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PubMed1999

A novel nonsense mutation of the PEX7 gene in a patient with rhizomelic chondrodysplasia punctata.

Mutations in the PEX7 gene encoding a peroxisome targeting signal 2 (PTS2) were identified in two patients with rhizomelic chondrodysplasia punctata (RCDP). A 7-year-old girl, the first Japanese individual to be diagnosed biochemically as a case of RCDP, had a novel nonsense mutation, R232ter, in the PEX7 gene, which had been inherited from her consanguineous parents. Another patient, a Chilean boy with RCDP, had compound heterozygous mutations of PEX7, L292ter and A218V, both of which have been documented. R232ter, which deletes all of the last two WP40 repeats in the PEX7 gene, is sufficient to inactivate functions of the PEX7 gene.

Amino Acid Sequence↗
PubMed2006

The ether lipid-deficient mouse: tracking down plasmalogen functions.

Chemical and physico-chemical properties as well as physiological functions of major mammalian ether-linked glycerolipids, including plasmalogens were reviewed. Their chemical structures were described and their effect on membrane fluidity and membrane fusion discussed. The recent generation of mouse models with ether lipid deficiency offered the possibility to study ether lipid and particularly plasmalogen functions in vivo. Ether lipid-deficient mice revealed severe phenotypic alterations, including arrest of spermatogenesis, development of cataract and defects in central nervous system myelination. In several cell culture systems lack of plasmalogens impaired intracellular cholesterol distribution affecting plasma membrane functions and structural changes of ER and Golgi cisternae. Based on these phenotypic anomalies that were accurately described conclusions were drawn on putative functions of plasmalogens. These functions were related to cell-cell or cell-extracellular matrix interactions, formation of lipid raft microdomains and intracellular cholesterol homeostasis. There are several human disorders, such as Zellweger syndrome, rhizomelic chondrodysplasia punctata, Alzheimer's disease, Down syndrome, and Niemann-Pick type C disease that are distinguished by altered tissue plasmalogen concentrations. The role plasmalogens might play in the pathology of these disorders is discussed.

Acyltransferases↗
PubMed2002

Isolation of Chinese hamster ovary cell pex mutants: two PEX7-defective mutants.

We searched for novel Chinese hamster ovary (CHO) cell mutants defective in peroxisome biogenesis by an improved method using peroxisome targeting signal 2 (PTS2)-tagged enhanced green fluorescent protein (EGFP). From mutagenized TKaEG2 cells, the wild-type CHO-K1 stably expressing rat Pex2p and PTS2-EGFP, cell colonies resistant to the 9-(1(')-pyrene)nonanol/ultraviolet treatment were examined for intracellular location of PTS2-EGFP. Of six mutant cell clones two, ZPEG227 and ZPEG231, showed cytosolic PTS2-EGFP, indicative of impaired PTS2 import, and numerous PTS1-positive particles. PEX7 expression restored the impaired PTS2 import in both mutants. Cell fusion with fibroblasts from a patient with PEX7-defective rhizomelic chondrodysplasia punctata did not complement PTS2 import defect of ZPEG227 and ZPEG231, confirming that these two are pex7 mutants. Mutation analysis of PEX7 by reverse transriptase (RT)-PCR indicated that ZPEG227-allele carried an inactivating nonsense mutation, Trp158Ter. Therefore, ZPEG227 is a pex7 mutant possessing a newly identified mutation in mammalian pex7 cell lines.

Amino Acid Substitution↗
PubMed1998

Mutational analyses of a type 2 peroxisomal targeting signal that is capable of directing oligomeric protein import into tobacco BY-2 glyoxysomes.

In this study of the type 2 peroxisomal targeting signal (PTS2) pathway, we examined the apparent discontinuity and conservation of residues within the PTS2 nonapeptide and demonstrated that this topogenic signal is capable of directing heteromultimeric protein import in plant cells. Based on cumulative data showing that at least 26 unique, putative PTS2 nonapeptides occur within 12 diverse peroxisomal-destined proteins, the current (-R/K-L/V/I-X5-H/Q-L/A-) as well as the original (-R-L-X5-H/Q-L-) PTS2 motif appear to be oversimplified. To assess the functionality of residues within the motif, rat liver thiolase (rthio) and various chimeric chloramphenicol acetyltransferase (CAT) proteins were expressed transiently in suspension-cultured tobacco (Nicotiana tabaccum L.) cv Bright Yellow cells (BY-2), and their subcellular location was determined by immunofluoresence microscopy. Hemagglutinin (HA)-epitope-tagged-CAT subunits, lacking a PTS2 (CAT-HA), were 'piggybacked' into glyoxysomes by PTS2-bearing CAT subunits (rthio-CAT), whereas signal-depleted CAT-HA subunits that were modified to prevent oligomerization did not import into glyoxysomes. These results provided direct evidence that signal-depleted subunits imported into peroxisomes were targeted to the organelle as oligomers (heteromers) by a PTS2. Mutational analysis of residues within PTS2 nonapeptides revealed that a number of amino acid substitutions were capable of maintaining targeting function. Furthermore, functionality of residues within the PTS2 nonapeptide did not appear to require a context-specific environment conferred by adjacent residues. These results collectively suggest that the functional PTS2 is not solely defined as a sequence-specific motif, i.e. -R/K-X6-H/Q-A/L/F-, but defined also by its structural motif that is dependent upon the physiochemical properties of residues within the nonapeptide.

