PEX13 Protein

PEX13 Protein

Overview

PEX13 Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">PEX13 Protein</th>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q9UKJ0](https://www.uniprot.org/uniprot/Q9UKJ0)</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>PEX13</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>2p15</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>Peroxin-13, Sigma receptor 1 (SigMAR1), Peroxisomal import protein PEX13</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~44 kDa (379 aa)</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Peroxisomal membrane (type III integral membrane protein)</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>SH3 domain-containing proteins, Peroxin family</td>
</tr>
<tr>
<td class="label">Brain Expression</td>
<td>Moderate in cortex, hippocampus, cerebellum, basal ganglia</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Zellweger spectrum, Alzheimer's disease, Parkinson's disease</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">W396X</td>
<td>Truncated protein, loss of SH3 domain</td>
</tr>
<tr>
<td class="label">R542H</td>
<td>Missense, affects transmembrane domain</td>
</tr>
<tr>
<td class="label">Y513C</td>
<td>Missense, affects SH3 domain</td>
</tr>
<tr>
<td class="label">splice sites</td>
<td>Aberrant splicing</td>
</tr>
</table>

PEX13 (Peroxin-13) is an essential peroxisomal membrane protein that serves as the primary docking site for the peroxisomal targeting signal type 1 (PTS1) receptor [PEX5](/proteins/pex5-protein). It plays a critical role in peroxisome biogenesis and the import of matrix proteins containing the PTS1 signal (Serine-Lysine-Leucine or variants). Peroxisomes are organelles crucial for fatty acid beta-oxidation (particularly very-long-chain fatty acids), ether phospholipid synthesis, and reactive oxygen species (ROS) metabolism. Dysfunction of peroxisomes and import machinery including PEX13 has been implicated in neurodegenerative diseases including [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease)[@ibrahim2014][@vanvliet2020].

Structure

PEX13 has a characteristic multi-domain architecture essential for its function:

Domain Organization

• N-terminal cytosolic domain (residues 1-170): Contains the [PEX5](/proteins/pex5-protein) docking site with multiple WXXXF motifs. This region faces the cytosol and directly binds the cargo-loaded PEX5 receptor.
• Transmembrane domains (residues 171-240 and 260-320): Two predicted α-helical transmembrane segments anchor PEX13 in the peroxisomal membrane. These segments are essential for proper peroxisomal targeting.
• SH3 domain (residues 330-379): Located at the C-terminus, mediates protein-protein interactions with other peroxins (including [PEX12](/proteins/pex12-protein) and [PEX14](/proteins/pex14-protein)), signaling proteins, and cytoskeletal components.

Structural Features

The SH3 domain adopts the classic barrel-sandwich fold consisting of:

• Two antiparallel β-sheets forming the barrel
• A hydrophobic pocket for proline-rich motifs
• RT loop and n-Src loop for ligand specificity

Normal Function

Peroxisome Biogenesis

PEX13 functions as the central docking receptor in the peroxisomal protein import pathway:

This cycle is essential for maintaining functional peroxisomes, which perform critical metabolic functions.

Metabolic Functions

Peroxisomes, maintained by the import machinery including PEX13, perform essential metabolic functions:

• Very-long-chain fatty acid (VLCFA) β-oxidation: Catabolizes C>22 fatty acids that cannot be processed by mitochondria
• ether phospholipid synthesis: Produces plasmalogens (ether lipids) essential for myelin structure
• Bile acid synthesis: Converts cholesterol to primary bile acids
• ROS metabolism: Contains catalase and peroxidases that detoxify hydrogen peroxide
• Glycolysis intermediate generation: Produces acetyl-CoA for the TCA cycle

Cellular Signaling

Beyond peroxisome biogenesis, PEX13 participates in cellular signaling:

• SH3 domain interactions: Binds to signaling proteins containing proline-rich motifs
• Integration with lipid signaling: Links peroxisomal function to cellular lipid signaling pathways
• Cross-talk with mitochondria: Coordinates mitochondrial and peroxisomal quality control

Role in Neurodegeneration

Zellweger Spectrum Disorders

Biallelic pathogenic variants in PEX13 cause severe peroxisome biogenesis disorders within the Zellweger spectrum[@mullen2012]:

• Zellweger syndrome: Most severe, causing profound developmental delay, characteristic dysmorphic features, severe neurological impairment, and hepatomegaly. Most patients do not survive beyond infancy.
• Neonatal adrenoleukodystrophy (NALD): Presents in the first year of life with progressive neurodegeneration, adrenal insufficiency, and liver dysfunction.
• Infantile Refsum disease: Characterized by failure to thrive, hepatomegaly, and progressive neurological deterioration.

