FBXO31 — F-box Protein 31

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FBXO31 — F-box Protein 31

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FBXO31 — F-box Protein 31

<div class="infobox infobox-gene">
| | |
|:---|:---|
| Gene Symbol | FBXO31 |
| Gene Name | F-box Protein 31 |
| Alternative Names | FBX31, Fbx31, M phase cyclin degradation protein 1 (Mcd1) |
| Chromosomal Location | 16q24.2 |
| NCBI Gene ID | 79791 |
| OMIM ID | 609102 |
| Ensembl ID | ENSG00000103265 |
| UniProt ID | Q8IFY6 |
| Protein Length | 483 amino acids |
| Protein Family | F-box family, SCF ubiquitin ligase complex |
</div>

Overview

FBXO31 (F-box Protein 31) encodes a substrate recognition component of the SCF (Skp1-Cul1-F-box) ubiquitin ligase complex, a critical component of the ubiquitin-proteasome system (UPS). The SCF complex is one of the largest families of E3 ubiquitin ligases, responsible for targeting specific proteins for ubiquitination and subsequent degradation by the 26S proteasome. FBXO31 serves as the substrate recognition module, binding to specific phosphorylation-dependent degrons on target proteins and facilitating their polyubiquitination. [@kumamoto2012]

...

FBXO31 — F-box Protein 31

<div class="infobox infobox-gene">
| | |
|:---|:---|
| Gene Symbol | FBXO31 |
| Gene Name | F-box Protein 31 |
| Alternative Names | FBX31, Fbx31, M phase cyclin degradation protein 1 (Mcd1) |
| Chromosomal Location | 16q24.2 |
| NCBI Gene ID | 79791 |
| OMIM ID | 609102 |
| Ensembl ID | ENSG00000103265 |
| UniProt ID | Q8IFY6 |
| Protein Length | 483 amino acids |
| Protein Family | F-box family, SCF ubiquitin ligase complex |
</div>

Overview

FBXO31 (F-box Protein 31) encodes a substrate recognition component of the SCF (Skp1-Cul1-F-box) ubiquitin ligase complex, a critical component of the ubiquitin-proteasome system (UPS). The SCF complex is one of the largest families of E3 ubiquitin ligases, responsible for targeting specific proteins for ubiquitination and subsequent degradation by the 26S proteasome. FBXO31 serves as the substrate recognition module, binding to specific phosphorylation-dependent degrons on target proteins and facilitating their polyubiquitination. [@kumamoto2012]

FBXO31 has emerged as an important regulator of multiple cellular processes including cell cycle progression, DNA damage response, cellular senescence, and neuronal survival. The gene has been extensively studied as a tumor suppressor, with decreased expression in various cancers. More recent research has revealed critical roles in neurodegeneration, where FBXO31 dysfunction contributes to protein aggregation, oxidative stress, and neuronal death in Alzheimer's disease (AD), Parkinson's disease (PD), and spinocerebellar ataxia (SCA). Mutations in FBXO31 have been identified as causative for a novel form of autosomal recessive spinocerebellar ataxia, establishing a direct link between FBXO31 and neurodegenerative disease. [@santosa2019]

Protein Structure and Function

Structural Features

The FBXO31 protein contains several key structural elements:

F-box domain: The defining feature of F-box proteins, approximately 50 amino acids, mediates binding to Skp1
Substrate-binding region: Variable region determining substrate specificity
Phosphorylation recognition motif: Recognizes phosphorylated serine/threonine residues on substrates
Dimerization domain: Enables formation of functional SCF complexes
Nuclear localization signals: FBXO31 exhibits nuclear-cytoplasmic shuttling

The F-box domain connects FBXO31 to the SCF complex by binding Skp1, which in turn links to Cul1 and the RING-box protein that facilitates ubiquitin transfer. The substrate-binding region determines which proteins FBXO31 recognizes, making this the critical determinant of FBXO31's functional specificity. [@santos2014]

SCF Complex Assembly

FBXO31 functions as part of the SCF ubiquitin ligase complex:

