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Mol Cell 2022 Sep 01;8217:3209-3225.e7. doi: 10.1016/j.molcel.2022.07.004.
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PEX5 translocation into and out of peroxisomes drives matrix protein import.

Skowyra ML , Rapoport TA .

Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal enzymes are imported from the cytosol by the receptor PEX5, which interacts with a docking complex in the peroxisomal membrane and then returns to the cytosol after monoubiquitination by a membrane-embedded ubiquitin ligase. The mechanism by which PEX5 shuttles between cytosol and peroxisomes and releases cargo inside the lumen is unclear. Here, we use Xenopus egg extract to demonstrate that PEX5 accompanies cargo completely into the lumen, utilizing WxxxF/Y motifs near its N terminus that bind a lumenal domain of the docking complex. PEX5 recycling is initiated by an amphipathic helix that binds to the lumenal side of the ubiquitin ligase. The N terminus then emerges in the cytosol for monoubiquitination. Finally, PEX5 is extracted from the lumen, resulting in the unfolding of the receptor and cargo release. Our results reveal the unique mechanism by which PEX5 ferries proteins into peroxisomes.

PubMed ID: 35931083
PMC ID: PMC9444985
Article link: Mol Cell
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: nedd8 pex5 phyh tpr
Antibodies: FLAG Ab2

Article Images: [+] show captions
References [+] :
Azevedo, Pex14p, more than just a docking protein. 2006, Pubmed