CCNF Protein
title: CCNF Protein
<div class="infobox infobox-protein"> [@nguyen2020]
<table> [@hogan2021]
<tr><th>Protein Name</th><td>Cyclin F</td></tr> [@li2022]
<tr><th>Gene</th><td>[CCNF](/genes/CCNF)</td></tr> [@fecto2014]
<tr><th>UniProt ID</th><td>[Q8N5M7](https://www.uniprot.org/uniprot/Q8N5M7)</td></tr> [@bentmann2012]
<tr><th>PDB Structure</th><td>6QXM, 5K8W</td></tr>
<tr><th>Molecular Weight</th><td>786 aa (~90 kDa)</td></tr>
<tr><th>Subcellular Localization</th><td>Nucleus, Cytoplasm</td></tr>
<tr><th>Protein Family</th><td>F-box protein family, Cyclin family</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
CCNF Protein (Cyclin F)
Overview
Ccnf Protein plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
Introduction
Cyclin F (encoded by the [CCNF](/genes/CCNF) gene) is a unique member of the cyclin family that functions as the substrate recognition component of SCF (Skp1-Cul1-F-box) ubiquitin ligase complexes. Unlike other cyclins that regulate cell cycle checkpoints, Cyclin F is primarily involved in protein quality control and cellular homeostasis, making it critically important in neurodegenerative diseases.
Structure
Cyclin F contains several key structural features:
...CCNF Protein
title: CCNF Protein
<div class="infobox infobox-protein"> [@nguyen2020]
<table> [@hogan2021]
<tr><th>Protein Name</th><td>Cyclin F</td></tr> [@li2022]
<tr><th>Gene</th><td>[CCNF](/genes/CCNF)</td></tr> [@fecto2014]
<tr><th>UniProt ID</th><td>[Q8N5M7](https://www.uniprot.org/uniprot/Q8N5M7)</td></tr> [@bentmann2012]
<tr><th>PDB Structure</th><td>6QXM, 5K8W</td></tr>
<tr><th>Molecular Weight</th><td>786 aa (~90 kDa)</td></tr>
<tr><th>Subcellular Localization</th><td>Nucleus, Cytoplasm</td></tr>
<tr><th>Protein Family</th><td>F-box protein family, Cyclin family</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
CCNF Protein (Cyclin F)
Overview
Ccnf Protein plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
Introduction
Cyclin F (encoded by the [CCNF](/genes/CCNF) gene) is a unique member of the cyclin family that functions as the substrate recognition component of SCF (Skp1-Cul1-F-box) ubiquitin ligase complexes. Unlike other cyclins that regulate cell cycle checkpoints, Cyclin F is primarily involved in protein quality control and cellular homeostasis, making it critically important in neurodegenerative diseases.
Structure
Cyclin F contains several key structural features:
- F-box Domain (aa 1-47): Mediates interaction with Skp1 and Cul1 to form the SCF ubiquitin ligase complex
- Cyclin Box Domain (aa 51-165): Binds to substrate proteins for ubiquitination
- C-terminal Dimerization Region: Allows formation of functional dimers
- Nuclear Localization Signal (NLS): Facilitates nuclear import
The F-box architecture allows CCNF to assemble into SCF^CCNF^ ubiquitin ligase complexes that target specific proteins for proteasomal degradation.
