Q13619 · CUL4A_HUMAN
- ProteinCullin-4A
- GeneCUL4A
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids759 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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).
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).
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).
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).
Pathway
Protein modification; protein ubiquitination.
GO annotations
Keywords
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameCullin-4A
- Short namesCUL-4A
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ13619
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 86-90 | Largely reduces interaction with DDB1; abolishes interaction with DDB2. | ||||
Sequence: LYQAV → AAAAA | ||||||
Mutagenesis | 139-142 | Largely reduces interaction with DDB1; abolishes interaction with DDB2. | ||||
Sequence: WQDH → AADA | ||||||
Natural variant | VAR_020341 | 644 | in dbSNP:rs2302757 | |||
Sequence: K → R |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 572 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, cross-link, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000119795 | 1-759 | UniProt | Cullin-4A | |||
Sequence: MADEAPRKGSFSALVGRTNGLTKPAALAAAPAKPGGAGGSKKLVIKNFRDRPRLPDNYTQDTWRKLHEAVRAVQSSTSIRYNLEELYQAVENLCSHKVSPMLYKQLRQACEDHVQAQILPFREDSLDSVLFLKKINTCWQDHCRQMIMIRSIFLFLDRTYVLQNSTLPSIWDMGLELFRTHIISDKMVQSKTIDGILLLIERERSGEAVDRSLLRSLLGMLSDLQVYKDSFELKFLEETNCLYAAEGQRLMQEREVPEYLNHVSKRLEEEGDRVITYLDHSTQKPLIACVEKQLLGEHLTAILQKGLDHLLDENRVPDLAQMYQLFSRVRGGQQALLQHWSEYIKTFGTAIVINPEKDKDMVQDLLDFKDKVDHVIEVCFQKNERFVNLMKESFETFINKRPNKPAELIAKHVDSKLRAGNKEATDEELERTLDKIMILFRFIHGKDVFEAFYKKDLAKRLLVGKSASVDAEKSMLSKLKHECGAAFTSKLEGMFKDMELSKDIMVHFKQHMQNQSDSGPIDLTVNILTMGYWPTYTPMEVHLTPEMIKLQEVFKAFYLGKHSGRKLQWQTTLGHAVLKAEFKEGKKEFQVSLFQTLVLLMFNEGDGFSFEEIKMATGIEDSELRRTLQSLACGKARVLIKSPKGKEVEDGDKFIFNGEFKHKLFRIKINQIQMKETVEEQVSTTERVFQDRQYQIDAAIVRIMKMRKTLGHNLLVSELYNQLKFPVKPGDLKKRIESLIDRDYMERDKDNPNQYHYVA | |||||||
Cross-link | 8 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) | ||||
Sequence: K | |||||||
Modified residue | 10 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 10 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 12 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Cross-link | 33 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 40 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 684 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Cross-link | 705 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in NEDD8) | ||||
Sequence: K |
Post-translational modification
Neddylated. Deneddylated via its interaction with the COP9 signalosome (CSN) complex.
(Microbial infection) Deneddylated by Epstein-Barr virus BPLF1 leading to a S-phase-like environment that is required for efficient replication of the viral genome.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Interaction
Subunit
Can self-associate (PubMed:17254749).
Component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes that seem to consist of DDB1, CUL4A or CUL4B, RBX1 and a variable substrate recognition component which seems to belong to a protein family described as DCAF (Ddb1- and Cul4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins (PubMed:12732143, PubMed:14578910, PubMed:14739464, PubMed:15548678, PubMed:29779948, PubMed:30166453).
Component of the CSA complex (DCX(ERCC8) complex) containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II (PubMed:12732143).
Component of the DCX(DET1-COP1) complex with the substrate recognition component DET1 and COP1 (PubMed:14739464).
Component of the DCX(DDB2) complex with the substrate recognition component DDB2 (PubMed:15811626, PubMed:16678110).
Component of the DCX(DTL) complex with the putative substrate recognition component DTL (PubMed:14578910, PubMed:15448697, PubMed:15548678).
Component of DCX complexes part of the DesCEND (destruction via C-end degrons) pathway, which contain either TRPC4AP or DCAF12 as substrate-recognition component (PubMed:29779948).
Component of the DCX(AMBRA1) complex with the substrate recognition component AMBRA1 (PubMed:30166453, PubMed:33854232, PubMed:33854239).
Interacts with DDB1, RBX1, RNF7, CDT1, TIP120A/CAND1, SKP2, CDKN1B, MDM2, TP53 and HOXA9 (PubMed:10230407, PubMed:12609982, PubMed:14609952, PubMed:16482215, PubMed:16537899, PubMed:16678110, PubMed:16964240, PubMed:22118460).
Interacts with DDB2; the interactions with DDB2 and CAND1 are mutually exclusive (PubMed:16482215, PubMed:16678110, PubMed:22118460).
Interacts with DCAF1, DTL, DDA1, DCAF6, DCAF4, DCAF16, DCAF17, DET1, WDTC1, DCAF5, DCAF11, WDR24A, COP1, PAFAH1B1, ERCC8, GRWD1, FBXW5, RBBP7, GNB2, WSB1, WSB2, NUP43, PWP1, FBXW8, ATG16L1, KATNB1, RBBP4, RBBP5, LRWD1 and DCAF8 (PubMed:16949367, PubMed:17079684, PubMed:22935713).
