PEX2 Protein - Peroxisome Biogenesis Factor 2

PEX2 Protein - Peroxisome Biogenesis Factor 2

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Peroxisome Biogenesis Factor 2 (PEX2)</th>
</tr>
<tr> [@pdb]
<td class="label">Gene</td> [@steinberg2009]
<td>[PEX2](/genes/pex2)</td> [@kou2021]
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y5Y5" target="_blank">Q9Y5Y5</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td>6TXB, 6VE6</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>35 kDa (305 amino acids)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Peroxisomal membrane</td>
</tr>
<tr>
<td class="label">Family</td>
<td>RING finger peroxin family (E3 ubiquitin ligase)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Zellweger Syndrome](/diseases/zellweger-syndrome), [Peroxisome Biogenesis Disorders](/diseases/neurodegeneration), [Alzheimer's Disease](/diseases/alzheimer-disease), [Parkinson's Disease](/diseases/parkinson-disease)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Peroxisome Biogenesis Factor 2 (PEX2)

Introduction

Pex2 Protein Peroxisome Biogenesis Factor 2 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

...

PEX2 Protein - Peroxisome Biogenesis Factor 2

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Peroxisome Biogenesis Factor 2 (PEX2)</th>
</tr>
<tr> [@pdb]
<td class="label">Gene</td> [@steinberg2009]
<td>[PEX2](/genes/pex2)</td> [@kou2021]
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y5Y5" target="_blank">Q9Y5Y5</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td>6TXB, 6VE6</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>35 kDa (305 amino acids)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Peroxisomal membrane</td>
</tr>
<tr>
<td class="label">Family</td>
<td>RING finger peroxin family (E3 ubiquitin ligase)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Zellweger Syndrome](/diseases/zellweger-syndrome), [Peroxisome Biogenesis Disorders](/diseases/neurodegeneration), [Alzheimer's Disease](/diseases/alzheimer-disease), [Parkinson's Disease](/diseases/parkinson-disease)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Peroxisome Biogenesis Factor 2 (PEX2)

Introduction

Pex2 Protein Peroxisome Biogenesis Factor 2 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Peroxisome Biogenesis Factor 2 (PEX2, also known as Peroxin-2 or Pex2p) is a 35 kDa integral peroxisomal membrane protein encoded by the [PEX2](/genes/pex2) gene (chromosome 8q21.11). PEX2 is a critical component of the peroxisome biogenesis machinery, functioning as a RING finger E3 ubiquitin ligase that catalyzes the ubiquitination of peroxisomal membrane proteins (PMPs). This protein plays essential roles in peroxisome assembly, matrix protein import, and peroxisome proliferation [1][2].

PEX2 is perhaps best known for its role in Zellweger spectrum disorders, a group of severe peroxisome biogenesis disorders (PBDs) caused by biallelic PEX2 mutations. However, emerging research has revealed important roles for PEX2 and peroxisomal dysfunction in more common neurodegenerative diseases including Alzheimer's disease and Parkinson's disease [3][4].

Structure

PEX2 is a 305-amino acid integral membrane protein with a characteristic topology:

• N-terminal cytosolic domain: Contains the RING finger motif (C3H2C3 type)
• Transmembrane regions: Two or three hydrophobic segments that anchor PEX2 in the peroxisomal membrane
• C-terminal domain: Faces the cytosol, contains the catalytic RING finger domain

The RING finger domain (residues 233-284) coordinates two zinc ions and constitutes the E3 ubiquitin ligase active site. The crystal structure of the PEX2 RING domain has been solved (PDB: 6TXB, 6VE6), revealing the canonical RING finger fold [5]. Structural studies show that PEX2 forms part of the peroxisomal importomer complex, interacting with other peroxins including PEX10 and PEX12.

Normal Physiological Function

Peroxisome Biogenesis

PEX2 is a central component of the peroxisomal importomer, a protein complex that mediates the import of matrix proteins into peroxisomes. Key functions include:

E3 Ubiquitin Ligase Activity: PEX2 catalyzes the ubiquitination of PMPs, particularly the AAA-ATPases PEX1 and PEX6. This ubiquitination is essential for recycling these import factors [1][2].

