title: Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients.
abstract: To investigate mechanisms related to functions of the peroxisome targeting signal (PTS) 1 receptor, Pex5p, we analyzed peroxisome matrix protein import in fibroblasts from three patients with peroxisome biogenesis disorders, all with different mutations in the PEX5 gene. The patients 2-01 (Zellweger syndrome) and 2-05 (neonatal adrenoleukodystrophy) have the reported mutations, R390X and N489K, and patient 2-03 (infantile Refsum disease) has a newly identified mutation, S563W. Fibroblasts from 2-03 (S563W) were detected in both PTS1 and PTS2 imports despite the PEX5 defect, findings in contrast with fibroblasts from 2-05 (N489K) severely defective in PTS1 import and those from 2-01 (R390X) severely defective in both PTS1 and PTS2. The PTS1 receptor in 2-03 is functional for only the C-terminal -SKL sequence (acyl-CoA oxidase) and had little or no function for C-terminal -AKL (D-bifunctional protein and sterol carrier protein 2) and -KANL (catalase) sequences, respectively. After transfection of these mutated PEX5 cDNA into the PEX5-defective CHO mutant, transformants of ZP102 revealed that each mutation was responsible for each dysfunction of the PTS1 import. It seems apparent that -AKL and -KANL are poorer variants of PTS1 and are likely to be more susceptible to effects of mutation of its receptor, Pex5p.
authors.affiliation: Department of Pediatrics, Gifu University School of Medicine, Gifu, 500-8076, Japan. nshim@cc.gifu-u.ac.jp
authors.forename: N
authors.initials: N
authors.lastname: Shimozawa
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: A
authors.initials: A
authors.lastname: Imamura
authors.forename: T
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: T
authors.initials: T
authors.lastname: Osumi
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiki
authors.forename: T
authors.initials: T
authors.lastname: Orii
authors.forename: P G
authors.initials: PG
authors.lastname: Barth
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: N
authors.initials: N
authors.lastname: Kondo
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D042962:Acyl-CoA Oxidase; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002451:Cell Compartmentation; D004746:Enoyl-CoA Hydratase; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D006836:Hydro-Lyases / Q000378:metabolism; D008830:Microbodies / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D010088:Oxidoreductases / Q000378:metabolism; D018901:Peroxisomal Disorders / Q000235:genetics*; D064029:Peroxisomal Multifunctional Protein-2; D000074437:Peroxisomal Targeting Signal 2 Receptor; D000074435:Peroxisome-Targeting Signal 1 Receptor; D021382:Protein Sorting Signals / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D013261:Sterols; D014170:Transformation, Genetic; D015211:Zellweger Syndrome / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D009097:Multienzyme Complexes; C000614264:PEX5 protein, human; D000074437:Peroxisomal Targeting Signal 2 Receptor; D000074435:Peroxisome-Targeting Signal 1 Receptor; D021382:Protein Sorting Signals; D018160:Receptors, Cytoplasmic and Nuclear; D013261:Sterols; D010088:Oxidoreductases; D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases; D042962:Acyl-CoA Oxidase; D006836:Hydro-Lyases; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human; D004746:Enoyl-CoA Hydratase