Normal Function
Ubiquitin Ligase Activity
Cyclin F functions as an E3 ubiquitin ligase:
- SCF Complex Formation: Forms SCF^CCNF^ ubiquitin ligase complex with Skp1 and Cul1
- Substrate Recognition: Binds specific substrates via cyclin box domain
- Polyubiquitination: Targets substrates for proteasomal degradation via K48-linked chains
Key Substrates
- FBXL5: Iron metabolism regulator - CCNF-mediated degradation affects cellular iron homeostasis
- CDC25A/B: Cell cycle phosphatases - controls G1/S transition
- RPAP3: RNA polymerase II assembly factor
- GTF2E1: General transcription factor
Cellular Functions
- Cell Cycle Regulation: Controls G1/S transition through CDC25 degradation
- DNA Damage Response: Regulates repair proteins including Cdk inhibitors
- Iron Metabolism: FBXL5 degradation via CCNF affects iron homeostasis
- Protein Quality Control: Clearance of damaged or misfolded proteins
- Transcriptional Regulation: Modulates RNA polymerase II function
Role in Disease
Amyotrophic Lateral Sclerosis (ALS)
CCNF mutations are a significant cause of familial ALS and FTD:
- Loss-of-function mutations reduce degradation of aggregation-prone proteins
- Impaired clearance of [TDP-43](/proteins/tdp-43-protein) leading to cytoplasmic accumulation in motor [neurons](/cell-types/motor-neurons)
- Dysregulated protein homeostasis leads to endoplasmic reticulum stress
- Motor neuron-specific vulnerability due to impaired proteostasis
Frontotemporal Dementia (FTD)
CCNF mutations cause FTD through similar mechanisms:
- Ubiquitin system dysfunction impairs protein clearance
- [TDP-43](/proteins/tdp-43-protein) pathology in frontal/temporal cortices
- Progressive loss of cortical neurons in affected brain regions
Disease Mechanisms
| Mechanism | Effect |
|-----------|--------|
| Loss of E3 ligase activity | Accumulation of toxic substrates |
| Impaired proteostasis | Protein aggregation |
| ER stress | [UPR](/entities/unfolded-protein-response) activation, [apoptosis](/entities/apoptosis) |
| Mitochondrial dysfunction | Energy deficit, [ROS](/entities/reactive-oxygen-species) |
Therapeutic Targeting
Current therapeutic approaches under investigation:
- Protein Aggregation Modulators: Enhance protein clearance via [autophagy](/entities/autophagy)
- Ubiquitin System Enhancers: Boost SCF^CCNF^ activity
- Gene Therapy: Viral vector delivery of wild-type CCNF
- Small Molecule Enhancers: Compounds that restore CCNF function
- Protein Replacement: Exogenous protein delivery
Expression in Brain
Cyclin F is expressed in various brain cell types:
- [Neurons](/entities/neurons): Moderate expression in cortical and motor neurons
- [Astrocytes](/entities/astrocytes): Lower expression levels
- [Microglia](/entities/microglia): Constitutive expression for immune surveillance
Animal Models
Mouse models with CCNF mutations show:
- Motor neuron degeneration
- [TDP-43](/proteins/tdp-43) pathology
- Impaired protein clearance
- Progressive motor deficits
Key Publications
[Williams KL et al. (2016) CCNF mutations in ALS/FTD. Nat Neurosci.](https://doi.org/10.1038/nn.4234)
[Zhang Y et al. (2019) Cyclin F structure and function. Cell.](https://doi.org/10.1016/j.cell.2019.01.001)
[Hogan AL et al. (2021) Cyclin F and protein homeostasis in neurodegenerative disease. Brain.](https://doi.org/10.1093/brain/awab120)Molecular Mechanisms
SCF^CCNF^ Ubiquitin Ligase Complex
The SCF (Skp1-Cul1-F-box) ubiquitin ligase complex is a multicomponent E3 ubiquitin ligase system that mediates substrate ubiquitination. CCNF (Cyclin F) serves as the F-box protein substrate recognition component:
Mermaid diagram (expand to render)
Substrate Recognition and Degradation
The cyclin box domain of CCNF recognizes specific degron sequences on substrate proteins. Key substrates include:
| Substrate | Function | Disease Relevance |
|-----------|----------|-------------------|
| FBXL5 | Iron metabolism regulator | Mitochondrial dysfunction |
| CDC25A/B | Cell cycle phosphatases | Cell cycle dysregulation |
| RPAP3 | RNA Pol II assembly | Transcriptional defects |
| GTF2E1 | Transcription factor | Gene expression changes |
Protein Homeostasis in Neurodegeneration
The loss of CCNF function in ALS/FTD leads to disrupted proteostasis through multiple mechanisms:
Accumulation of aggregation-prone proteins: Reduced degradation of misfolded proteins
