Pex5

Pex5, also known as peroxin 5, is a cytosolic receptor that recognizes peroxisomal matrix proteins bearing the peroxisomal targeting signal 1 (PTS1) and delivers them to the peroxisome import machinery. The import of matrix proteins into peroxisomes is post-translational and essential for peroxisome function.

Structurally, Pex5 contains an N-terminal domain and a C-terminal core composed of several tetratricopeptide repeat (TPR) motifs that form the cargo-binding site for PTS1-bearing proteins. The N-terminal region mediates interactions with peroxisomal membrane proteins, notably Pex14, Pex13, and Pex17, thereby forming the docking platform at the peroxisomal membrane.

PTS2 import in many organisms involves the co-receptor Pex7. Pex7 binds PTS2-containing cargo and associates with Pex5 to effect import of PTS2 proteins. In mammals, an extended isoform of Pex5 (Pex5L) supports PTS2 import, while the shorter form primarily handles PTS1 cargo.

Following cargo delivery, Pex5 is ubiquitinated and then recycled to the cytosol by the Pex1–Pex6 ATPase complex, with Pex15 (or its homologs) serving as a membrane anchor. Mono-ubiquitination at a conserved lysine residue triggers this retrotranslocation; deubiquitination resets Pex5 for another round of import.

Pex5 is essential for peroxisome biogenesis and the proper functioning of peroxisomal enzymes. Mutations in the human PEX5 gene are associated with peroxisome biogenesis disorders, including Zellweger spectrum disorders, which can present with developmental, hepatic, and metabolic abnormalities.

Pex5 is highly conserved across eukaryotes and remains a central model for understanding how cytosolic receptors recognize organelle-targeted proteins and coordinate their import.