Cullin-4A

UniProt Q13619 Organism Homo sapiens Gene CUL4A

Also known as: CUL4A

Function

Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the 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 E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. DCX(DET1-COP1) directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of XPC. 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. 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. DCX(DTL) directs autoubiquitination of DTL. In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip. Is involved in ubiquitination of HOXA9. The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1. The DCX(ERCC8) complex (also named CSA complex) plays a role in transcription-coupled repair (TCR). 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. 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). 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. With CUL4B, contributes to ribosome biogenesis.

Classification

Family (Pfam): PF00888 Cullin, PF26557 Cullin_AB, PF10557 Cullin_Nedd8
InterPro: Cullin, Cullin-like_AB, Cullin_CS, Cullin_homology, Cullin_homology_sf, Cullin_N, Cullin_neddylation_domain, Cullin_repeat-like_dom_sf, WH-like_DNA-bd_sf, WH_DNA-bd_sf
Functional cluster: Mixed Regulatory & Membrane Proteins

Experimental structures · PDB · 8

2HYE X-ray 3.10A
4A0K X-ray 5.93A
7OKQ EM 8.40A
7OPC EM 3.00A
7OPD EM 3.00A
8B3G EM 4.40A
8B3I EM 3.50A
9EG8 EM 3.39A

A predicted model is available from AlphaFold.

Gene Ontology · 37

Drugs targeting this protein · 5

IBERDOMIDE modulator
POMALIDOMIDE inhibitor
THALIDOMIDE inhibitor
LENALIDOMIDE HYDROCHLORIDE MONOHYDRATE modulator
LENALIDOMIDE inhibitor

Related proteins · sequence + function similarity

Cullin-4A 1.00
Cullin-4B 0.92
Cullin-4B 0.89
Cullin-1 0.79
Cullin-1 0.79
Cullin-1 0.79
Vacuolar protein sorting-associated protein 53 homolog 0.74
Vacuolar protein sorting-associated protein 53 homolog 0.73
Vacuolar protein sorting-associated protein 53 homolog 0.73
Vacuolar protein sorting-associated protein 53 homolog 0.73
Exportin-1 0.71
Exportin-1 0.71

Co-cited proteins · studied together in the literature

Cullin-4B 16 shared papers
DNA damage-binding protein 1 16 shared papers
DET1 homolog 1 shared papers
Bystin 1 shared papers
Ribosomal biogenesis factor 1 shared papers
Cullin-1 9 shared papers
Cullin-2 8 shared papers
Cullin-3 8 shared papers
DNA excision repair protein ERCC-8 5 shared papers
Activating molecule in BECN1-regulated autophagy protein 1 4 shared papers
DNA damage-binding protein 2 6 shared papers
E3 ubiquitin-protein ligase RBX1 7 shared papers

Literature · 46 cited papers

Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair. Nat. Struct. Mol. Biol. · 2024
The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D. Nature · 2021
AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity. Nature · 2021
The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II. Nat. Commun. · 2020
CRL4AMBRA1 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling. EMBO J. · 2018
The eukaryotic proteome is shaped by E3 ubiquitin ligases targeting C-terminal degrons. Cell · 2018
Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
Characterization of the mammalian family of DCN-type NEDD8 E3 ligases. J. Cell Sci. · 2016
Genome-wide RNAi Screening Identifies Protein Modules Required for 40S Subunit Synthesis in Human Cells. Cell Rep. · 2015
CUL4-DDB1-CDT2 E3 ligase regulates the molecular clock activity by promoting ubiquitination-dependent degradation of the mammalian CRY1. PLoS ONE · 2015
An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
A Cul4 E3 ubiquitin ligase regulates histone hand-off during nucleosome assembly. Cell · 2013
… and 34 more in the literature graph

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