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. 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 β-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 and Parkinson's disease[1][2].
| Property | Value |
|---|---|
| UniProt ID | Q9UKJ0 |
| Gene Symbol | PEX13 |
| Chromosome | 2p15 |
| Alternative Names | Peroxin-13, Sigma receptor 1 (SigMAR1), Peroxisomal import protein PEX13 |
| Molecular Weight | ~44 kDa (379 aa) |
| Subcellular Localization | Peroxisomal membrane (type III integral membrane protein) |
| Protein Family | SH3 domain-containing proteins, Peroxin family |
| Brain Expression | Moderate in cortex, hippocampus, cerebellum, basal ganglia |
| Associated Diseases | Zellweger spectrum, Alzheimer's disease, Parkinson's disease |
PEX13 has a characteristic multi-domain architecture essential for its function:
N-terminal cytosolic domain (residues 1-170): Contains the PEX5 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 and PEX14), signaling proteins, and cytoskeletal components.
The SH3 domain adopts the classic barrel-sandwich fold consisting of:
Mutations affecting any of these domains can impair peroxisome biogenesis and cause severe human disease.
PEX13 functions as the central docking receptor in the peroxisomal protein import pathway:
Cargo recognition: PEX5 recognizes proteins containing the PTS1 signal (SKL motif or variant) in the cytosol.
Docking at PEX13: The PEX5-cargo complex translocates to the peroxisomal membrane and docks at PEX13 through the PEX5 N-terminal domain.
Translocation: PEX13, together with PEX14 and PEX12, forms a transient translocation pore allowing matrix protein import.
Recycling: After cargo delivery, PEX5 is recycled to the cytosol for another round of import.
This cycle is essential for maintaining functional peroxisomes, which perform critical metabolic functions.
Peroxisomes, maintained by the import machinery including PEX13, perform essential metabolic functions:
Beyond peroxisome biogenesis, PEX13 participates in cellular signaling:
Biallelic pathogenic variants in PEX13 cause severe peroxisome biogenesis disorders within the Zellweger spectrum[3]:
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.
These disorders result from the inability to import peroxisomal matrix proteins, leading to:
Peroxisomal dysfunction is a recognized feature of Alzheimer's disease[1:1][4]:
Reduced PEX13 expression: Studies show decreased PEX13 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.
PEX13 dysfunction in AD may contribute to:
Emerging evidence links peroxisomal dysfunction to Parkinson's disease[5][6]:
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.
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.
PEX13 and peroxisomal function represent emerging therapeutic targets:
PPAR agonists: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists can enhance peroxisomal function and are being investigated for AD/PD[7].
Antioxidants: Compounds targeting peroxisomal oxidative stress.
Gene therapy: Approaches to restore PEX13 function in peroxisome biogenesis disorders.
Pex13 levels in cerebrospinal fluid or blood may serve as biomarkers for peroxisomal dysfunction in neurodegenerative disease.
| Variant | Effect | Clinical Significance |
|---|---|---|
| W396X | Truncated protein, loss of SH3 domain | Severe peroxisome biogenesis disorder |
| R542H | Missense, affects transmembrane domain | Variable phenotype |
| Y513C | Missense, affects SH3 domain | Moderate peroxisome dysfunction |
| splice sites | Aberrant splicing | Variable severity |
Peroxisomal proteins in Alzheimer's disease brain: The subcellular localization and abundance of PEX13 and PEX11. Neurobiology of Aging. 2014. ↩︎ ↩︎
Peroxisomes in neurodegenerative disorders. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2020. ↩︎
Peroxisomes in brain: A developmental, evolutionary and species-specific perspective. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2012. ↩︎
Modulation of peroxisomal protein import in aging and Alzheimer's disease. Redox Biology. 2021. ↩︎
Peroxisomal dysfunction in Parkinson's disease models. Molecular Brain. 2023. ↩︎
Targeting peroxisomes for neuroprotection in AD and PD. Journal of Neural Transmission. 2023. ↩︎
Peroxisome proliferator-activated receptor gamma (PPARγ) in neurodegenerative disease. Ageing Research Reviews. 2014. ↩︎