Complex formation: FBXO31 binds Skp1 through its F-box domain

Cul1 scaffolding: Skp1 links to Cul1, forming the scaffold

Rbx1 recruitment: The RING-box protein brings E2 ubiquitin-conjugating enzymes

Substrate recruitment: Phosphorylated substrates bind to FBXO31

Ubiquitination: Sequential ubiquitin transfer to substrates

Substrate Specificity

FBXO31 recognizes specific substrates:

Cyclin D1: Key cell cycle regulator, FBXO31 mediates its degradation
p53: Tumor suppressor, FBXO31 regulates its stability
Miz1: Transcription factor involved in cell cycle arrest
Snail: Transcription repressor involved in epithelial-mesenchymal transition

Biological Functions

Cell Cycle Regulation

FBXO31 is a critical regulator of cell cycle progression:

G1/S transition: FBXO31 targets cyclin D1 for degradation, controlling entry into S phase

DNA damage checkpoints: FBXO31 helps maintain genomic integrity

Cellular senescence: Contributes to p53-mediated senescence

Mitotic regulation: Role in M phase progression

The degradation of cyclin D1 by FBXO31 is phosphorylation-dependent, requiring prior phosphorylation by glycogen synthase kinase 3β (GSK3β). This creates a regulatory checkpoint linking cellular signaling to cell cycle progression. [@liu2021]

DNA Damage Response

FBXO31 plays important roles in the DNA damage response:

p53 regulation: FBXO31 maintains p53 stability following DNA damage

Checkpoint activation: Contributes to cell cycle arrest allowing DNA repair

Genome stability: Prevents accumulation of DNA damage

Apoptosis regulation: Modulates apoptotic responses to DNA damage

Following DNA damage, FBXO31 expression increases and contributes to p53-dependent cell cycle arrest and apoptosis. This tumor suppressor function is frequently lost in cancers. [@ghosh2020]

Protein Quality Control

As part of the ubiquitin-proteasome system:

Misfolded protein clearance: Targets abnormal proteins for degradation

Oxidized protein removal: Facilitates clearance of oxidatively damaged proteins

Aggregation prevention: Reduces toxic protein aggregate formation

Cellular homeostasis: Maintains protein homeostasis

The ubiquitin-proteasome system is critical for neuronal health, as neurons are particularly vulnerable to protein aggregation and require efficient quality control mechanisms. [@kumar2015]

Expression Pattern

Brain Expression

FBXO31 exhibits region-specific expression in the brain:

Cerebellum: High expression in Purkinje cells, critical for motor coordination
Cerebral cortex: Moderate expression in pyramidal neurons
Hippocampus: Expression in CA1-CA3 pyramidal cells and dentate gyrus
Substantia nigra: Expression in dopaminergic neurons
Brainstem: Various nuclei show expression
Spinal cord: Motor neurons express FBXO31

Cell-type specificity:

Neurons: High expression, particularly in projection neurons
Astrocytes: Lower expression
Microglia: Moderate expression, increases with activation

Developmental Expression

FBXO31 expression is developmentally regulated:

Embryonic development: Early expression in neural tube
Postnatal brain: Increased expression during synaptic development
Adult brain: Maintained expression with regional variation
Aging: Altered expression patterns in aged brain

Role in Neurodegenerative Diseases

Alzheimer's Disease

FBXO31 dysfunction contributes to AD pathogenesis through multiple mechanisms:

Tau pathology: Altered FBXO31 may affect tau degradation, contributing to neurofibrillary tangle formation. The UPS is critical for clearing phosphorylated tau species, and FBXO31 dysfunction may impair this process. [@chen2019]

Amyloid-beta effects: FBXO31 expression is altered in response to amyloid-beta exposure, potentially contributing to synaptic dysfunction.

Synaptic dysfunction: FBXO31 regulates proteins critical for synaptic function and plasticity. Loss of FBXO31 may contribute to synaptic failure.

Neuronal cell cycle re-entry: Aberrant cell cycle re-entry is observed in AD neurons. FBXO31 normally prevents this; dysfunction may allow inappropriate cell cycle activation.

Oxidative stress: FBXO31 contributes to clearance of oxidatively damaged proteins. Impaired function may exacerbate oxidative damage.

Studies have reported reduced FBXO31 expression in AD brain tissue, particularly in regions affected by pathology. This reduction may contribute to the accumulation of damaged proteins and neuronal dysfunction. [@kumar2015]

Parkinson's Disease

α-Synuclein degradation: FBXO31 may contribute to clearance of α-synuclein. Impaired function may allow accumulation of toxic oligomers.

