Peroxisome biogenesis and human peroxisome biogenesis disorders

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1) PEX3 encoding 42-kDa membrane peroxin was cloned by using a peroxisome membrane assembly-defective CHO mutant, ZPG208. Dysfunction of PEX3 was responsible for peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome of complementation group G.2) Of 3 RING peroxins, including Pex2p, Pex10p, and Pex12p, Pex12p RING finger was essential for peroxisome restoring activity but not necessary for targeting to peroxisomes. Pex12p RING finger binds to Pex10p and peroxisome targeting signal 1 (PTS1)-receptor Pex5p.3) We showed that PEX6, the CG4 pathogenic gene, restored peroxisome assembly in CG6 PBD fibroblasts. This patient was compound heterozygous for PEX6 alleles. Accordingly, human PBDs are classified into 12 CGs by merging CG6 with CG4.4) Two isoforms of Pex5p, Pex5pS and 37-amino acid-longer Pex5pL, are expressed in mammals. We found that Pex5pL interacts with the PTS2 receptor Pex7p-PTS2-protein complexes in the cytosol and translocates them to Pex14p. We defined the functio … More nal Pex5p domains interacting with Pex7p, Pex13p, and Pex14p. An N-terminal half Pex5pL comprising amino acid residues at 1-243 bound to Pex7p, Pex13p and Pex14p and was sufficient for restoring the impaired PTS2 import of pex5 cell mutants, whilst the C-terminal tetratricopeptide repeat motifs were required for PTS1-binding. Seven (six in Pex5pS) pentapeptide WxxxF/Y-motifs residing at the N-terminal region were essential for Pex5p interaction with Pex14p and Pex13p. Pex14p and Pex13p formed a complex with PTS1-loaded Pex5p but dissociated in the presence of cargo-unloaded Pex5p, hence implying that PTS cargoes are released from Pex5p at the step downstream of Pex14p and upstream of Pex13p. We reported that Pex7p shows a bimodal distribution between the cytoplasm and peroxisomes in CHO and human cells, implying that Pex7p shuttles between peroxisomes and the cytosol, like Pex5p. Pex7p requires nearly the full length, including all WD motifs, for its function.5) We recently isolated human PEX26 encoding a novel, 34-kDa type II peroxisomal membrane protein, using a CHO cell mutant ZP167. PEX26 expression restored peroxisomal protein import in only the CG8 PBD patient's fibroblasts. This patient possessed a homozygous, inactivating pathogenic point mutation, R98W. Accordingly, we can state that all of pathogenic genes responsible for 12 CGs PBDs have been cloned. Moreover, Pex6p and Pex1p of the AAA ATPase family were co-immunoprecipitated with Pex26p. Together with several lines of morphological evidence, we concluded that Pex26p recruits Pex6p-Pex1p complexes to peroxisomes. Less