The cycling peroxisomal targeting signal type 1 - receptor Pex5p: reaching the circle’s end with ubiquitin

Peroxisomes are single-membrane bound organelles that are found nearly ubiquitiously in eukaryotic cells. Their main task is the breakdown of fatty acids by beta-oxidation and the detoxification of hydrogen peroxide. However, these so called “multi-purpose organelles” also display several other metabolic functions, which can differ between species, tissues or growth conditions of the cells. This high plasticity of peroxisomal functions is enabled by an adjustment of the protein composition, which in turn is regulated by the dynamically operating protein import receptors. Subsequent to their synthesis on free ribosomes in the cytosol, peroxisomal matrix proteins are recognizes by import receptors by means of a peroxisomal targeting sequence (PTS). Most peroxisomal matrix proteins harbor a PTS-type 1 (PTS1) signal, which is bound by the PTS1-receptor Pex5p in the cytosol. The PTS1-receptor/cargo-complex reaches a docking complex at the peroxisome, where Pex5p is thought to become a building block of a transiently opened translocation pore. After the translocation of the folded cargo proteins over the membrane into the peroxisomal matrix, Pex5p is exported back to the cytosol for further rounds of matrix protein import. This dislocation step comprises the only energy-consuming reactions of the entire receptor cycle, because Pex5p has to be monoubiquitinated at a conserved cysteine before it can be extracted from the membrane by the AAA-type ATPases Pex1p and Pex6p. In case this recycling pathway is hampered, Pex5p gets polyubiquitinated on lysine residues and degraded by the proteasome. This review focuses on the PTS1-receptor Pex5p and discusses recent data and concepts regarding the molecular mechanism of cargo recognition, pore formation, cargo release and ubiquitination-dependent export and highlights the clinical relevance of Pex5p in health and disease.