May interact with WDR26, WDR51B, SNRNP40, WDR61, WDR76, WDR5 (PubMed:17041588).
Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655).
The DDB1-CUL4A complex interacts with CRY1 (PubMed:26431207).
Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:23201271, PubMed:26906416).
Component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes that seem to consist of DDB1, CUL4A or CUL4B, RBX1 and a variable substrate recognition component which seems to belong to a protein family described as DCAF (Ddb1- and Cul4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins (PubMed:12732143, PubMed:14578910, PubMed:14739464, PubMed:15548678, PubMed:29779948, PubMed:30166453).
Component of the CSA complex (DCX(ERCC8) complex) containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II (PubMed:12732143).
Component of the DCX(DET1-COP1) complex with the substrate recognition component DET1 and COP1 (PubMed:14739464).
Component of the DCX(DDB2) complex with the substrate recognition component DDB2 (PubMed:15811626, PubMed:16678110).
Component of the DCX(DTL) complex with the putative substrate recognition component DTL (PubMed:14578910, PubMed:15448697, PubMed:15548678).
Component of DCX complexes part of the DesCEND (destruction via C-end degrons) pathway, which contain either TRPC4AP or DCAF12 as substrate-recognition component (PubMed:29779948).
Component of the DCX(AMBRA1) complex with the substrate recognition component AMBRA1 (PubMed:30166453, PubMed:33854232, PubMed:33854239).
Interacts with DDB1, RBX1, RNF7, CDT1, TIP120A/CAND1, SKP2, CDKN1B, MDM2, TP53 and HOXA9 (PubMed:10230407, PubMed:12609982, PubMed:14609952, PubMed:16482215, PubMed:16537899, PubMed:16678110, PubMed:16964240, PubMed:22118460).
Interacts with DDB2; the interactions with DDB2 and CAND1 are mutually exclusive (PubMed:16482215, PubMed:16678110, PubMed:22118460).
Interacts with DCAF1, DTL, DDA1, DCAF6, DCAF4, DCAF16, DCAF17, DET1, WDTC1, DCAF5, DCAF11, WDR24A, COP1, PAFAH1B1, ERCC8, GRWD1, FBXW5, RBBP7, GNB2, WSB1, WSB2, NUP43, PWP1, FBXW8, ATG16L1, KATNB1, RBBP4, RBBP5, LRWD1 and DCAF8 (PubMed:16949367, PubMed:17079684, PubMed:22935713).
May interact with WDR26, WDR51B, SNRNP40, WDR61, WDR76, WDR5 (PubMed:17041588).
Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655).
The DDB1-CUL4A complex interacts with CRY1 (PubMed:26431207).
Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:23201271, PubMed:26906416).
(Microbial infection) Interacts with Epstein-Barr virus BPLF1.
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q13619 | ATXN1 P54253 | 6 | EBI-456106, EBI-930964 | |
BINARY | Q13619 | CAND1 Q86VP6 | 6 | EBI-456106, EBI-456077 | |
BINARY | Q13619 | DDB1 Q16531 | 16 | EBI-456106, EBI-350322 | |
BINARY | Q13619 | DDB2 Q92466 | 12 | EBI-456106, EBI-1176171 | |
BINARY | Q13619 | HSP90AB1 P08238 | 2 | EBI-456106, EBI-352572 | |
BINARY | Q13619 | UBXN7 O94888 | 7 | EBI-456106, EBI-1993627 | |
BINARY | Q13619 | VCP P55072 | 2 | EBI-456106, EBI-355164 |
Protein-protein interaction databases
Miscellaneous
Structure
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q13619-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length759
- Mass (Da)87,680
- Last updated2006-05-30 v3
- Checksum3C4C6A1BBD94D51B
Q13619-2
- Name2
- Differences from canonical
- 1-100: Missing
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A0A0MR50 | A0A0A0MR50_HUMAN | CUL4A | 667 | ||
A0A087WWN2 | A0A087WWN2_HUMAN | CUL4A | 174 |
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_018577 | 1-100 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 281 | in Ref. 3; BAD93235 | ||||
Sequence: S → T | ||||||
Sequence conflict | 496 | in Ref. 3; BAD93235 | ||||
Sequence: K → R |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF077188 EMBL· GenBank· DDBJ | AAD45191.1 EMBL· GenBank· DDBJ | mRNA | ||
AY365124 EMBL· GenBank· DDBJ | AAR13072.1 EMBL· GenBank· DDBJ | mRNA | ||
AB178950 EMBL· GenBank· DDBJ | BAD93235.1 EMBL· GenBank· DDBJ | mRNA | ||
AL136221 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC008308 EMBL· GenBank· DDBJ | AAH08308.2 EMBL· GenBank· DDBJ | mRNA | ||
AB012193 EMBL· GenBank· DDBJ | BAA33146.1 EMBL· GenBank· DDBJ | mRNA | ||
U58090 EMBL· GenBank· DDBJ | AAC50547.2 EMBL· GenBank· DDBJ | mRNA |