Acetyl-CoA C-Acetyltransferase↗
PubMed2005

Hansenula polymorpha Pex20p is an oligomer that binds the peroxisomal targeting signal 2 (PTS2).

We have cloned and characterized the Hansenula polymorpha PEX20 gene. The HpPEX20 gene encodes a protein of 309 amino acids (HpPex20p) with a calculated molecular mass of approximately 35 kDa. In cells of an HpPEX20 disruption strain, PTS2 proteins were mislocalized to the cytosol, whereas PTS1 matrix protein import proceeded normally. Also, the PTS2 proteins amine oxidase and thiolase were normally assembled and active in these cells, suggesting HpPex20p is not involved in oligomerization/activation of these proteins. Localization studies revealed that HpPex20p is predominantly associated with peroxisomes. Using fluorescence correlation spectroscopy we determined the native molecular mass of purified HpPex20p and binding of a synthetic peptide containing a PTS2 sequence. The data revealed that purified HpPex20p forms oligomers, which specifically bind PTS2-containing peptides.

Cloning, Molecular↗
PubMed2004

Long term follow-up of two sibs with an autosomal recessive form of chrondrodysplasia punctata and epilepsy.

Long term follow-up of two sibs with an autosomal recessive form of chrondrodysplasia punctata and epilepsy: A variety of osteodysplasias are referred to with the term chondrodysplasia punctata (CDP). Here we report on two sibs, a boy and a girl, with probable autosomal recessive form of CDP and epilepsy followed-up for 30 and 19 years, respectively. Family history was unremarkable but for consanguinity. Pregnancies and deliveries were uneventful. At birth, length was 46 (-3SD) and 45 (-4SD) cm, respectively. Craniofacial dysmorphism was noted: severe nasal hypoplasia, flat face, hypertelorism, a low nasal bridge, short stature. Skeletal abnormalities included epiphyseal stippling in the thoracic spine, bilateral proximal and distal humeri, femur, tibia and bilateral carpal and tarsal bones. The boy had a hemivertebrae T12, with absence of a rib. After the age of 6 years facial dysmorphism had improved. Final height was 154 cm (-3SD) in the boy and 158 cm (-0,5SD) in the girl. The boy was operated on for scoliosis. Both sibs had club feet, the girl had also genu valgum. IQ was evaluated to be 55 in the girl and 83 in the boy. The first non febrile generalized seizure appeared in the boy when he was 11 months of age, and in the girl when she was 25 months of age. Both had many other seizures and were taking antiepileptics. EEG were abnormal. Karyotypes were normal. Extensive screening for metabolic disorders was normal. Acquired in utero CDP were excluded. We suggest the sibs described in this report have yet another provisionally unique possibly autosomal recessive syndrome, with CDP and epilepsy as phenotypic traits.

Adult↗
PubMed1997

Isolation of a new peroxisome-deficient CHO cell mutant defective in peroxisome targeting signal-1 receptor.

For the study of mechanism of peroxisome biogenesis, we attempted to isolate CHO cell mutants deficient in peroxisome biogenesis. We used as the parent strain a stable CHO transformant of rat PEX2 (formerly named peroxisome assembly factor-1) cDNA, to avoid unusually frequent isolation of Pex2 mutants. Among the three peroxisome-deficient mutants obtained, ZP102 was a new CHO mutant of complementation group 2, and was restored for peroxisome assembly by the transfection of human PEX5 (formerly called PXR1 or PTS1R) cDNA. This approach would facilitate the isolation of new complementation gorups of peroxisome-deficient CHO mutants and the identification of essential genes for peroxisome biogenesis.

Animals↗
PubMed2001

Zellweger syndrome knockout mouse models challenge putative peroxisomal beta-oxidation involvement in docosahexaenoic acid (22:6n-3) biosynthesis.

