| 1. |
- Chen, Jue, et al.
(författare)
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Mechanism of oxidative inactivation of human presequence protease by hydrogen peroxide
- 2014
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 77, s. 57-63
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Tidskriftsartikel (refereegranskat)abstract
- The mitochondrial presequence protease (PreP) is a member of the pitrilysin class of metalloproteases. It degrades the mitochondrial targeting presequences of mitochondria-localized proteins as well as unstructured peptides such as amyloid-beta peptide. The specific activity of PreP is reduced in Alzheimer patients and animal models of Alzheimer disease. The loss of activity can be mimicked in vitro by exposure to oxidizing conditions, and indirect evidence suggested that inactivation was due to methionine oxidation. We performed peptide mapping analyses to elucidate the mechanism of inactivation. None of the 24 methionine residues in recombinant human PreP was oxidized. We present evidence that inactivation is due to oxidation of cysteine residues and consequent oligomerization through intermolecular disulfide bonds. The most susceptible cysteine residues to oxidation are Cys34, Cys112, and Cys119. Most, but not all, of the activity loss is restored by the reducing agent dithiothreitol. These findings elucidate a redox mechanism for regulation of PreP and also provide a rational basis for therapeutic intervention in conditions characterized by excessive oxidation of PreP.
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| 2. |
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| 3. |
- Jonsson, Anders, et al.
(författare)
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A novel peroxiredoxin activity is located within the C-terminal end of Rhodospirillum rubrum adenylyltransferase.
- 2008
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Ingår i: Journal of Bacteriology. - 0021-9193 .- 1098-5530. ; 190:1, s. 434-7
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Tidskriftsartikel (refereegranskat)abstract
- Adenylyltransferase (GlnE) catalyzes the reversible adenylylation of glutamine synthetase. In this report we present, for the first time, evidence for a peroxiredoxin activity of Rhodospirillum rubrum GlnE, through the carboxyl-terminal AhpC/thiol-specific antioxidant (TSA) domain. The combination of GlnE and AhpC/TSA domains within the same polypeptide constitutes a unique domain architecture that has not previously been identified among proteobacteria.
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| 4. |
- Jonsson, Anders, et al.
(författare)
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Reduced activity of glutamine synthetase in Rhodospirillum rubrum mutants lacking the adenylyltransferase GlnE
- 2009
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Ingår i: Research in Microbiology. - : Elsevier BV. - 0923-2508 .- 1769-7123. ; 160:8, s. 581-4
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Tidskriftsartikel (refereegranskat)abstract
- In the nitrogen-fixing bacterium Rhodospirillum rubrum, the GlnE adenylyltransferase (encoded by glnE) catalyzes reversible adenylylation of glutamine synthetase, thereby regulating nitrogen assimilation. We have generated glnE mutant strains that are unable to adenylylate glutamine synthetase (GS). Surprisingly, the activity of GS was lower in the mutants than in the wild type, even when grown in nitrogen-fixing conditions. Our results support the proposal that R. rubrum can only cope with the absence of an adenylylation system in the presence of lowered GS expression or activity. In general terms, this report also provides further support for the central role of GS in bacterial metabolism.
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| 5. |
- Langer, Yeshaya, et al.
(författare)
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Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy
- 2018
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 55:9, s. 599-606
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Tidskriftsartikel (refereegranskat)abstract
- Objective To identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy. Methods Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients' cells and in yeast. Results Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10-65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides >= 40 amino acids. Conclusion PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.
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| 6. |
- Mossmann, Dirk, et al.
(författare)
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Amyloid-beta Peptide Induces Mitochondrial Dysfunction by Inhibition of Preprotein Maturation
- 2014
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 20:4, s. 662-669
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Tidskriftsartikel (refereegranskat)abstract
- Most mitochondrial proteins possess N-terminal presequences that are required for targeting and import into the organelle. Upon import, presequences are cleaved off by matrix processing peptidases and subsequently degraded by the peptidasome Cym1/PreP, which also degrades Amyloid-beta peptides (A beta). Here we find that impaired turnover of presequence peptides results in feedback inhibition of presequence processing enzymes. Moreover, A beta inhibits degradation of presequence peptides by PreP, resulting in accumulation of mitochondrial preproteins and processing intermediates. Dysfunctional preprotein maturation leads to rapid protein degradation and an imbalanced organellar proteome. Our findings reveal a general mechanism by which A beta peptide can induce the multiple diverse mitochondrial dysfunctions accompanying Alzheimer's disease.
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| 7. |
- Pinho, Catarina Moreira, et al.