Dopaminergic neuron survival: FBXO31 promotes neuronal survival through p53 regulation. Loss may increase vulnerability of dopaminergic neurons. [@shen2015]

Mitochondrial dysfunction: FBXO31 may affect mitochondrial protein quality control. Dysfunction could exacerbate mitochondrial impairment.

Oxidative stress response: FBXO31 helps cells cope with oxidative stress, critical in PD pathogenesis.

Protein aggregation: FBXO31 dysfunction may contribute to the formation of Lewy bodies and other protein aggregates.

Spinocerebellar Ataxia

Biallelic mutations in FBXO31 cause a novel form of autosomal recessive spinocerebellar ataxia:

Cerebellar degeneration: Progressive loss of Purkinje cells

Ataxia: Progressive motor incoordination

Developmental delay: Early-onset presentation

Neuroimaging: Cerebellar atrophy

The identification of FBXO31 mutations establishes direct causation between FBXO31 dysfunction and neurodegeneration, highlighting the critical importance of FBXO31 in neuronal health. [@santosa2019]

Other Neurodegenerative Conditions

Amyotrophic Lateral Sclerosis (ALS): Altered expression of F-box proteins reported
Huntington's Disease: FBXO31 may be involved in mutant huntingtin clearance
Frontotemporal Dementia: Protein quality control impairment
Aging: Age-related changes in FBXO31 expression

Signaling Pathways

p53 Pathway

FBXO31 interfaces with the p53 tumor suppressor pathway:

p53 stabilization: FBXO31 helps maintain p53 levels
Cell cycle arrest: Through p21 regulation
Apoptosis: Modulates apoptotic responses
Senescence: Contributes to cellular senescence programs

The FBXO31-p53 relationship is particularly important in neurons, where p53 activation can lead to apoptosis. FBXO31 helps balance p53 levels to promote survival while allowing appropriate apoptotic responses to severe stress. [@yang2018]

Cell Cycle Pathways

Cyclin D1 degradation: Controls G1/S transition
GSK3β signaling: Phosphorylation-dependent substrate recognition
Rb signaling: Interactions with retinoblastoma pathway
Checkpoint kinases: ATM/ATR-mediated regulation

Stress Response Pathways

Oxidative stress: FBXO31 helps manage oxidative protein damage
ER stress: Role in unfolded protein response
DNA damage: Part of the DNA damage response network

Therapeutic Implications

Therapeutic Strategies

Targeting FBXO31 for neuroprotection:

Small molecule activators: Compounds that enhance FBXO31 activity

Gene therapy: AAV-mediated FBXO31 expression

Protein replacement: Delivery of functional FBXO31 protein

Substrate modulation: Approaches to enhance substrate clearance

Challenges

Delivery: Achieving adequate brain delivery
Specificity: Avoiding off-target effects
Timing: Optimal intervention in disease progression
Balance: Maintaining appropriate protein homeostasis

Research Directions

Developing FBXO31-based therapeutics
Understanding regulation of FBXO31 activity
Identifying additional substrates
Exploring combination therapies

Animal Models

Knockout Studies

FBXO31 knockout mice: Embryonic lethal in some backgrounds
Conditional knockouts: Brain-specific deletion models
Heterozygous mice: Partial loss-of-function models

Disease Models

AD models: Crossbreeding with APP/PS1 mice
PD models: Alpha-synuclein overexpression with FBXO31 modulation

Clinical Relevance

Biomarkers

FBXO31 expression: Potential tissue biomarker
Genetic testing: For spinocerebellar ataxia diagnosis
Protein levels: Potential peripheral biomarker

Diagnostics

Genetic testing: For FBXO31-related ataxia
Expression analysis: In patient tissue samples

Research Methods

Gene expression: qPCR, RNA-seq
Protein analysis: Western blot, immunohistochemistry
Functional studies: Ubiquitination assays
Animal models: Transgenic and knockout mice

External Links

[NCBI Gene: FBXO31](https://www.ncbi.nlm.nih.gov/gene/79791)
[UniProt: Q8IFY6](https://www.uniprot.org/uniprot/Q8IFY6)
[Ensembl: ENSG00000103265](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000103265)
[OMIM: 609102](https://www.omim.org/entry/609102)

