scholarly journals Defective Peroxisome Membrane Synthesis Due To Mutations in Human PEX3 Causes Zellweger Syndrome, Complementation Group G

2000 ◽  
Vol 67 (4) ◽  
pp. 967-975 ◽  
Author(s):  
Ania C. Muntau ◽  
Peter U. Mayerhofer ◽  
Barbara C. Paton ◽  
Stefan Kammerer ◽  
Adelbert A. Roscher
Keyword(s):  
Zellweger Syndrome ◽  
Complementation Group ◽  
Membrane Synthesis ◽  
Peroxisome Membrane

scholarly journals Inhibitors of Copi and Copii Do Not Block PEX3-Mediated Peroxisome Synthesis

2000 ◽  
Vol 149 (7) ◽  
pp. 1345-1360 ◽  
Author(s):  
Sarah T. South ◽  
Katherine A. Sacksteder ◽  
Xiaoling Li ◽  
Yifei Liu ◽  
Stephen J. Gould
Keyword(s):  
Membrane Proteins ◽  
Zellweger Syndrome ◽  
Brefeldin A ◽  
Membrane Traffic ◽  
Dominant Negative ◽  
Peroxisome Biogenesis ◽  
Membrane Synthesis ◽  
Peroxisomal Membrane ◽  
Peroxisome Membrane ◽  
Inactivating Mutations

In humans, defects in peroxisome biogenesis are the cause of lethal diseases typified by Zellweger syndrome. Here, we show that inactivating mutations in human PEX3 cause Zellweger syndrome, abrogate peroxisome membrane synthesis, and result in reduced abundance of peroxisomal membrane proteins (PMPs) and/or mislocalization of PMPs to the mitochondria. Previous studies have suggested that PEX3 may traffic through the ER en route to the peroxisome, that the COPI inhibitor, brefeldin A, leads to accumulation of PEX3 in the ER, and that PEX3 overexpression alters the morphology of the ER. However, we were unable to detect PEX3 in the ER at early times after expression. Furthermore, we find that inhibition of COPI function by brefeldin A has no effect on trafficking of PEX3 to peroxisomes and does not inhibit PEX3-mediated peroxisome biogenesis. We also find that inhibition of COPII-dependent membrane traffic by a dominant negative SAR1 mutant fails to block PEX3 transport to peroxisomes and PEX3-mediated peroxisome synthesis. Based on these results, we propose that PEX3 targeting to peroxisomes and PEX3-mediated peroxisome membrane synthesis may occur independently of COPI- and COPII-dependent membrane traffic.

scholarly journals PEX3 Is the Causal Gene Responsible for Peroxisome Membrane Assembly–Defective Zellweger Syndrome of Complementation Group G

2000 ◽  
Vol 67 (4) ◽  
pp. 976-981 ◽  
Author(s):  
Kamran Ghaedi ◽  
Masanori Honsho ◽  
Nobuyuki Shimozawa ◽  
Yasuyuki Suzuki ◽  
Naomi Kondo ◽  
...  
Keyword(s):  
Zellweger Syndrome ◽  
Complementation Group ◽  
Causal Gene ◽  
Membrane Assembly ◽  
Peroxisome Membrane

Phenotype–genotype relationships in peroxisome biogenesis disorders of PEX1-defective complementation group 1 are defined by Pex1p–Pex6p interaction

2001 ◽  
Vol 357 (2) ◽  
pp. 417-426 ◽  
Author(s):  
Shigehiko TAMURA ◽  
Naomi MATSUMOTO ◽  
Atsushi IMAMURA ◽  
Nobuyuki SHIMOZAWA ◽  
Yasuyuki SUZUKI ◽  
...  
Keyword(s):  
Zellweger Syndrome ◽  
Complementation Group ◽  
Temperature Sensitive ◽  
Permissive Temperature ◽  
Peroxisome Biogenesis ◽  
Causative Gene ◽  
Aaa Atpase ◽  
Peroxisome Biogenesis Disorders ◽  
The Stability

The peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (ZS), neonatal adrenoleucodystrophy (NALD) and infantile Refsum disease (IRD), are fatal autosomal recessive diseases caused by impaired peroxisome biogenesis, of which 12 genotypes have been reported. ZS patients manifest the severest clinical and biochemical abnormalities, whereas those with NALD and IRD show less severity and the mildest features respectively. We have reported previously that temperature-sensitive peroxisome assembly is responsible for the mildness of the clinical features of IRD. PEX1 is the causative gene for PBDs of complementation group E (CG-E, CG1 in the U.S.A. and Europe), the PBDs of highest incidence, encoding the peroxin Pex1p of the AAA ATPase family. It has been also reported that Pex1p and Pex6p interact with each other. In the present study we investigated phenotype–genotype relationships of CG1 PBDs. Pex1p from IRD such as Pex1p with the most frequently identified mutation at G843D was largely degraded in vivo at 37°C, whereas a normal level of Pex1p was detectable at the permissive temperature. In contrast, PEX1 proteins derived from ZS patients, including proteins with a mutation at L664P or the deletion of residues 634–690, were stably present at both temperatures. Pex1p-G843D interacted with Pex6p at approx. 50% of the level of normal Pex1p, whereas Pex1p from ZS patients mostly showing non-temperature-sensitive peroxisome biogenesis hardly bound to Pex6p. Taking these results together, we consider it most likely that the stability of Pex1p reflects temperature-sensitive peroxisome assembly in IRD fibroblasts. Failure in Pex1p–Pex6p interaction gives rise to more severe abnormalities, such as those manifested by patients with ZS.

scholarly journals Pex19 Binds Multiple Peroxisomal Membrane Proteins, Is Predominantly Cytoplasmic, and Is Required for Peroxisome Membrane Synthesis

2000 ◽  
Vol 148 (5) ◽  
pp. 931-944 ◽  
Author(s):  
Katherine A. Sacksteder ◽  
Jacob M. Jones ◽  
Sarah T. South ◽  
Xiaoling Li ◽  
Yifei Liu ◽  
...  
Keyword(s):  
Steady State ◽  
Membrane Proteins ◽  
Broad Spectrum ◽  
Matrix Protein ◽  
Protein Import ◽  
Nuclear Accumulation ◽  
Eukaryotic Cells ◽  
Membrane Synthesis ◽  
Peroxisomal Membrane ◽  
Peroxisome Membrane

Peroxisomes are components of virtually all eukaryotic cells. While much is known about peroxisomal matrix protein import, our understanding of how peroxisomal membrane proteins (PMPs) are targeted and inserted into the peroxisome membrane is extremely limited. Here, we show that PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes. Furthermore, mislocalization of PEX19 to the nucleus leads to nuclear accumulation of newly synthesized PMPs. At steady state, PEX19 is bimodally distributed between the cytoplasm and peroxisome, with most of the protein in the cytoplasm. We propose that PEX19 may bind newly synthesized PMPs and facilitate their insertion into the peroxisome membrane. This hypothesis is supported by the observation that the loss of PEX19 results in degradation of PMPs and/or mislocalization of PMPs to the mitochondrion.

scholarly journals PEX12, the Pathogenic Gene of Group III Zellweger Syndrome: cDNA Cloning by Functional Complementation on a CHO Cell Mutant, Patient Analysis, and Characterization of Pex12p

1998 ◽  
Vol 18 (7) ◽  
pp. 4324-4336 ◽  
Author(s):  
Kanji Okumoto ◽  
Nobuyuki Shimozawa ◽  
Atsusi Kawai ◽  
Shigehiko Tamura ◽  
Toshiro Tsukamoto ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Zellweger Syndrome ◽  
Complementation Group ◽  
Functional Complementation ◽  
Peroxisome Biogenesis ◽  
Cho Cell ◽  
Site Mutation ◽  
Transient Transfection Assay ◽  
Group Iii ◽  
Pathogenic Gene

ABSTRACT Rat PEX12 cDNA was isolated by functional complementation of peroxisome deficiency of a mutant CHO cell line, ZP109 (K. Okumoto, A. Bogaki, K. Tateishi, T. Tsukamoto, T. Osumi, N. Shimozawa, Y. Suzuki, T. Orii, and Y. Fujiki, Exp. Cell Res. 233:11–20, 1997), using a transient transfection assay and an ectopic, readily visible marker, green fluorescent protein. This cDNA encodes a 359-amino-acid membrane protein of peroxisomes with two transmembrane segments and a cysteine-rich zinc finger, the RING motif. A stable transformant of ZP109 with the PEX12 was morphologically and biochemically restored for peroxisome biogenesis. Pex12p was shown by expression of bona fide as well as epitope-tagged Pex12p to expose both N- and C-terminal regions to the cytosol. Fibroblasts derived from patients with the peroxisome deficiency Zellweger syndrome of complementation group III (CG-III) were also complemented for peroxisome biogenesis with PEX12. Two unrelated patients of this group manifesting peroxisome deficiency disorders possessed homozygous, inactivating PEX12mutations: in one, Arg180Thr by one point mutation, and in the other, deletion of two nucleotides in codons for 291Asn and292Ser, creating an apparently unchanged codon for Asn and a codon 292 for termination. These results indicate that the gene encoding peroxisome assembly factor Pex12p is a pathogenic gene of CG-III peroxisome deficiency. Moreover, truncation and site mutation studies, including patient PEX12analysis, demonstrated that the cytoplasmically oriented N- and C-terminal parts of Pex12p are essential for biological function.

scholarly journals Human peroxisomal targeting signal-1 receptor restores peroxisomal protein import in cells from patients with fatal peroxisomal disorders.

1995 ◽  
Vol 130 (1) ◽  
pp. 51-65 ◽  
Author(s):  
E A Wiemer ◽  
W M Nuttley ◽  
B L Bertolaet ◽  
X Li ◽  
U Francke ◽  
...  
Keyword(s):  
Protein Import ◽  
Zellweger Syndrome ◽  
Complementation Group ◽  
Cell System ◽  
Peroxisomal Disorders ◽  
Peroxisomal Membrane ◽  
Peroxisomal Protein ◽  
Peroxisomal Targeting ◽  
Targeting Signal

Two peroxisomal targeting signals, PTS1 and PTS2, are involved in the import of proteins into the peroxisome matrix. Human patients with fatal generalized peroxisomal deficiency disorders fall into at least nine genetic complementation groups. Cells from many of these patients are deficient in the import of PTS1-containing proteins, but the causes of the protein-import defect in these patients are unknown. We have cloned and sequenced the human cDNA homologue (PTS1R) of the Pichia pastoris PAS8 gene, the PTS1 receptor (McCollum, D., E. Monosov, and S. Subramani. 1993. J. Cell Biol. 121:761-774). The PTS1R mRNA is expressed in all human tissues examined. Antibodies to the human PTS1R recognize this protein in human, monkey, rat, and hamster cells. The protein is localized mainly in the cytosol but is also found to be associated with peroxisomes. Part of the peroxisomal PTS1R protein is tightly bound to the peroxisomal membrane. Antibodies to PTS1R inhibit peroxisomal protein-import of PTS1-containing proteins in a permeabilized CHO cell system. In vitro-translated PTS1R protein specifically binds a serine-lysine-leucine-peptide. A PAS8-PTS1R fusion protein complements the P. pastoris pas8 mutant. The PTS1R cDNA also complements the PTS1 protein-import defect in skin fibroblasts from patients--belonging to complementation group two--diagnosed as having neonatal adrenoleukodystrophy or Zellweger syndrome. The PTS1R gene has been localized to a chromosomal location where no other peroxisomal disorder genes are known to map. Our findings represent the only case in which the molecular basis of the protein-import deficiency in human peroxisomal disorders is understood.

scholarly journals Mutation in PEX16 Is Causal in the Peroxisome-Deficient Zellweger Syndrome of Complementation Group D

1998 ◽  
Vol 63 (6) ◽  
pp. 1622-1630 ◽  
Author(s):  
Masanori Honsho ◽  
Shigehiko Tamura ◽  
Nobuyuki Shimozawa ◽  
Yasuyuki Suzuki ◽  
Naomi Kondo ◽  
...  
Keyword(s):  
Zellweger Syndrome ◽  
Complementation Group ◽  
Group D

