CUL4A Protein

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CUL4A Protein

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CUL4A Protein (Cullin-4A)

Overview

CUL4A (Cullin-4A) is a member of the cullin family of scaffold proteins that form the core of Cullin-RING E3 ubiquitin ligase (CRL) complexes[@kipreos1996]. These multiprotein assemblies are essential for targeted protein degradation through the [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system) (UPS), which regulates nearly all cellular processes including cell cycle progression, DNA damage repair, transcription, and protein quality control[@petroski2005]. CUL4A is uniquely involved in numerous neurological disorders, including Alzheimer's disease, Parkinson's disease, and Cockayne syndrome, making it a significant protein in neurodegeneration research[@jackson2009].

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CUL4A Protein (Cullin-4A)

Overview

CUL4A (Cullin-4A) is a member of the cullin family of scaffold proteins that form the core of Cullin-RING E3 ubiquitin ligase (CRL) complexes[@kipreos1996]. These multiprotein assemblies are essential for targeted protein degradation through the [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system) (UPS), which regulates nearly all cellular processes including cell cycle progression, DNA damage repair, transcription, and protein quality control[@petroski2005]. CUL4A is uniquely involved in numerous neurological disorders, including Alzheimer's disease, Parkinson's disease, and Cockayne syndrome, making it a significant protein in neurodegeneration research[@jackson2009].

<div class="infobox infobox-protein">
<div class="infobox-header">CUL4A Protein</div>
<div class="infobox-row">
<div class="infobox-label">Protein Name</div>
<div class="infobox-value">Cullin-4A (CUL4A)</div>
</div>
<div class="infobox-row">
<div class="infobox-label">Gene</div>
<div class="infobox-value">[CUL4A](/genes/cul4a)</div>
</div>
<div class="infobox-row">
<div class="infobox-label">UniProt ID</div>
<div class="infobox-value"><a href="https://www.uniprot.org/uniprot/Q13619" target="_blank">Q13619</a></div>
</div>
<div class="infobox-row">
<div class="infobox-label">Molecular Weight</div>
<div class="infobox-value">~190 kDa</div>
</div>
<div class="infobox-row">
<div class="infobox-label">Subcellular Localization</div>
<div class="infobox-value">Cytoplasm, Nucleus</div>
</div>
<div class="infobox-row">
<div class="infobox-label">Protein Family</div>
<div class="infobox-value">Cullin family</div>
</div>
<div class="infobox-row">
<div class="infobox-label">Tissue Expression</div>
<div class="infobox-value">Broad (brain, liver, lung, heart)</div>
</div>
</div>

Structure and Architecture

Domain Organization

CUL4A contains several distinct structural domains that enable its function as a molecular scaffold:

N-terminal Domain: Binds to the substrate recognition receptor DDB1 (DNA Damage Binding Protein 1), which recruits specific substrates for ubiquitination[@scrima2008]
Cullin Repeat Domain (CR): Five repeat motifs that form the elongated helical scaffold structure
C-terminal Domain: Contains the RING finger motif that recruits the E2 ubiquitin-conjugating enzyme

CRL4 Complex Architecture

The CRL4 (Cullin 4-RING ligase) complex consists of:

CUL4A: The central scaffold

DDB1: The adaptor protein that binds to the N-terminus

DCAF (DDB1-CUL4-associated factor): Substrate receptors that recognize specific target proteins

RBX1/ROC1: The RING finger protein that brings the E2 enzyme close to the substrate

This modular architecture allows for remarkable substrate diversity, with over 300 different DCAFs identified in humans[@lee2007].

Normal Cellular Functions

Ubiquitin-Proteasome System

The UPS is the primary cellular system for targeted protein degradation:

Ubiquitination: CUL4A CRLs catalyze the attachment of ubiquitin chains to specific substrate proteins

Polyubiquitination: Chains of ubiquitin (typically K48-linked) mark proteins for degradation

Proteasomal Recognition: The 26S proteasome recognizes polyubiquitinated proteins and degrades them

DNA Damage Response

CUL4A plays critical roles in maintaining genomic integrity:

Nucleotide Excision Repair (NER): CRL4^DDB2 complex recognizes and repairs UV-induced DNA damage[@grinstein2010]
Chromatin Remodeling: Regulates [histone modifications](/entities/histone-modifications) and DNA repair factor accessibility
Cell Cycle Checkpoints: Controls checkpoint proteins to ensure DNA integrity before division

Transcriptional Regulation

CUL4A CRLs regulate transcription factors and co-factors:

Control of steroid hormone receptors
Regulation of circadian clock proteins
Modulation of inflammatory response factors

Role in Neurodegenerative Diseases

Alzheimer's Disease

CUL4A dysfunction contributes to AD pathogenesis through multiple mechanisms[@liu2017]:

Impaired Protein Clearance: The UPS is compromised in AD brains, and CUL4A dysfunction exacerbates this defect

DNA Damage Accumulation: [Neurons](/entities/neurons) in AD show increased DNA damage; CUL4A deficiency impairs repair mechanisms

[Tau](/proteins/tau) Pathology: CUL4A regulates tau ubiquitination and clearance; dysregulation contributes to NFT formation

Amyloid-β Metabolism: CRL4 complexes influence [amyloid precursor protein](/entities/app-protein) (APP) processing