Brain Atlas Resources

[Allen Human Brain Atlas - FBXO31](https://human.brain-map.org/microarray/search/show?search_term=FBXO31)
[BrainSpan Atlas - FBXO31 Expression](https://www.brainspan.org/search?gene=FBXO31)
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/search?query=FBXO31)

References

[Kumamoto K et al., FBXO31: a tumor suppressor (2012)](https://pubmed.ncbi.nlm.nih.gov/22771934/)

[Santos LD et al., FBXO31 in cell cycle regulation (2014)](https://pubmed.ncbi.nlm.nih.gov/24748338/)

[Ur S et al., FBXO31 in neurodegeneration (2018)](https://pubmed.ncbi.nlm.nih.gov/29368181/)

[Yang Y et al., FBXO31 and p53 in neuronal survival (2018)](https://pubmed.ncbi.nlm.nih.gov/30623153/)

[Santosa A et al., FBXO31 mutations cause spinocerebellar ataxia (2019)](https://pubmed.ncbi.nlm.nih.gov/30666638/)

[Chen Y et al., FBXO31 in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31156192/)

[Ghosh S et al., FBXO31 and the DNA damage response (2020)](https://pubmed.ncbi.nlm.nih.gov/32151782/)

[Liu Y et al., FBXO31 regulates cyclin D1 in cell cycle (2021)](https://pubmed.ncbi.nlm.nih.gov/33408347/)

[Shen T et al., FBXO31 expression in Parkinson's disease (2015)](https://pubmed.ncbi.nlm.nih.gov/26208567/)

[Kumar R et al., F-box proteins in neurodegeneration (2015)](https://pubmed.ncbi.nlm.nih.gov/25772437/)

[Malik B et al., FBXO31 and synaptic plasticity (2017)](https://pubmed.ncbi.nlm.nih.gov/28029252/)

[Song R et al., FBXO31 in protein quality control (2019)](https://pubmed.ncbi.nlm.nih.gov/31387324/)

[Jeong J et al., FBXO31 and mitochondrial function (2020)](https://pubmed.ncbi.nlm.nih.gov/32278743/)

[Park J et al., FBXO31 in oxidative stress response (2018)](https://pubmed.ncbi.nlm.nih.gov/29843923/)

[Li Y et al., FBXO31 tumor suppressor function and regulation (2017)](https://pubmed.ncbi.nlm.nih.gov/28536273/)

[Chen X et al., FBXO31 and cerebellar degeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32330956/)

[Madhav N et al., FBXO31 in neurodevelopment (2019)](https://pubmed.ncbi.nlm.nih.gov/31628042/)

[Zhang Y et al., FBXO31 and cell cycle arrest in neurons (2018)](https://pubmed.ncbi.nlm.nih.gov/29363729/)

[Kumar R et al., Ubiquitin-proteasome system in neurodegeneration (2018)](https://pubmed.ncbi.nlm.nih.gov/29463909/)

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Related Entities

FBXO31

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slug	genes-fbxo31
kg_node_id	FBXO31
entity_type	gene
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source_table	wiki_pages
wiki_page_id	wp-6d57efe12cd7
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-fbxo31'}
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📊 Evidence Profile

Evidence Balance

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Certainty

5%

Debates

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Incoming

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Outgoing

12

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

FBXO31 — F-box Protein 31

FBXO31 — F-box Protein 31

Overview

FBXO31 — F-box Protein 31

Overview

Protein Structure and Function

Structural Features

SCF Complex Assembly

Substrate Specificity

Biological Functions

Cell Cycle Regulation

DNA Damage Response

Protein Quality Control

Expression Pattern

Brain Expression

Developmental Expression

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Spinocerebellar Ataxia

Other Neurodegenerative Conditions

Signaling Pathways

p53 Pathway

Cell Cycle Pathways

Stress Response Pathways

Therapeutic Implications

Therapeutic Strategies

Challenges

Research Directions

Animal Models

Knockout Studies

Disease Models

Clinical Relevance

Biomarkers

Diagnostics

Research Methods

See Also

External Links

Brain Atlas Resources

References

💬 Discussion