The putative involvement of peroxisomal beta-oxidation in the biosynthetic pathway of docosahexaenoic acid (22:6n-3, DHA) synthesis is critically reviewed in light of experiments with two recently developed knockout mouse models for Zellweger syndrome, a peroxisomal disorder affecting brain development. These mice were generated by targeted disruption of the PEX2 and PEX5 peroxisomal assembly genes encoding targeting signal receptor peroxins for the recognition and transport of a set of peroxisomal enzymes, including those of peroxisomal beta-oxidation, to the peroxisomal matrix. Analysis of esterified 22:6n-3 concentrations in PEX2-/- and PEX5-/- mice do not support the hypothesized requirement of peroxisomal beta-oxidation in 22:6n-3 synthesis, as only brain, but not liver or plasma, 22:6n-3 levels were decreased. Supplementation of PEX5+/- dams with 22:6n-3, although restoring the levels of brain 22:6n-3 in total lipids to that of controls, did not normalize the phenotype. These decreased brain 22:6n-3 concentrations appear to be secondary to impaired plasmalogen (sn-1-alkyl-, alkenyl-2-acyl glycerophospholipids) synthesis, probably at the level of the dihydroxyacetonephosphate acyltransferase (DHAP-AT), a peroxisomal enzyme catalyzing the first step in the synthesis of 22:6n-3-rich plasmalogens. To diminish the confounding effects of impaired plasmalogen synthesis in the brains of these Zellweger syndrome mouse models, kinetic experiments with labeled precursors, such as 18:3n-3 or 20:5n-3, in liver or isolated hepatocytes, which have negligible amounts of plasmalogens, are suggested to establish the rates of 22:6n-3 biosynthesis and precursor-product relationships. Similar experiments using brain of the acyl-CoA oxidase knockout mouse model are proposed to confirm the lack of peroxisomal beta-oxidation involvement in 22:6n-3 synthesis, since this mutation would not impair plasmalogen synthesis.

Animals↗
PubMed2005

Analysis of human Pex19p's domain structure by pentapeptide scanning mutagenesis.

Pex19p, a primarily cytosolic protein, is essential for the biogenesis of numerous peroxisomal membrane proteins (PMPs); however, its precise function is unclear. Pex19p might function as a PMP-specific chaperone, a cycling PMP-receptor protein, a PMP membrane insertion factor, or an association/dissociation factor of membrane-associated protein complexes. Alternatively, Pex19p might act as a multifunctional peroxin and participate in a number of these activities. Here, we have employed transposon mutagenesis to generate a library of human pex19 alleles coding for Pex19p variants containing random in-frame pentapeptide insertions. A total of 87 different variants were characterized to identify functionally important regions. These studies revealed that Pex19p has a tripartite domain structure consisting of: (i) an amino-terminal domain that binds to Pex3p and is essential for docking at the peroxisome membrane; (ii) a central domain that competes with Pex5p and Pex13p for binding to Pex14p and may play a role in the assembly of PTS-receptor docking complexes; and (iii) a carboxy-terminal domain that interacts with multiple PMPs including Pex3p, Pex11pbeta, Pex12p, Pex13p, Pex16p, and Pex26p. Whether the latter interactions constitute the chaperone or transport functions (or both), remains to be determined. Finally, our observation that Pex19p contains two distinct binding sites for Pex3p suggests that the peroxin may bind PMPs in multiple places and for multiple purposes.

Amino Acid Sequence↗
PubMed2003

Pex8p: an intraperoxisomal organizer of the peroxisomal import machinery.

Peroxisomes transport folded and oligomeric proteins across their membrane. Two cytosolic import receptors, Pex5p and Pex7p, along with approximately 12 membrane-bound peroxins participate in this process. While interactions among individual peroxins have been described, their organization into functional units has remained elusive. We have purified and defined two core complexes of the peroxisomal import machinery: the docking complex comprising Pex14p and Pex17p, with the loosely associated Pex13p, and the RING finger complex containing Pex2p, Pex10p, and Pex12p. Association of both complexes into a larger import complex requires Pex8p, an intraperoxisomal protein. We conclude that Pex8p organizes the formation of the larger import complex from the trans side of the peroxisomal membrane and thus might enable functional communication between both sides of the membrane.

Carrier Proteins↗
PubMed1998

Newly identified Chinese hamster ovary cell mutants are defective in biogenesis of peroxisomal membrane vesicles (Peroxisomal ghosts), representing a novel complementation group in mammals.

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 peroxisome-deficient CG in mammals, including humans.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2001

Characterization of the mammalian peroxisomal import machinery: Pex2p, Pex5p, Pex12p, and Pex14p are subunits of the same protein assembly.

