PEX5L

PEX5L is an alternative, longer isoform of the peroxisomal import receptor PEX5, encoded by the PEX5 gene in vertebrates. It arises through alternative splicing and features an extended N-terminal region compared with the shorter isoform PEX5S. The C-terminal region of PEX5L contains the conserved tetratricopeptide repeat (TPR) cargo-binding domain that recognizes the peroxisomal targeting signal type 1 (PTS1) on soluble matrix proteins.

Functionally, PEX5L acts as the cytosolic receptor that captures PTS1-containing proteins and ferries them to the peroxisome for import. It interacts with peroxisomal membrane docking factors, such as PEX13 and PEX14, to facilitate cargo delivery. Following cargo release, PEX5L is mono-ubiquitinated and recycled back to the cytosol by the PEX1–PEX6–PEX26 complex; prolonged ubiquitination can channel PEX5L toward degradation. The N-terminal extension of PEX5L is thought to influence docking efficiency and trafficking, potentially affecting import requirements in a tissue- or condition-specific manner.

Expression of PEX5L varies across tissues and developmental stages, and the relative abundance of PEX5L versus PEX5S can modulate peroxisomal import efficiency under certain physiological conditions. Regulation of PEX5L involves the same core peroxisomal biogenesis machinery that governs PEX5 turnover and recycling, including ubiquitination and ATP-dependent extraction.

Clinical relevance is linked to peroxisome biogenesis disorders caused by defects in the PEX5–PEX import pathway, such as Zellweger spectrum disorders. While specific disease associations with PEX5L alone are not always distinct, proper function and balance of PEX5 isoforms contribute to normal peroxisomal protein import. See also PEX5, PTS1, peroxisome, PEX14, PEX1, and PEX6.