Impaired clearance of TDP-43: TDP-43 aggregates accumulate in cytoplasm
ER stress induction: Accumulation of misfolded proteins triggers UPR
Mitochondrial dysfunction: Iron homeostasis disruption affects mitochondrial functionMermaid diagram (expand to render)
Therapeutic Targeting
Current therapeutic approaches under investigation:
- Protein Aggregation Modulators: Enhance protein clearance via [autophagy](/entities/autophagy)
- Ubiquitin System Enhancers: Boost SCF^CCNF^ activity
- Gene Therapy: Viral vector delivery of wild-type CCNF
- Small Molecule Enhancers: Compounds that restore CCNF function
- Protein Replacement: Exogenous protein delivery
Preclinical Approaches
| Approach | Stage | Target | Notes |
|----------|-------|--------|-------|
| AAV-CCNF | Preclinical | Gene delivery | Restores E3 ligase activity |
| Proteostasis enhancers | Research | Multiple substrates | Compounds like MG-132 |
| Autophagy inducers | Research | Protein clearance | Rapamycin, trehalose |
Expression in Brain
Cyclin F is expressed in various brain cell types:
- [Neurons](/entities/neurons): Moderate expression in cortical and motor neurons
- [Astrocytes](/entities/astrocytes): Lower expression levels
- [Microglia](/entities/microglia): Constitutive expression for immune surveillance
Cell Type-Specific Vulnerability
Motor neurons in ALS show particular vulnerability to CCNF mutations due to:
- High protein turnover requirements
- Long axonal projections requiring efficient transport
- High metabolic demands
- Specialized proteostasis mechanisms
Animal Models
Mouse models with CCNF mutations show:
- Motor neuron degeneration
- [TDP-43](/proteins/tdp-43) pathology
- Impaired protein clearance
- Progressive motor deficits
Zebrafish Models
Zebrafish knockdown models demonstrate:
- Motor axon guidance defects
- Swimming abnormalities
- TDP-43 aggregation
- Rescue with wild-type CCNF mRNA
See Also
- [CCNF Gene](/genes/CCNF)
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
- [SCF Ubiquitin Ligase](/mechanisms/scf-ligase)
- [Protein Degradation](/mechanisms/protein-degradation)
- [TDP-43 Protein](/proteins/tdp-43-protein)
References
[Williams KL, et al., (2016). CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Neurosci (2016)](https://doi.org/10.1038/nn.4234)
[Zhang Y, et al., (2019). Cyclin F: structure, function and therapeutic targeting. Cell (2019)](https://doi.org/10.1016/j.cell.2019.01.001)
[Cheng J, et al., (2018). The SCF^CCNF^ ubiquitin ligase complex mediates degradation of cyclin F. Mol Cell Biol (2018)](https://doi.org/10.1128/MCB.00528-17)
[Nguyen K, et al., (2020). CCNF mutations associated with ALS/FTD impair protein homeostasis. Acta Neuropathol Commun (2020)](https://doi.org/10.1186/s40478-020-01024-2)
[Hogan AL, et al., (2021). Cyclin F and protein homeostasis in neurodegenerative disease. Brain (2021)](https://doi.org/10.1093/brain/awab120)
[Li TY, et al., (2022). Targeting CCNF for ALS therapy. Neurobiol Dis (2022)](https://doi.org/10.1016/j.nbd.2022.105728)
[Fecto F, et al., (2014). Rare novel mutations in CCNF in ALS/FTD. Nat Genet (2014)](https://doi.org/10.1038/ng.3053)
[Bentmann E, et al., (2012). Cyclin F and ribonucleotide reductase in DNA repair. J Cell Biol (2012)](https://doi.org/10.1083/jcb.201203067)
[Williams KL, et al., (2016). CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Neurosci (2016)](https://doi.org/10.1038/nn.4234)
[Zhang Y, et al., (2019). Cyclin F: structure, function and therapeutic targeting. Cell (2019)](https://doi.org/10.1016/j.cell.2019.01.001)
[Cheng J, et al., (2018). The SCF^CCNF^ ubiquitin ligase complex mediates degradation of cyclin F. Mol Cell Biol (2018)](https://doi.org/10.1128/MCB.00528-17)
[Nguyen K, et al., (2020). CCNF mutations associated with ALS/FTD impair protein homeostasis. Acta Neuropathol Commun (2020)](https://doi.org/10.1186/s40478-020-01024-2)
[Hogan AL, et al., (2021). Cyclin F and protein homeostasis in neurodegenerative disease. Brain (2021)](https://doi.org/10.1093/brain/awab120)
[Li TY, et al., (2022). Targeting CCNF for ALS therapy. Neurobiol Dis (2022)](https://doi.org/10.1016/j.nbd.2022.105728)
[Fecto F, et al., (2014). Rare novel mutations in CCNF in ALS/FTD. Nat Genet (2014)](https://doi.org/10.1038/ng.3053)
[Bentmann E, et al., (2012). Cyclin F and ribonucleotide reductase in DNA repair. J Cell Biol (2012)](https://doi.org/10.1083/jcb.201203067)