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Ebba Nexo - One of the best experts on this subject based on the ideXlab platform.
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The cobalamin-binding Protein in Zebrafish is an intermediate between the three cobalamin-binding Proteins in human.
PloS one, 2012Co-Authors: Eva Greibe, Ebba NexoAbstract:In humans, three soluble extracellular cobalamin-binding Proteins; transcobalamin (TC), intrinsic factor (IF), and haptocorrin (HC), are involved in the uptake and transport of cobalamin. In this study, we investigate a cobalamin-binding Protein from Zebrafish (Danio rerio) and summarize current knowledge concerning the phylogenetic evolution of kindred Proteins. We identified a cobalamin binding capacity in Zebrafish Protein extracts (8.2 pmol/fish) and ambient water (13.5 pmol/fish) associated with a single Protein. The Protein showed resistance toward degradation by trypsin and chymotrypsin (like human IF, but unlike human HC and TC). The cobalamin analogue, cobinamide, bound weaker to the Zebrafish cobalamin binder than to human HC, but stronger than to human TC and IF. Affinity for another analogue, adenosyl-pseudo-cobalamin was low compared with human HC and TC, but high compared with human IF. The absorbance spectrum of the purified Protein in complex with hydroxo-cobalamin resembled those of human HC and IF, but not TC. We searched available databases to further explore the phylogenies of the three cobalamin-binding Proteins in higher vertebrates. Apparently, TC-like Proteins are the oldest evolutionary derivatives followed by IF and HC (the latter being present only in reptiles and most but not all mammals). Our findings suggest that the only cobalamin-binding Protein in Zebrafish is an intermediate between the three human cobalamin binders. These findings support the hypothesis about a common ancestral gene for all cobalamin-binding Proteins in higher vertebrates.
Eva Greibe - One of the best experts on this subject based on the ideXlab platform.
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The cobalamin-binding Protein in Zebrafish is an intermediate between the three cobalamin-binding Proteins in human.
PloS one, 2012Co-Authors: Eva Greibe, Ebba NexoAbstract:In humans, three soluble extracellular cobalamin-binding Proteins; transcobalamin (TC), intrinsic factor (IF), and haptocorrin (HC), are involved in the uptake and transport of cobalamin. In this study, we investigate a cobalamin-binding Protein from Zebrafish (Danio rerio) and summarize current knowledge concerning the phylogenetic evolution of kindred Proteins. We identified a cobalamin binding capacity in Zebrafish Protein extracts (8.2 pmol/fish) and ambient water (13.5 pmol/fish) associated with a single Protein. The Protein showed resistance toward degradation by trypsin and chymotrypsin (like human IF, but unlike human HC and TC). The cobalamin analogue, cobinamide, bound weaker to the Zebrafish cobalamin binder than to human HC, but stronger than to human TC and IF. Affinity for another analogue, adenosyl-pseudo-cobalamin was low compared with human HC and TC, but high compared with human IF. The absorbance spectrum of the purified Protein in complex with hydroxo-cobalamin resembled those of human HC and IF, but not TC. We searched available databases to further explore the phylogenies of the three cobalamin-binding Proteins in higher vertebrates. Apparently, TC-like Proteins are the oldest evolutionary derivatives followed by IF and HC (the latter being present only in reptiles and most but not all mammals). Our findings suggest that the only cobalamin-binding Protein in Zebrafish is an intermediate between the three human cobalamin binders. These findings support the hypothesis about a common ancestral gene for all cobalamin-binding Proteins in higher vertebrates.
Davide Pirolli - One of the best experts on this subject based on the ideXlab platform.
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Insights from Molecular Dynamics Simulations: Structural Basis for the V567D Mutation-Induced Instability of Zebrafish Alpha-Dystroglycan and Comparison with the Murine Model
2014Co-Authors: Davide Pirolli, Francesca Sciandra, Bruno Giardina, Andrea Brancaccio, Manuela Bozzi, Maria Cristina De RosaAbstract:A missense amino acid mutation of valine to aspartic acid in 567 position of alpha-dystroglycan (DG), identified in dag1-mutated Zebrafish, results in a reduced transcription and a complete absence of the Protein. Lacking experimental structural data for Zebrafish DG domains, the detailed mechanism for the observed mutation-induced destabilization of the DG complex and membrane damage, remained unclear. With the aim to contribute to a better clarification of the structure-function relationships featuring the DG complex, three-dimensional structural models of wild-type and mutant (V567D) C-terminal domain of alpha-DG from Zebrafish were constructed by a template-based modelling approach. We then ran extensive molecular dynamics (MD) simulations to reveal the structural and dynamic properties of the C-terminal domain and to evaluate the effect of the single mutation on alpha-DG stability. A comparative study has been also carried out on our previously generated model of murine alpha-DG C-terminal domain including the I591D mutation, which is topologically equivalent to the V567D mutation found in Zebrafish. Trajectories from MD simulations were analyzed in detail, revealing extensive structural disorder involving multiple beta-strands in the mutated variant of the Zebrafish Protein whereas local effects have been detected in the murine Protein. A biochemical analysis of the murine alpha-DG mutant I591D confirmed a pronounced instability of the Protein. Taken together, the computational and biochemical analysis suggest that the V567D/I591D mutation, belonging to the G beta-strand, plays a key role in inducing a destabilization of the alpha-DG C-terminal Ig-like domain that could possibly affect and propagate to the entire DG complex. The structural features herein identified may be of crucial help to understand the molecular basis of primary dystroglycanopathies.
