical evidence count for most; literature co-mention counts for little, because two entities sharing an abstract is not evidence that one drives the other.
The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the underlying per-type scores are shown above so the calculation can be checked.
What's happening now
Recent activity around this target, drawn from one canonical event stream. Every item is reached through 2 drugs that target this protein, so each event is news about that drug rather than about the protein directly.
- Label change
Label change: LENALIDOMIDE (NDA021880)
- Industry developmentAdvanced hierarchical ZnFe-LDH@MnO₂ nanostructures for sensitive voltammetric determination of lenalidomide
- Label change
Label change: LENALIDOMIDE (ANDA201452)
- Label change
Label change: LENALIDOMIDE (ANDA201452)
- Supplemental approval
Supplemental approval: LENALIDOMIDE (ANDA201452)
- Supplemental approval
Supplemental approval: LENALIDOMIDE (NDA021880)
- Supplemental approval
Supplemental approval: LENALIDOMIDE (ANDA201452)
- Supplemental approval
Supplemental approval: LENALIDOMIDE (NDA021880)
- Regulatory approval
Approval: LENALIDOMIDE (ANDA201452)
- Regulatory approval
Approval: Thalidomide Lipomed (EMA)
- Label change
Label change: LENALIDOMIDE (NDA021880)
- Label change
Label change: LENALIDOMIDE (NDA021880)
Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.