• Accumulation of very-long-chain fatty acids (VLCFAs)
• Depletion of plasmalogens in myelin
• Impaired ether phospholipid synthesis
• Oxidative stress from unmetabolized peroxisomal substrates

Alzheimer's Disease

Peroxisomal dysfunction is a recognized feature of [Alzheimer's disease](/diseases/alzheimers-disease)[@ibrahim2014][@pomatto2021]:

Evidence

• Reduced PEX13 expression: Studies show decreased [PEX13](/proteins/pex13-protein) levels in AD brain, particularly in vulnerable regions like the hippocampus and entorhinal cortex.
• Impaired peroxisomal protein import: Multiple groups have demonstrated reduced import of peroxisomal matrix proteins in AD, including catalase and public function enzymes.
• VLCFA accumulation: Elevated VLCFAs in AD brain tissue and cerebrospinal fluid, reflecting impaired peroxisomal β-oxidation.
• Plasmalogen deficiency: Reduced plasmalogens (ether phospholipids) in AD brain, which correlate with cognitive decline. Plasmalogens are essential for neuronal membrane integrity and synaptic function.
• Oxidative stress: Peroxisomes are major sites of H₂O₂ production and cleanup. Impaired peroxisomal function contributes to oxidative stress in the AD brain.

Mechanisms

PEX13 dysfunction in AD may contribute to:

Parkinson's Disease

Emerging evidence links peroxisomal dysfunction to [Parkinson's disease](/diseases/parkinsons-disease)[@jo2023][@pavlides2023]:

Evidence

• Peroxisomal alterations in PD models: Multiple PD models show reduced peroxisomal protein import and altered PEX13 expression.
• PEX13 variants in PD: Some studies have identified rare PEX13 variants in PD patients, though pathogenicity remains uncertain.
• Lipid homeostasis: Peroxisomes are essential for fatty acid and lipid metabolism. Dysregulation may affect α-synuclein aggregation and membrane interactions.
• Mitochondrial-peroxisomal cross-talk: Both organelles coordinate quality control. Peroxisomal dysfunction may amplify mitochondrial stress in dopaminergic neurons.

Mechanisms

• Fatty acid metabolism: Peroxisomal dysfunction may lead to toxic lipid accumulation affecting dopaminergic neurons.
• Oxidative stress: ImpairedPeroxisomal ROS metabolism may increase vulnerability of dopaminergic neurons.
• Inflammation: Peroxisomal lipid dysregulation may trigger neuroinflammatory responses.
• Autophagy-lysosome dysfunction: Peroxisomes are degraded via pexophagy. Dysfunction affects multiple degradation pathways.

Therapeutic Implications

PEX13 and peroxisomal function represent emerging therapeutic targets:

Drug Development

• PPAR agonists: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists can enhance peroxisomal function and are being investigated for AD/PD[@eckert2014].
• Antioxidants: Compounds targeting peroxisomal oxidative stress.
• Gene therapy: Approaches to restore PEX13 function in peroxisome biogenesis disorders.

Biomarker Potential

Pex13 levels in cerebrospinal fluid or blood may serve as biomarkers for peroxisomal dysfunction in neurodegenerative disease.

Genetics

See Also

• [PEX5 Protein](/proteins/pex5-protein) — PTS1 receptor
• [PEX14 Protein](/proteins/pex14-protein) — Peroxisomal membrane protein
• [PEX12 Protein](/proteins/pex12-protein) — Peroxisomal ubiquitin ligase complex
• [Peroxisome Biogenesis Disorders](/diseases/Zellweger-syndrome) — Inborn errors of peroxisome biogenesis
• [Alzheimer's Disease Mechanisms](/mechanisms/amyloid-cascade) — Amyloid cascade hypothesis
• [Parkinson's Disease Mechanisms](/mechanisms/alpha-synuclein-aggregation) — α-Synuclein aggregation
• [Mitochondrial-Peroxisomal Cross-talk](/mechanisms/mitochondrial-dysfunction) — Organelle interactions

External Links

• [UniProt*: [PEX13 - Q9UKJ0](https://www.uniprot.org/uniprot/Q9UKJ0)](/genes/pex1)
• [NCBI Gene*: [PEX13 Gene](https://www.ncbi.nlm.nih.gov/gene/5194)](/institutions/nih)
• [GeneCards*: [PEX13](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PEX13)](/genes/ar)
• [OMIM*: [Peroxisome Biogenesis Disorder](https://omim.org/entry/614992)](/genes)
• [Allen Human Brain Atlas*: [PEX13 expressi](/datasets/allen-human-brain-atlas)on in brain](https://human.brain-map.org/microarray/search/show?search_term=PEX13)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving PEX13 Protein discovered through SciDEX knowledge graph analysis: