The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.

Yahraus, Tami; Braverman, Nancy; Dodt, Gabriele; Kalish, Jennifer E.; Morrell, James C.; Moser, Hugo W.; Valle, David; Gould, Stephen J.

doi:10.1002/j.1460-2075.1996.tb00654.x

Cited by 174 publications

(155 citation statements)

References 62 publications

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“…One possible explanation for the observed stability of Pex5p in these mutants is that the ubiquitinated Pex5p species contain less than four ubiquitin moieties, which may be insufficient for optimal recognition by the proteasome (32). It is interesting to note, however, that Pex5p is extremely unstable in exactly the same set of mutants in human and P. pastoris cells (22,24,42,51).…”

Section: Discussionmentioning

confidence: 94%

The Saccharomyces cerevisiae Peroxisomal Import Receptor Pex5p Is Monoubiquitinated in Wild Type Cells

Kragt

Voorn-Brouwer

Berg

et al. 2005

Journal of Biological Chemistry

121

113

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Pex5p is a mobile receptor for peroxisomal targeting signal type I-containing proteins that cycles between the cytoplasm and the peroxisome. Here we show that Pex5p is a stable protein that is monoubiquitinated in wild type cells. By making use of mutants defective in vacuolar or proteasomal degradation we demonstrate that monoubiquitinated Pex5p is not a breakdown intermediate of either system. Monoubiquitinated Pex5p is localized to peroxisomes, and ubiquitination requires the presence of functional docking and RING finger complexes, which suggests that it is a late event in peroxisomal matrix protein import. In pex1, pex4, pex6, pex15, and pex22 mutants, all of which are blocked in the terminal steps of peroxisomal matrix protein import, polyubiquitinated forms of Pex5p accumulate, ubiquitination being dependent on the ubiquitin-conjugating enzyme Ubc4p. However, Ubc4p is not required for Pex5p ubiquitination in wild type cells, and cells lacking Ubc4p are not affected in peroxisome biogenesis. These results indicate that Pex5p monoubiquitination in wild type cells serves to regulate rather than to degrade Pex5p, which is supported by the observed stability of Pex5p. We propose that Pex5p monoubiquitination in wild type cells is required for the recycling of Pex5p from the peroxisome, whereas Ubc4p-mediated polyubiquitination of Pex5p in mutants blocked in the terminal steps of peroxisomal matrix protein import may function as a disposal mechanism for Pex5p when it gets stuck in the import pathway.

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Section: Discussionmentioning

confidence: 94%

The Saccharomyces cerevisiae Peroxisomal Import Receptor Pex5p Is Monoubiquitinated in Wild Type Cells

Kragt

Voorn-Brouwer

Berg

et al. 2005

Journal of Biological Chemistry

121

113

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“…This implies that mammalian peroxisome assembly requires at least 14 genes or their products. Five peroxins, Pex2p (29,40,55,56), Pex5p (18,30,31), Pex6p (32,33,41), Pex12p (34,35), and recently isolated Pex1p (26 -28), have been elucidated to be required for peroxisome biogenesis in mammals. PEX7 encoding a PTS2 receptor was also recently shown to be responsible for a peroxisomal disorder, rhizomelic chondrodysplasia punctata, where only PTS2 import is defective and peroxisomes are morphologically recognizable (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Newly Identified Chinese Hamster Ovary Cell Mutants Are Defective in Biogenesis of Peroxisomal Membrane Vesicles (Peroxisomal Ghosts), Representing a Novel Complementation Group in Mammals

Kinoshita

Ghaedi

Shimozawa

et al. 1998

Journal of Biological Chemistry

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We isolated peroxisome biogenesis-defective mutants from Chinese hamster ovary cells by the 9-(1-pyrene)nonanol/ultraviolet (P9OH/UV) method. Seven cell mutants, ZP116, ZP119, ZP160, ZP161, ZP162, ZP164, and ZP165, of 11 P9OH/UV-resistant cell clones showed cytosolic localization of catalase, a peroxisomal matrix enzyme, apparently indicating a defect of peroxisome biogenesis. By transfection of PEX cDNAs and cell fusion analysis, mutants ZP119 and ZP165 were found to belong to a novel complementation group (CG), distinct from earlier mutants. CG analysis by cell fusion with fibroblasts from patients with peroxisome biogenesis disorders such as Zellweger syndrome indicated that ZP119 and ZP165 were in the same CG as the most recently identified human CG-J. The peroxisomal matrix proteins examined, including PTS1 proteins as well as a PTS2 protein, 3-ketoacyl-CoA thiolase, were also found in the cytosol in ZP119 and ZP165. Furthermore, these mutants showed typical peroxisome assembly-defective phenotype such as severe loss of resistance to 12-(1-pyrene)dodecanoic acid/UV treatment. Most strikingly, peroxisomal reminiscent vesicular structures, so-called peroxisomal ghosts noted in all CGs of earlier Chinese hamster ovary cell mutants as well as in eight CGs of patients' fibroblasts, were not discernible in ZP119 and ZP165, despite normal synthesis of peroxisomal membrane proteins. Accordingly, ZP119 and ZP165 are the first cell mutants defective in import of both soluble and membrane proteins, representing the 14th peroxisomedeficient CG in mammals, including humans.

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“…Each AAA cassette includes Walker A (amino acids 470-477 and 744-751 ) and Walker B (amino acids 520-532 and 791-803) nucleotide binding motifs. The second Walker A motif is essential for biological activity of PEX6 (Yahraus et al, 1996). Ten of the eighteen novel missense mutations are located in the AAA cassette domains, of which three mutations (p.L511R, p.A518D and p.R786W) are located in one of the two Walker B motifs and one mutation (p.F864S) is located in the AAA protein family signature.…”

Section: Spectrum Of Pex6mentioning

confidence: 99%

Spectrum ofPEX6mutations in Zellweger syndrome spectrum patients

et al. 2010

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ABSTRACT:The autosomal recessive Zellweger syndrome spectrum (ZSS) disorders comprise a main subgroup of the peroxisome biogenesis disorders. The ZSS disorders can be caused by mutations in any of 12 different currently identified PEX genes resulting in severe, often lethal, multi-systemic disorders. Defects in the PEX6 gene are the second most common cause for ZSS disorders. The encoded protein PEX6 belongs to the AAA ATPase family and contains two AAA cassettes and an AAA protein family signature. The PEX6 gene consists of 17 exons and previously mutations in the PEX6 gene were found to be scattered over all exons. We developed a post-PCR high-resolution melting (HRM) curve assay to scan the PEX6 gene for potential sequence variations followed by selective sequencing to identify these. We analyzed the PEX6 genes of 75 patients assigned to the PEX6 complementation group. We identified a total of 77 different mutations of which 47 mutations have not been reported previously, and 14 polymorphic variants.

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The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.

Cited by 174 publications

References 62 publications

The Saccharomyces cerevisiae Peroxisomal Import Receptor Pex5p Is Monoubiquitinated in Wild Type Cells

The Saccharomyces cerevisiae Peroxisomal Import Receptor Pex5p Is Monoubiquitinated in Wild Type Cells

Newly Identified Chinese Hamster Ovary Cell Mutants Are Defective in Biogenesis of Peroxisomal Membrane Vesicles (Peroxisomal Ghosts), Representing a Novel Complementation Group in Mammals

Spectrum ofPEX6mutations in Zellweger syndrome spectrum patients

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