| 1. |
- Teixeira, Pedro F., et al.
(författare)
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Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin
- 2018
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Ingår i: Journal of Molecular Biology. - : Academic Press. - 0022-2836 .- 1089-8638. ; 430:3, s. 348-362
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Tidskriftsartikel (refereegranskat)abstract
- Proteolysis plays an important role in mitochondrial biogenesis, from the processing of newly imported precursor proteins to the degradation of mitochondrial targeting peptides. Disruption of peptide degradation activity in yeast, plant and mammalian mitochondria is known to have deleterious consequences for organism physiology, highlighting the important role of mitochondrial peptidases. In the present work, we show that the human mitochondrial peptidase neurolysin (hNLN) can degrade mitochondrial presequence peptides as well as other fragments up to 19 amino acids long. The crystal structure of hNLNE475Q in complex with the products of neurotensin cleavage at 2.7 Å revealed a closed conformation with an internal cavity that restricts substrate length and highlighted the mechanism of enzyme opening/closing that is necessary for substrate binding and catalytic activity. Analysis of peptide degradation in vitro showed that hNLN cooperates with presequence protease (PreP or PITRM1) in the degradation of long targeting peptides and amyloid-β peptide, Aβ1–40, associated with Alzheimer disease, particularly cleaving the hydrophobic fragment Aβ35–40. These findings suggest that a network of proteases may be required for complete degradation of peptides localized in mitochondria.
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| 2. |
- Andrade, Pedro, et al.
(författare)
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Regulatory changes in pterin and carotenoid genes underlie balanced color polymorphisms in the wall lizard
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:12, s. 5633-5642
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Tidskriftsartikel (refereegranskat)abstract
- Reptiles use pterin and carotenoid pigments to produce yellow, orange, and red colors. These conspicuous colors serve a diversity of signaling functions, but their molecular basis remains unresolved. Here, we show that the genomes of sympatric color morphs of the European common wall lizard (Podarcis muralis), which differ in orange and yellow pigmentation and in their ecology and behavior, are virtually undifferentiated. Genetic differences are restricted to two small regulatory regions near genes associated with pterin [sepiapterin reductase (SPR)] and carotenoid [beta-carotene oxygenase 2 (BCO2)] metabolism, demonstrating that a core gene in the housekeeping pathway of pterin biosynthesis has been coopted for bright coloration in reptiles and indicating that these loci exert pleiotropic effects on other aspects of physiology. Pigmentation differences are explained by extremely divergent alleles, and haplotype analysis revealed abundant transspecific allele sharing with other lacertids exhibiting color polymorphisms. The evolution of these conspicuous color ornaments is the result of ancient genetic variation and cross-species hybridization.
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| 3. |
- 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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| 4. |
- Teixeira, Pedro Filipe, et al.
(författare)
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In vitro oxidative inactivation of human presequence protease (hPreP)
- 2012
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 53:11, s. 2188-2195
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Tidskriftsartikel (refereegranskat)abstract
- The mitochondrial peptidasome called presequence protease (Prep) is responsible for the degradation of presequences and other unstructured peptides including the amyloid-beta, peptide, whose accumulation may have deleterious effects on mitochondrial function. Recent studies showed that PreP activity is reduced in Alzheimer disease (AD) patients and AD mouse models compared to controls, which correlated with an enhanced reactive oxygen species production in mitochondria. In this study, we have investigated the effects of a biologically relevant oxidant, hydrogen peroxide (H2O2), on the activity of recombinant human PreP (hPreP). H2O2 inhibited hPreP activity in a concentration-dependent manner, resulting in oxidation of amino acid residues (detected by carbonylation) and lowered protein stability. Substitution of the evolutionarily conserved methionine 206 for leucine resulted in increased sensitivity of hPreP to oxidation, indicating a possible protective role of M2O6 as internal antioxidant. The activity of hPreP oxidized at low concentrations of H2O2 could be restored by methionine sulfoxide reductase A (MsrA), an enzyme that localizes to the mitochondrial matrix, suggesting that hPreP constitutes a substrate for MsrA. In summary, our in vitro results suggest a possible redox control of hPreP in the mitochondrial matrix and support the protective role of the conserved methionine 206 residue as an internal antioxidant.
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| 5. |
- Yang, Weizhao, et al.
(författare)
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Extensive introgression and mosaic genomes of Mediterranean endemic lizards
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The Mediterranean basin is a hotspot of biodiversity, fuelled by climatic oscillation and geological change over the past 20 million years. Wall lizards of the genus Podarcis are among the most abundant, diverse, and conspicuous Mediterranean fauna. Here, we unravel the remarkably entangled evolutionary history of wall lizards by sequencing genomes of 34 major lineages covering 26 species. We demonstrate an early (>11 MYA) separation into two clades centred on the Iberian and Balkan Peninsulas, and two clades of Mediterranean island endemics. Diversification within these clades was pronounced between 6.5–4.0 MYA, a period spanning the Messinian Salinity Crisis, during which the Mediterranean Sea nearly dried up before rapidly refilling. However, genetic exchange between lineages has been a pervasive feature throughout the entire history of wall lizards. This has resulted in a highly reticulated pattern of evolution across the group, characterised by mosaic genomes with major contributions from two or more parental taxa. These hybrid lineages gave rise to several of the extant species that are endemic to Mediterranean islands. The mosaic genomes of island endemics may have promoted their extraordinary adaptability and striking diversity in body size, shape and colouration, which have puzzled biologists for centuries.
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| 6. |
- Yang, Weizhao, et al.
(författare)
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Population Genomics of Wall Lizards Reflects the Dynamic History of the Mediterranean Basin
- 2022
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 39:1
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Tidskriftsartikel (refereegranskat)abstract
- The Mediterranean Basin has experienced extensive change in geology and climate over the past six million years. Yet, the relative importance of key geological events for the distribution and genetic structure of the Mediterranean fauna remains poorly understood. Here, we use population genomic and phylogenomic analyses to establish the evolutionary history and genetic structure of common wall lizards (Podarcis muralis). This species is particularly informative because, in contrast to other Mediterranean lizards, it is widespread across the Iberian, Italian, and Balkan Peninsulas, and in extra-Mediterranean regions. We found strong support for six major lineages within P. muralis, which were largely discordant with the phylogenetic relationship of mitochondrial DNA. The most recent common ancestor of extant P. muralis was likely distributed in the Italian Peninsula, and experienced an "Out-of-Italy" expansion following the Messinian salinity crisis (∼5 Mya), resulting in the differentiation into the extant lineages on the Iberian, Italian, and Balkan Peninsulas. Introgression analysis revealed that both inter- and intraspecific gene flows have been pervasive throughout the evolutionary history of P. muralis. For example, the Southern Italy lineage has a hybrid origin, formed through admixture between the Central Italy lineage and an ancient lineage that was the sister to all other P. muralis. More recent genetic differentiation is associated with the onset of the Quaternary glaciations, which influenced population dynamics and genetic diversity of contemporary lineages. These results demonstrate the pervasive role of Mediterranean geology and climate for the evolutionary history and population genetic structure of extant species.
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