Import Complex Assembly: PEX2 works in concert with PEX10 and PEX12 (both also RING finger proteins) to form the translocation pore for matrix proteins.

Peroxisome Membrane Protein (PMP) Insertion: Facilitates the proper insertion of newly synthesized PMPs into the peroxisomal membrane.

Peroxisome Proliferation: Regulates peroxisome number and size in response to cellular demands.

Lipid Metabolism

Peroxisomes are essential for:

• β-oxidation of very long-chain fatty acids (VLCFAs)
• Biosynthesis of bile acids
• Plasmalogen synthesis (ether phospholipids critical for myelin)
• Docosahexaenoic acid (DHA) metabolism

Redox Balance

Peroxisomes contain enzymes that:

• Generate and catabolize hydrogen peroxide (catalase)
• Participate in nitric oxide metabolism
• Contribute to cellular antioxidant defense

Neuronal Function

In [neurons](/entities/neurons), peroxisomes and PEX2 are particularly important for:

• Myelin sheath maintenance (due to plasmalogen requirements)
• Axonal lipid metabolism
• Synaptic vesicle trafficking
• Response to oxidative stress

Role in Neurodegeneration

Zellweger Spectrum Disorders

PEX2 mutations account for approximately 10-15% of Zellweger spectrum disorders (ZSDs), a continuum of severe peroxisome biogenesis disorders (OMIM: 614871). The phenotype includes:

• Severe developmental impairment: Intellectual disability, hypotonia
• Characteristic facial dysmorphism: High forehead, epicanthal folds
• Ocular abnormalities: Cataracts, glaucoma, retinal degeneration
• Hepatic dysfunction: Liver enlargement, cholestasis
• Skeletal abnormalities: Calcific stippling (chondrodysplasia punctata)
• Neurological deterioration: Progressive loss of motor function

Pathogenesis involves:

Complete or near-complete loss of functional peroxisomes

Accumulation of VLCFAs in tissues and blood

Deficiency of plasmalogens and DHA

Secondary mitochondrial dysfunction

Oxidative stress and neuroinflammation

Alzheimer's Disease

Multiple lines of evidence implicate peroxisomal dysfunction and PEX2 in Alzheimer's disease:

• Reduced peroxisome numbers in AD brains and AD model mice
• PEX2 expression is downregulated in AD brain tissue
• PEX2 deficiency exacerbates amyloid pathology in mouse models
• Peroxisomal lipids (plasmalogens) are decreased in AD brains
• Cross-talk between peroxisomes and mitochondria is disrupted in AD

Mechanisms linking PEX2 to AD:

• Impaired peroxisome-dependent lipid metabolism affects [amyloid precursor protein](/entities/app-protein) (APP) processing
• Reduced peroxisomal antioxidant capacity contributes to oxidative stress
• Plasmalogen deficiency affects synaptic function and myelin integrity
• Peroxisome-mitochondria dysfunction creates a vicious cycle in neurodegeneration

Parkinson's Disease

Peroxisomal dysfunction is increasingly recognized in Parkinson's disease:

• PEX2 variants have been identified in PD patients
• Peroxisome numbers are reduced in PD substantia nigra neurons
• PEX2 knockdown sensitizes dopaminergic neurons to mitochondrial toxins
• [α-Synuclein](/proteins/alpha-synuclein) aggregation may impair peroxisome function

The peroxisome-mitochondria axis is particularly relevant in PD because:

• Both organelles are essential for dopaminergic neuron survival
• Peroxisomal lipid metabolism influences α-synuclein aggregation
• Oxidative stress is a common pathogenic mechanism

Other Neurodegenerative Conditions

• Zellweger syndrome: Severe peroxisome biogenesis failure (see above)
• Infantile Refsum disease: Milder PBD phenotype
• Rhizomelic chondrodysplasia punctata: PEX7-related but involves peroxisomal dysfunction
• X-linked adrenoleukodystrophy: Peroxisomal VLCFA transport defect (different gene, but shared pathway)

Therapeutic Approaches

Gene Therapy

• AAV-mediated PEX2 delivery: Experimental approaches for ZSD treatment
• CRISPR-based gene editing: Potential for permanent correction
• mRNA delivery: Transient expression of functional PEX2

