Functional Heterogeneity of C-Terminal Peroxisome Targeting Signal 1 in PEX5-Defective Patients

• Published in: Biochemical and biophysical research communications Vol. 262; no. 2; pp. 504 - 508
• Main Authors: Shimozawa, Nobuyuki, Zhang, Zhongyi, Suzuki, Yasuyuki, Imamura, Atsushi, Tsukamoto, Toshiro, Osumi, Takashi, Fujiki, Yukio, Orii, Tadao, Barth, Peter G, Wanders, Ronald J.A, Kondo, Naomi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.08.1999
• Subjects: 17-Hydroxysteroid Dehydrogenases; 3-Hydroxyacyl CoA Dehydrogenases - metabolism; Acyl-CoA Oxidase; Biological Transport; Carrier Proteins - metabolism; Cell Compartmentation; Chinese hamster ovary cell mutant; Enoyl-CoA Hydratase; Fibroblasts - cytology; Humans; Hydro-Lyases - metabolism; Microbodies - metabolism; Multienzyme Complexes - metabolism; Mutation; Oxidoreductases - metabolism; Peroxisomal Disorders - genetics; Peroxisomal Multifunctional Protein-2; Peroxisomal Targeting Signal 2 Receptor; peroxisome biogenesis disorders; peroxisome targeting signal; Peroxisome-Targeting Signal 1 Receptor; PEX5; protein import; Protein Sorting Signals - genetics; Receptors, Cytoplasmic and Nuclear - genetics; Sterols; Transformation, Genetic; Zellweger Syndrome - genetics; peroxisome targeting signal; protein import; peroxisome biogenesis disorders; PEX5; Chinese hamster ovary cell mutant
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1999.1232

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.