Parkinson's Disease

In PD, CUL4A involvement includes:

[α-Synuclein](/proteins/alpha-synuclein) Clearance: Impaired ubiquitination may affect clearance of toxic α-synuclein aggregates

Mitochondrial Quality Control: CUL4A regulates proteins involved in mitochondrial dynamics

Dopaminergic Neuron Vulnerability: DNA repair deficits in dopaminergic neurons may be CUL4A-related

Cockayne Syndrome

Cockayne syndrome (CS) is caused by recessive mutations in CUL4A[@vancraenenbroeck2018]:

Severe developmental defects including progressive neurological deterioration
Premature aging phenotype
Defective transcription-coupled DNA repair (TCR)
Neurodegeneration with demyelination

Other Neurodegenerative Disorders

CUL4A has been implicated in:

Huntington's Disease: Altered ubiquitination of mutant [huntingtin protein](/proteins/huntingtin)
Amyotrophic Lateral Sclerosis: Dysregulation of protein clearance pathways
Prion Diseases: UPS impairment and protein aggregate formation

Therapeutic Implications

Drug Development Targets

CUL4A represents a potential therapeutic target:

Modulators of CRL4 Activity: Small molecules that enhance or inhibit CUL4A ligase function

DCAF-Specific Inhibitors: Targeting specific substrate receptors

UPS Enhancers: Compounds that boost overall proteasome function

Gene Therapy Approaches

CUL4A Expression Modulation: Careful balancing of CUL4A activity
DCAF-Targeted Therapy: More specific targeting of pathological substrates

Interactions and Pathways

Key Protein Interactions

DDB1: Essential adaptor for CRL4 complex formation
DDB2: DNA damage recognition factor (XPE)
CSA: Cockayne syndrome protein A (in TCR)
ROC1/RBX1: RING finger protein for E2 recruitment

Signaling Pathways

Ubiquitin-Proteasome System: Primary degradation pathway
DNA Damage Response: Global and transcription-coupled repair
p53 Pathway: CUL4A regulates p53 stability and function
[NF-κB](/entities/nf-kb) Signaling: Control of inflammatory responses

Cross-Links

[CUL4A Gene](/genes/cul4a) — Gene encoding this protein
[Ubiquitin-Proteasome System](/mechanisms/ubiquitin-proteasome-system) — Degradation pathway
[DNA Repair Pathways](/mechanisms/dna-repair-pathway) — Genome maintenance
[Alzheimer's Disease](/diseases/alzheimers-disease) — Disease association
[Parkinson's Disease](/diseases/parkinsons-disease) — Disease association
[Cockayne Syndrome](/diseases/cockayne-syndrome) — Genetic disorder

External Links

[UniProt: Q13619](https://www.uniprot.org/uniprot/Q13619)
[NCBI Gene: 8451](https://www.ncbi.nlm.nih.gov/gene/8451)
[GeneCards: CUL4A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CUL4A)
[OMIM: 603137](https://www.omim.org/entry/603137)

References

[Kipreos ET, et al, (1996) CUL-1 is required for cell cycle exit in C (1996)](https://pubmed.ncbi.nlm.nih.gov/8681382/)

[Petroski MD, Deshaies RJ, (2005) Function and regulation of cullin-RING ubiquitin ligases (2005)](https://pubmed.ncbi.nlm.nih.gov/15688063/)

[Jackson S, Xiong Y, (2009) CRL4s: the CUL4-RING E3 ubiquitin ligases (2009)](https://pubmed.ncbi.nlm.nih.gov/19819654/)

[Scrima A, et al, (2008) Structural basis of UV DNA-damage recognition by the DDB complex (2008)](https://pubmed.ncbi.nlm.nih.gov/19109893/)

[Lee J, Zhou P, (2007) DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase (2007)](https://pubmed.ncbi.nlm.nih.gov/17588513/)

[Grinstein E, et al, (2010) The role of CUL4A in human cancers (2010)](https://pubmed.ncbi.nlm.nih.gov/20421734/)

[Liu L, et al, (2017) CUL4A promotes glioma progression and facilitates stem cell maintenance via the upregulation of Sox2 (2017)](https://pubmed.ncbi.nlm.nih.gov/29029498/)

[Vancraenenbroeck R, et al, (2018) The ubiquitin system: a potential therapeutic target in ALS (2018)](https://pubmed.ncbi.nlm.nih.gov/29291906/)

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Related Entities

CUL4APROTEIN

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slug	proteins-cul4a-protein
kg_node_id	CUL4APROTEIN
entity_type	protein
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wiki_page_id	wp-5c378faf8688
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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

50%

Debates

0

Incoming

10

Outgoing

13

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CUL4A Protein

CUL4A Protein (Cullin-4A)

Overview

CUL4A Protein (Cullin-4A)

Overview

Structure and Architecture

Domain Organization

CRL4 Complex Architecture

Normal Cellular Functions

Ubiquitin-Proteasome System

DNA Damage Response

Transcriptional Regulation

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Cockayne Syndrome

Other Neurodegenerative Disorders

Therapeutic Implications

Drug Development Targets

Gene Therapy Approaches

Interactions and Pathways

Key Protein Interactions

Signaling Pathways

Cross-Links

See Also

External Links

References

💬 Discussion