Protein Import into the Peroxisomes

Peroxisomes lack DNA and cannot encode their own enzymes, so they must import proteins synthesized in the ER or cytosol. Peroxins, a group of matrix proteins, cytosolic receptors, and membrane proteins, facilitate this import process. This dependency on external protein synthesis distinguishes peroxisomes from other organelles like mitochondria.

Peroxisomal targeting sequences (PTS1 and PTS2) are short import signals located at the C- or N-terminus of peroxisomal proteins. The most common PTS1 is the tripeptide serine-lysine-leucine. Peroxisomal receptors like Pex5 recognize these sequences in the cytosol and bind membrane-bound translocators to form complexes that transport proteins into the peroxisomal matrix.

Pex5 recognizes PTS1 signals on cytosolic proteins like catalase. It then binds the membrane-bound translocator Pex14 to form a multimeric complex that allows the protein to cross into the peroxisomal matrix. After cargo delivery, ubiquitination of Pex5 by Pex2, Pex10, and Pex12 triggers its release and recycling back to the cytosol.

After delivering cargo, Pex5 is ubiquitinated by membrane proteins containing Pex2, Pex10, and Pex12. The Pex1-Pex6 ATPase complex then helps dissociate the modified Pex5 from the membrane. Deubiquitinating enzymes remove the ubiquitin tag, allowing Pex5 to recycle and import additional proteins.

Unlike mitochondrial import systems, peroxisomal import machinery can transport fully folded proteins into the organelle. Peroxisomal proteins are synthesized in the cytoplasm or ER and recognized by targeting sequences, while proteins destined for ER insertion are packaged into specialized vesicles for transport and membrane insertion.

Zellweger syndrome results from mutations in PEX genes, particularly Pex5 and Pex7, which encode peroxin proteins essential for protein import. These mutations prevent peroxisomal enzymes from being imported, creating empty peroxisomes and causing severe metabolic disorders affecting the brain, kidney, and liver.

Adrenoleukodystrophy is an X-linked genetic defect that impairs the transport and oxidation of long-chain fatty acids in peroxisomes. This causes fatty acids to accumulate in the bloodstream and damages myelin in neurons, affecting the brain's white matter and resulting in severe neurological complications.