Dynamic and functional assembly of the AAA peroxins, Pex1p and Pex6p, and their membrane receptor Pex26p involved in shuttling of the PTS1 receptor Pex5p in peroxisome biogenesis

2008 ◽  
Vol 36 (1) ◽  
pp. 109-113 ◽  
Author(s):  
Yukio Fujiki ◽  
Non Miyata ◽  
Naomi Matsumoto ◽  
Shigehiko Tamura
Keyword(s):  
Atp Hydrolysis ◽  
Zellweger Syndrome ◽  
Complementation Group ◽  
Peroxisome Biogenesis ◽  
Aaa Atpase ◽  
Causal Genes ◽  
Signal Type ◽  
Targeting Signal ◽  
Membrane Bound

The peroxisome is a single-membrane-bound organelle found in eukaryotes. The functional importance of peroxisomes in humans is highlighted by peroxisome-deficient PBDs (peroxisome biogenesis disorders), such as Zellweger syndrome. Two AAA (ATPase associated with various cellular activities) peroxins, Pex1p and Pex6p, are encoded by PEX1 and PEX6, the causal genes for CG (complementation group) 1 and CG4 PBDs respectively. PEX26, which is responsible for CG8 PBDs, codes for Pex26p, the recruiter of Pex1p–Pex6p complexes to peroxisomes. We recently assigned the binding regions between human Pex1p and Pex6p and elucidated the pivotal roles that the AAA cassettes, D1 and D2 domains, play in Pex1p–Pex6p interaction and in peroxisome biogenesis. ATP binding to both AAA cassettes of Pex1p and Pex6p was a prerequisite for the Pex1p–Pex6p interaction and peroxisomal localization, but ATP hydrolysis by the D2 domains was not required. Pex1p exists in two distinct oligomeric forms, a homo-oligomer in the cytosol and a hetero-oligomer on peroxisome membranes, with these possibly having distinct functions in peroxisome biogenesis. AAA peroxins are involved in the export from peroxisomes of Pex5p, the PTS1 (peroxisome-targeting signal type 1) receptor.

scholarly journals Isolation of peroxisome assembly mutants from Saccharomyces cerevisiae with different morphologies using a novel positive selection procedure.

1992 ◽  
Vol 119 (1) ◽  
pp. 153-162 ◽  
Author(s):  
I Van der Leij ◽  
M Van den Berg ◽  
R Boot ◽  
M Franse ◽  
B Distel ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Positive Selection ◽  
Protein Import ◽  
Zellweger Syndrome ◽  
Signal Transduction Pathway ◽  
Selection Procedure ◽  
Complementation Group ◽  
Cell Fractionation ◽  
Wild Type ◽  
Beta Oxidation

We have developed a positive selection system for the isolation of Saccharomyces cerevisiae mutants with disturbed peroxisomal functions. The selection is based on the lethality of hydrogen peroxide (H2O2) that is produced in wild type cells during the peroxisomal beta-oxidation of fatty acids. In total, 17 mutants having a general impairment of peroxisome biogenesis were isolated, as revealed by their inability to grow on oleic acid as the sole carbon source and their aberrant cell fractionation pattern of peroxisomal enzymes. The mutants were shown to have monogenetic defects and to fall into 12 complementation groups. Representative members of each complementation group were morphologically examined by immunocytochemistry using EM. In one mutant the induction and morphology of peroxisomes is normal but import of thiolase is abrogated, while in another the morphology differs from the wild type: stacked peroxisomal membranes are present that are able to import thiolase but not catalase. These mutants suggest the existence of multiple components involved in peroxisomal protein import. Some mutants show the phenotype characteristic of glucose-repressed cells, an indication for the interruption of a signal transduction pathway resulting in organelle proliferation. In the remaining mutants morphologically detectable peroxisomes are absent: this phenotype is also known from fibroblasts of patients suffering from Zellweger syndrome, a disorder resulting from impairment of peroxisomes.

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