PEX5 Protein - Peroxisome Biogenesis Factor 5

PEX5 Protein - Peroxisome Biogenesis Factor 5

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Peroxisome Biogenesis Factor 5 (PEX5)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[PEX5](/genes/pex5)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P50571" target="_blank">P50571</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td>1FCH, 3MK4, 4B7K</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>131 kDa (631 amino acids)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytosol and peroxisomal membrane (cycling)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>TPR repeat protein family (PTS1 receptor)</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 5 (PEX5)

Introduction

Overview

...

PEX5 Protein - Peroxisome Biogenesis Factor 5

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Peroxisome Biogenesis Factor 5 (PEX5)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[PEX5](/genes/pex5)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P50571" target="_blank">P50571</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td>1FCH, 3MK4, 4B7K</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>131 kDa (631 amino acids)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytosol and peroxisomal membrane (cycling)</td>
</tr>
<tr>
<td class="label">Family</td>
<td>TPR repeat protein family (PTS1 receptor)</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 5 (PEX5)

Introduction

Overview

Peroxisome Biogenesis Factor 5 (PEX5, also known as Peroxin-5 or Pex5p) is a 131 kDa cytosolic and peroxisomal membrane protein encoded by the [PEX5](/genes/pex5) gene (chromosome 12p13.3). PEX5 serves as the primary peroxisomal targeting signal type 1 (PTS1) receptor, recognizing and importing proteins containing the canonical C-terminal tripeptide SKL (Ser-Lys-Leu) or variant sequences into peroxisomes [1][2]. This protein is absolutely essential for peroxisome function and mutations in PEX5 cause severe peroxisome biogenesis disorders (PBDs).

Beyond its fundamental role in peroxisome assembly, PEX5 has emerged as a protein of interest in common neurodegenerative diseases. Peroxisomal dysfunction is increasingly recognized in Alzheimer's disease, Parkinson's disease, and other neurological conditions, with PEX5 playing a central role in peroxisome homeostasis [3][4].

Structure

PEX5 is a 631-amino acid protein with a complex multi-domain architecture:

• N-terminal domain (NTD): Approximately 300 residues, contains the binding sites for PEX7 (the PTS2 receptor) and the PEX1-PEX6 AAA-ATPase complex. This region is involved in receptor recycling.
• TPR domain: The C-terminal portion contains tetratricopeptide repeat (TPR) motifs that form a superhelical structure responsible for recognizing the PTS1 cargo.
• Cargo-binding pocket: A hydrophobic pocket that accommodates the PTS1 motif and related sequences.

The structure of the TPR domain has been solved (PDB: 1FCH, 3MK4, 4B7K), revealing how PEX5 recognizes the SKL sequence and various PTS1 variants [5]. The N-terminal domain is intrinsically disordered in many regions, allowing flexibility for multiple protein interactions.

Normal Physiological Function

Peroxisomal Protein Import

PEX5 is the central component of the peroxisomal matrix protein import pathway:

Cargo Recognition: PEX5 binds proteins containing the PTS1 signal (typically -SKL or variant) in the cytosol.

Docking: The PEX5-cargo complex docks at the peroxisomal membrane through interactions with the docking complex (PEX13, PEX14, PEX5).

Translocation: The cargo is translocated across the peroxisomal membrane through the importomer pore.

Receptor Recycling: After cargo release, PEX5 is mono-ubiquitinated, extracted from the membrane by the PEX1-PEX6 AAA-ATPase complex, and recycled back to the cytosol for another round of import.

Peroxisome Biogenesis

• Peroxisome proliferation: PEX5-mediated import is required for maintaining functional peroxisomes
• Quality control: The ubiquitin-dependent recycling mechanism ensures proper peroxisome assembly
• Membrane protein import: PEX5 also imports some peroxisomal membrane proteins (PMPs)

PTS2 Pathway Support

PEX5 interacts with PEX7, the PTS2 receptor (for proteins with N-terminal -RLx5HLA motif), forming a co-receptor complex for import of proteins that use the alternative targeting pathway.

Role in Neurodegeneration

Zellweger Spectrum Disorders

Biallelic loss-of-function mutations in PEX5 cause severe peroxisome biogenesis disorders within the Zellweger spectrum (OMIM: 614920). The clinical phenotype includes:

• Severe neurological impairment: Profound intellectual disability, hypotonia, seizures
• Developmental arrest: Failure to achieve developmental milestones
• Characteristic dysmorphism: High forehead, epicanthal folds, micrognathia
• Ocular abnormalities: Cataracts, optic atrophy, retinal degeneration
• Hepatic dysfunction: Hepatomegaly, cholestasis, cirrhosis
• Skeletal abnormalities: Chondrodysplasia punctata, calcific stippling
• Hearing loss: Sensorineural deafness

Pathogenesis involves:

Complete failure of peroxisomal matrix protein import

Absence of functional peroxisomes

Systemic accumulation of VLCFAs and phytanic acid

Deficiency of plasmalogens and bile acid intermediates

Secondary mitochondrial dysfunction

Neuroinflammation and oxidative stress

Alzheimer's Disease

PEX5 and peroxisomal function are implicated in Alzheimer's disease through multiple mechanisms:

• PEX5 expression is dysregulated in AD brain tissue
• Peroxisome numbers are reduced in AD [neurons](/entities/neurons) and glia
• PTS1 protein import is impaired in AD models
• Peroxisomal lipid metabolism is altered in AD (plasmalogen depletion)

The peroxisome-mitochondria-lipid axis is particularly relevant:

• Plasmalogens, synthesized in peroxisomes, are critical for synaptic function
• VLCFA accumulation from peroxisomal dysfunction promotes neuroinflammation
• Oxidative stress from peroxisomal dysfunction synergizes with mitochondrial deficits
• [Amyloid-beta](/proteins/amyloid-beta) may directly impair peroxisomal function

Parkinson's Disease

Peroxisomal dysfunction contributes to Parkinson's disease pathogenesis:

• PEX5 variants have been identified in PD patients
• Peroxisome deficiency sensitizes dopaminergic neurons to mitochondrial toxins
• PEX5 dysfunction may synergize with [α-synuclein](/proteins/alpha-synuclein) aggregation
• Peroxisomal lipid metabolism influences α-synuclein toxicity

Other Neurodegenerative Conditions

• Infantile Refsum disease: Milder PBD phenotype
• Rhizomelic chondrodysplasia punctata: PEX5 can partially compensate for PEX7 defects
• Zellweger-like disorders: Variable phenotypes depending on mutation severity

Therapeutic Approaches

Gene Therapy

• AAV-mediated PEX5 delivery: Experimental approaches for PBD treatment
• Lentiviral vectors: For ex vivo gene therapy
• CRISPR-Cas9: Potential for permanent correction of pathogenic variants

Small Molecule Strategies

• Pharmacological chaperones: Stabilize mutant PEX5 protein
• PPAR agonists: Stimulate peroxisome proliferation via PPARα
• Antioxidants: Counteract oxidative stress
• VLCFA-lowering agents: Reduce toxic lipid accumulation

Experimental Approaches

• Plasmalogen supplementation: Address plasmalogen deficiency
• mRNA therapeutics: Deliver functional PEX5 mRNA
• Protein replacement: Experimental enzyme replacement approaches

Animal Models

• Pex5-null mice: Complete peroxisome deficiency, embryonic or early postnatal lethal
• Pex5 conditional knockouts: Brain-specific deletion reveals neuronal vulnerability
• Pex5 knock-in mice: Expressing mutant PEX5 to model human disease
• Zebrafish models: For developmental studies and drug screening

Key Publications

[Dodt et al., PEX5 is a cycling cytosolic protein](https://doi.org/10.1083/jcb.131.5.1143). Journal of Cell Biology, 1995.

[Gatto et al., Structural analysis of PEX5 TPR domain](https://doi.org/10.1074/jbc.275.8.5666). Journal of Biological Chemistry, 2000.

[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: 1FCH - PEX5 TPR domain structure](https://www.rcsb.org/structure/1FCH). RCSB Protein Data Bank.

[Steinberg et al., PEX5 mutations cause peroxisome biogenesis disorders](https://doi.org/10.1093/hmg/ddp325). Human Molecular Genetics, 2009.

[Apanasets et al., PEX5, the gatekeeper of peroxisomal matrix protein import](https://doi.org/10.1016/j.bbamcr.2014.03.022). Biochimica et Biophysica Acta, 2014.

External Links

• UniProt: [P50571](https://www.uniprot.org/uniprot/P50571)
• AlphaFold: [Peroxisome Biogenesis Factor 5](https://alphafold.ebi.ac.uk/entry/P50571)
• PDB: [1FCH](https://www.rcsb.org/structure/1FCH), [3MK4](https://www.rcsb.org/structure/3MK4), [4B7K](https://www.rcsb.org/structure/4B7K)
• OMIM: [614920 - Zellweger Syndrome](https://www.omim.org/entry/614920)
• GeneCards: [PEX5](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PEX5)

See Also

• [Proteins Index](/proteins)
• [Genes Index](/genes)
• [PEX5 Gene](/genes/pex5)
• [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)
• [PEX1 Protein](/proteins/pex1-protein)
• [PEX6 Protein](/proteins/pex6-protein)
• [PEX2 Protein](/proteins/pex2-protein)

References

[Dodt et al., The PTS1 receptor, PEX5, is a cycling cytosolic protein (1995)](https://doi.org/10.1083/jcb.131.5.1143)

[Gatto et al., Structural analysis of PEX5, the peroxisomal import receptor (2000)](https://doi.org/10.1074/jbc.275.8.5666)

[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: 1FCH - Structure of PEX5 TPR domain (n.d.)

[Steinberg et al., PEX5 mutations in peroxisome biogenesis disorders (2009)](https://doi.org/10.1093/hmg/ddp325)

[Apanasets et al., PEX5, the gatekeeper of peroxisomal matrix protein import (2014)](https://doi.org/10.1016/j.bbamcr.2014.03.022)