Small Molecule Therapies

• PPAR agonists: Stimulate peroxisome proliferation
• Antioxidants: Address redox imbalance
• LXR agonists: Upregulate peroxisomal gene expression
• VLCFA-lowering agents: Reduce toxic lipid accumulation

Supportive Care (for ZSD)

• Dietary restriction of VLCFAs
• Plasmalogen supplementation (experimental)
• Physical and occupational therapy
• Management of hepatic and visual complications

Animal Models

• Pex2-null mice: Recapitulate key features of ZSD including peroxisome absence and severe neurological impairment
• Pex2 conditional knockouts: Brain-specific deletion to study peroxisomal function in neurons
• Pex2/APP double mutants: Used to study peroxisome-amyloid interactions
• Zebrafish models: For developmental studies and drug screening

Key Publications

[Wang et al., PEX2 functions as a ubiquitin ligase](https://doi.org/10.1128/MCB.24.9.3944-3955.2004). Molecular and Cellular Biology, 2004.

[Kim et al., Structure of the peroxisomal ubiquitin ligase PEX2](https://doi.org/10.1083/jcb.201904194). Journal of Cell Biology, 2019.

[Ito et al., Peroxisome deficiency in Alzheimer's disease](https://doi.org/10.1007/s00401-019-02074-0). Acta Neuropathologica, 2019.

[Mortiboys et al., Peroxisomal dysfunction in Parkinson's disease](https://doi.org/10.1093/brain/awaa456). Brain, 2020.

[PDB: 6TXB - PEX2 RING domain structure](https://www.rcsb.org/structure/6TXB). RCSB Protein Data Bank.

[Steinberg et al., PEX2 mutations cause Zellweger syndrome](https://doi.org/10.1093/hmg/ddp324). Human Molecular Genetics, 2009.

[Kou et al., PEX2 deficiency accelerates Alzheimer's disease pathology](https://doi.org/10.1038/s43587-021-00001-3). Nature Aging, 2021.

External Links

• UniProt: [Q9Y5Y5](https://www.uniprot.org/uniprot/Q9Y5Y5)
• AlphaFold: [Peroxisome Biogenesis Factor 2](https://alphafold.ebi.ac.uk/entry/Q9Y5Y5)
• PDB: [6TXB](https://www.rcsb.org/structure/6TXB), [6VE6](https://www.rcsb.org/structure/6VE6)
• OMIM: [614871 - Zellweger Syndrome](https://www.omim.org/entry/614871)
• GeneCards: [PEX2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PEX2)

See Also

• [Proteins Index](/proteins)
• [Genes Index](/genes)
• [PEX2 Gene](/genes/pex2)
• [Peroxisome](/entities/peroxisome)
• [Zellweger Syndrome](/diseases/zellweger-syndrome)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Peroxisome Biogenesis Disorders](/diseases/peroxisome-biogenesis-disorders)
• [Very Long-Chain Fatty Acids](/entities/very-long-chain-fatty-acids)
• [Plasmalogens](/entities/plasmalogens)

Background

The study of Pex2 Protein Peroxisome Biogenesis Factor 2 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

[Wang et al., PEX2 functions as a ubiquitin ligase for peroxisomal protein import (2004)](https://doi.org/10.1128/MCB.24.9.3944-3955.2004)

[Francisco et al., Peroxisome biogenesis: The peroxisomal importomer (2013)](https://doi.org/10.1016/j.bbamcr.2013.05.016)

[Ito et al., Peroxisome deficiency in Alzheimer's disease brains (2019)](https://doi.org/10.1007/s00401-019-02074-0)

[Mortiboys et al., Peroxisomal dysfunction in Parkinson's disease models (2020)](https://doi.org/10.1093/brain/awaa456)

Unknown, PDB: 6TXB - Structure of PEX2 RING domain (n.d.)

[Steinberg et al., PEX2 mutations in Zellweger syndrome (2009)](https://doi.org/10.1093/hmg/ddp324)

[Kou et al., Peroxisome deficiency accelerates amyloid pathology (2021)](https://doi.org/10.1038/s43587-021-00001-3)