Although many of the proteins involved in the biogenesis of the mammalian peroxisome have already been identified, our knowledge of the architecture of all this machinery is still very limited. In this work we used native gel electrophoresis and sucrose gradient sedimentation analysis in combination with immunoprecipitation experiments to address this issue. After solubilization of rat liver peroxisomes with the mild detergent digitonin, comigration of Pex5p, Pex14p, and a fraction of Pex12p was observed upon native electrophoresis and sucrose gradient sedimentation. The existence of a complex comprising Pex2p, Pex5p, Pex12p, and Pex14p was demonstrated by preparative coimmunoprecipitation experiments using an antibody directed to Pex14p. No stoichiometric amounts of Pex13p were detected in the Pex2p-Pex5p-Pex12p-Pex14p complex, although the presence of a small fraction of Pex13p in this complex could be demonstrated by Western blot analysis. Pex13p is also a component of a high molecular mass complex. Strikingly, partial purification of this Pex13p-containing complex revealed Pex13p as the major (if not the only) component. Taken together, our data indicate that Pex2p, Pex5p, Pex12p, and Pex14p, on one side, and Pex13p, on the other, are subunits of two stable protein complexes that probably interact with each other in the peroxisomal membrane.

Animals↗
PubMed1995

Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders.

The peroxisome biogenesis disorders (PBDs) are lethal recessive diseases caused by defects in peroxisome assembly. We have isolated PXR1, a human homologue of the yeast P. pastoris PAS8 (peroxisome assembly) gene. PXR1, like PAS8, encodes a receptor for proteins with the type-1 peroxisomal targeting signal (PTS1). Mutations in PXR1 define complementation group 2 of PBDs and expression of PXR1 rescues the PTS1 import defect of fibroblasts from these patients. Based on the observation that PXR1 exists both in the cytosol and in association with peroxisomes, we propose that PXR1 protein recognizes PTS1-containing proteins in the cytosol and directs them to the peroxisome.

Amino Acid Sequence↗
PubMed2005

Oxidative-nitrosative stress in hypertension.

Reactive oxygen species (ROS) are important signaling molecules in the vasculature. However, when there is imbalance between their occurrence and antioxidant defense mechanisms, ROS can contribute to the vascular abnormalities that lead to hypertension. Evidence accumulated in the last decade strongly supports the notion that ROS are generated in the vasculature mainly by NAD(P)H oxidase in a mechanism that is angiotensin II-dependent. Activation of this enzyme leads to superoxide production and uncouples endothedial NO synthase (eNOS), which sustains oxidative stress while increasing the levels of tissue-damaging peroxynitrite. The latter can result in vascular dysfunction. NAD(P)H-dependent ROS formation, in particular H(2)O(2), could also contribute to vascular injury by sustaining NAD(P)H oxidase activation, promoting inflammatory gene expression, extracellular matrix reorganization, and growth (hypertrophy/hyperplasia) of vascular smooth muscle cells. The effect of ROS appears to be mediated by redox-sensitive targets such as tyrosine kinases and phosphatases, mitogen-activated protein kinases, transcription factors, matrix metalloproteinases, peroxisome proliferator activated receptor-alpha, poly(ADP-ribose)polymerase-1, Ca(2+) signaling mechanisms and secreted factors such as cyclophilin A and heat shock protein 90-alpha. Redox-sensitive targets appear to play a central role in normal vascular function, but can also lead to remodeling of the vascular wall, increasing vascular reactivity and hypertension. Polymorphisms in the p22phox gene promoter could determine susceptibility to NAD(P)H-mediated oxidative stress in humans and animals with hypertension. Although ROS are strongly implicated in the etiology of hypertension, clinical trials with antioxidants are inconclusive regarding their effectiveness in treating the disease. New drugs with both antihypertensive action and antioxidant properties (Celiprolol, Carvedilol) offer promising results in the management of hypertension.

Angiotensin II↗
PubMed2004

Penicillium chrysogenum Pex5p mediates differential sorting of PTS1 proteins to microbodies of the methylotrophic yeast Hansenula polymorpha.

We have isolated the Penicillium chrysogenum pex5 gene encoding the receptor for microbody matrix proteins containing a type 1 peroxisomal targeting signal (PTS1). Pc-pex5 contains 2 introns and encodes a protein of approximately 75 kDa. P. chrysogenum pex5 disruptants appear to be highly unstable, show poor growth, and are unable to sporulate asexually. Furthermore, pex5 cells mislocalize a fluorescent PTS1 reporter protein to the cytosol. Pc-pex5 was expressed in a PEX5 null mutant of the yeast Hansenula polymorpha. Detailed analysis demonstrated that the PTS1 proteins dihydroxyacetone synthase and catalase were almost fully imported into microbodies. Surprisingly, alcohol oxidase, which also depends on Pex5p for import into microbodies, remained mainly in the cytosol. Thus, P. chrysogenum Pex5p has a different specificity of cargo recognition than its H. polymorpha counterpart. This was also suggested by the observation that Pc-Pex5p sorted a reporter protein fused to various functional PTS1 signals with different efficiencies.

Alcohol Oxidoreductases↗