(författare)
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Mitochondrial import and degradation of amyloid-beta peptide
- 2014
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 1837:7, s. 1069-1074
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Forskningsöversikt (refereegranskat)abstract
- Mitochondrial dysfunctions associated with amyloid-beta peptide (A beta) accumulation in mitochondria have been observed in Alzheimer's disease (AD) patients' brains and in AD mice models. A beta is produced by sequential action of beta- and gamma-secretases cleaving the amyloid precursor protein (APP). The gamma-secretase complex was found in mitochondria-associated endoplasmic reticulum membranes (MAM) suggesting that this could be a potential site of A beta production, from which A beta is further transported into the mitochondria. In vitro, A beta was shown to be imported into the mitochondria through the translocase of the outer membrane (TOM) complex. The mitochondrial presequence protease (Prep) is responsible for A beta degradation reducing toxic effects of A beta on mitochondrial functions. The proteolytic activity of PreP is, however, lower in AD brain temporal lobe mitochondria and in AD transgenic mice models, possibly due to an increased reactive oxygen species (ROS) production. Here, we review the intracellular mechanisms of A beta production, its mitochondrial import and the intra-mitochondrial degradation. We also discuss the implications of a reduced efficiency of mitochondrial A beta clearance for AD. Understanding the underlying mechanisms may provide new insights into mitochondria related pathogenesis of AD and development of drug therapy against AD. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.
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| 8. |
- Pinho, Catarina, et al.
(författare)
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Presequence processing increases the stability of the human Presequence Protease, hPreP
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Most of the mitochondrial matrix proteins are nuclear encoded, synthesized in the cytoplasm and have to be targeted to the mitochondria. For matrix proteins, this is generally achieved due to the presence of a N-terminal sequence, called presequence. After reaching the mitochondrial matrix, the presequence is cleaved off by the mitochondrial processing peptidase, MPP, giving rise to the mature protein and the presequence. Free presequences are degraded in the mitochondrial matrix by the Presequence Protease, PreP. Previous studies demonstrated that the correct maturation of mitochondrial proteins is important either for stability or catalytic activity of the protein.In the present study, we estimated the presequence length of the human PreP, hPreP, to be 28 amino acids long, using HEK293T cells and recombinant MPP. Furthermore, we analyzed the activity of the recombinant hPreP precursor and its mature form using two peptides, amyloid-β (1-40) peptide or the synthetic peptide substrate V, and we observed that the proteolytic maturation does not affect hPreP enzymatic activity. However, we detected a significantly lower stability for the hPreP precursor in comparison to the mature form of the enzyme, through pulse-chase experiments using vaccinia virus expression system in mammalian cells. These results show that the mitochondrial processing is required for the hPreP stability.
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| 9. |
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| 10. |
- Teixeira, Marcos A.L., et al.
(författare)
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Revealing the diversity of the green Eulalia (Annelida, Phyllodocidae) species complex along the European coast, with description of three new species
- 2023
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Ingår i: Organisms Diversity and Evolution. - : Springer Science and Business Media LLC. - 1439-6092 .- 1618-1077. ; 23:3, s. 477-503
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Tidskriftsartikel (refereegranskat)abstract
- The green phyllodocids Eulalia clavigera and E. viridis are a known European pseudo-cryptic complex, but questions about its distribution and evidence of additional lineages in previous studies call for an investigation of the real diversity within the complex. We analyze DNA sequences (mtCOI-5P, ITS, and 28S rRNA) of different populations of E. clavigera from intertidal and subtidal marine waters along the North East Atlantic, Mediterranean Sea, theAzores and Webbnesia (Madeira, Savage islands andCanaries), and populations of E. viridis from the Scandinavia. This provided compelling evidence for the existence of six additional divergent evolutionary lineages, three of the most abundant being described here as new species: Eulalia feliciae sp. nov., intertidal and unique to the Western Mediterranean, Eulalia madeirensis sp. nov., subtidal and unique to the Madeira Island (Portugal), and Eulalia xanthomucosa sp. nov., mostly subtidal and occurring in the British Isles and southern France. Complementary morphometric analyses showed that E. feliciae sp. nov. and E. madeirensis sp. nov. formed two independent morphometric clusters, while E. xanthomucosa sp. nov. often overlapped with E. clavigera sensu stricto (s. s.), although being unique in showing a yellow coloration and parapodial cirri on median segments larger in relation to its body size. Recent biotechnological findings based on “E. clavigera” specimens highlight the importance of formally describing cryptic complexes, since each lineage chemistry might be unique and may have a range of distinct effects and applications.
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