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
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.