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Insights from molecular dynamics simulations: structural basis for the V567D mutation-induced instability of Zebrafish α-dystroglycan and comparison with the murine model
2014Co-Authors: Davide Pirolli, Bruno Giardina, Andrea Brancaccio, Manuela Bozzi, Francesca Sci, Maria Cristina, De RosaAbstract:A missense amino acid mutation of valine to aspartic acid in 567 position of alpha-dystroglycan (DG), identified in dag1-mutated Zebrafish, results in a reduced transcription and a complete absence of the Protein. Lacking experimental structural data for Zebrafish DG domains, the detailed mechanism for the observed mutation-induced destabilization of the DG complex and membrane damage, remained unclear. With the aim to contribute to a better clarification of the structure-function relationships featuring the DG complex, three-dimensional structural models of wild-type and mutant (V567D) C-terminal domain of alpha-DG from Zebrafish were constructed by a template-based modelling approach. We then ran extensive molecular dynamics (MD) simulations to reveal the structural and dynamic properties of the C-terminal domain and to evaluate the effect of the single mutation on alpha-DG stability. A comparative study has been also carried out on our previously generated model of murine alpha-DG C-terminal domain including the I591D mutation, which is topologically equivalent to the V567D mutation found in Zebrafish. Trajectories from MD simulations were analyzed in detail, revealing extensive structural disorder involving multiple beta-strands in the mutated variant of the Zebrafish Protein whereas local effects have been detected in the murine Protein. A biochemical analysis of the murine alpha-DG mutant I591D confirmed a pronounced instability of the Protein. Taken together, the computational and biochemical analysis suggest that the V567D/I591D mutation, belonging to the G beta-strand, plays a key role in inducing a destabilization of th
Isaac J Nijman - One of the best experts on this subject based on the ideXlab platform.
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a systematic genome wide analysis of Zebrafish Protein coding gene function
Nature, 2013Co-Authors: Ross Kettleborough, Elisabeth M Buschnentwich, Steven A Harvey, Christopher M Dooley, Ewart De Bruijn, Freek Van Eeden, Ian M Sealy, Richard J White, Colin Herd, Isaac J NijmanAbstract:Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 Protein-coding genes, this number falls considerably short of the more than 22,000 mouse Protein-coding genes. Similarly, in Zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 Zebrafish Protein-coding genes. Importantly, for both mice and Zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every Zebrafish Protein-coding gene, using a well-annotated Zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known Zebrafish Protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.
De Rosa - One of the best experts on this subject based on the ideXlab platform.
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Insights from molecular dynamics simulations: structural basis for the V567D mutation-induced instability of Zebrafish α-dystroglycan and comparison with the murine model
2014Co-Authors: Davide Pirolli, Bruno Giardina, Andrea Brancaccio, Manuela Bozzi, Francesca Sci, Maria Cristina, De RosaAbstract:A missense amino acid mutation of valine to aspartic acid in 567 position of alpha-dystroglycan (DG), identified in dag1-mutated Zebrafish, results in a reduced transcription and a complete absence of the Protein. Lacking experimental structural data for Zebrafish DG domains, the detailed mechanism for the observed mutation-induced destabilization of the DG complex and membrane damage, remained unclear. With the aim to contribute to a better clarification of the structure-function relationships featuring the DG complex, three-dimensional structural models of wild-type and mutant (V567D) C-terminal domain of alpha-DG from Zebrafish were constructed by a template-based modelling approach. We then ran extensive molecular dynamics (MD) simulations to reveal the structural and dynamic properties of the C-terminal domain and to evaluate the effect of the single mutation on alpha-DG stability. A comparative study has been also carried out on our previously generated model of murine alpha-DG C-terminal domain including the I591D mutation, which is topologically equivalent to the V567D mutation found in Zebrafish. Trajectories from MD simulations were analyzed in detail, revealing extensive structural disorder involving multiple beta-strands in the mutated variant of the Zebrafish Protein whereas local effects have been detected in the murine Protein. A biochemical analysis of the murine alpha-DG mutant I591D confirmed a pronounced instability of the Protein. Taken together, the computational and biochemical analysis suggest that the V567D/I591D mutation, belonging to the G beta-strand, plays a key role in inducing a destabilization of th
