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Alfred Nordheim - One of the best experts on this subject based on the ideXlab platform.
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WIPI-1α (WIPI49), a member of the novel 7-bladed WIPI Protein Family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy
Oncogene, 2004Co-Authors: Tassula Proikas-cezanne, Scott Waddell, Anja Gaugel, Tancred Frickey, Andrei Lupas, Alfred NordheimAbstract:WD-repeat Proteins are regulatory beta-propeller platforms that enable the assembly of multiProtein complexes. Here, we report the functional and bioinformatic analysis of human WD-repeat Protein I nteracting with P hospho I nosides (WIPI)-1 α (WIPI49/Atg18), a member of a novel WD-repeat Protein Family with autophagic capacity in Saccharomyces cerevisiae and Caenorhabditis elegans , recently identified as phospholipid-binding effectors. Our phylogenetic analysis divides the WIPI Protein Family into two paralogous groups that fold into 7-bladed beta-propellers. Structural modeling identified two evolutionary conserved interaction sites in WIPI propellers, one of which may bind phospholipids. Human WIPI-1 α has LXXLL signature motifs for nuclear receptor interactions and binds androgen and estrogen receptors in vitro . Strikingly, human WIPI genes were found aberrantly expressed in a variety of matched tumor tissues including kidney, pancreatic and skin cancer. We found that endogenous hWIPI-1 Protein colocalizes in part with the autophagosomal marker LC3 at punctate cytoplasmic structures in human melanoma cells. In addition, hWIPI-1 accumulated in large vesicular and cup-shaped structures in the cytoplasm when autophagy was induced by amino-acid deprivation. These cytoplasmic formations were blocked by wortmannin, a classic inhibitor of PI-3 kinase-mediated autophagy. Our data suggest that WIPI Proteins share an evolutionary conserved function in autophagy and that autophagic capacity may be compromised in human cancers.
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wipi 1alpha wipi49 a member of the novel 7 bladed wipi Protein Family is aberrantly expressed in human cancer and is linked to starvation induced autophagy
Oncogene, 2004Co-Authors: Tassula Proikascezanne, Scott Waddell, Anja Gaugel, Tancred Frickey, Andrei Lupas, Alfred NordheimAbstract:WD-repeat Proteins are regulatory beta-propeller platforms that enable the assembly of multiProtein complexes. Here, we report the functional and bioinformatic analysis of human WD-repeat Protein Interacting with PhosphoInosides (WIPI)-1α (WIPI49/Atg18), a member of a novel WD-repeat Protein Family with autophagic capacity in Saccharomyces cerevisiae and Caenorhabditis elegans, recently identified as phospholipid-binding effectors. Our phylogenetic analysis divides the WIPI Protein Family into two paralogous groups that fold into 7-bladed beta-propellers. Structural modeling identified two evolutionary conserved interaction sites in WIPI propellers, one of which may bind phospholipids. Human WIPI-1α has LXXLL signature motifs for nuclear receptor interactions and binds androgen and estrogen receptors in vitro. Strikingly, human WIPI genes were found aberrantly expressed in a variety of matched tumor tissues including kidney, pancreatic and skin cancer. We found that endogenous hWIPI-1 Protein colocalizes in part with the autophagosomal marker LC3 at punctate cytoplasmic structures in human melanoma cells. In addition, hWIPI-1 accumulated in large vesicular and cup-shaped structures in the cytoplasm when autophagy was induced by amino-acid deprivation. These cytoplasmic formations were blocked by wortmannin, a classic inhibitor of PI-3 kinase-mediated autophagy. Our data suggest that WIPI Proteins share an evolutionary conserved function in autophagy and that autophagic capacity may be compromised in human cancers.
W W De Jong - One of the best experts on this subject based on the ideXlab platform.
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the expanding small heat shock Protein Family and structure predictions of the conserved alpha crystallin domain
Journal of Molecular Evolution, 1995Co-Authors: Gert-jan Caspers, Jack A M Leunissen, W W De JongAbstract:The ever-increasing number of Proteins identified as belonging to the Family of small heat-shock Proteins (shsps) and α-crystallins enables us to reassess the phylogeny of this ubiquitous Protein Family. While the prokaryotic and fungal representatives are not properly resolved, most of the plant and animal shsps and related Proteins are clearly grouped in distinct clades, reflecting a history of repeated gene duplications. The members of the shsp Family are characterized by the presence of a conserved homologous “α-crystallin domain,” which sometimes is present in duplicate. Predictions are made of secondary structure and solvent accessibility of this domain, which together with hydropathy profiles and intron positions support the presence of two similar hydrophobic β-sheet-rich motifs, connected by a hydrophilic α-helical region. Together with an overview of the newly characterized members of the shsp Family, these data help to define this Family as being involved as stable structural Proteins and as molecular chaperones during normal development and induced under pathological and stressful conditions.
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Evolution of the alpha-crystallin/small heat-shock Protein Family.
Molecular Biology and Evolution, 1993Co-Authors: W W De Jong, Jack A M Leunissen, Christina E M VoorterAbstract:Abstract The common characteristic of the alpha-crystallin/small heat-shock Protein Family is the presence of a conserved homologous sequence of 90-100 residues. Apart from the vertebrate lens Proteins--alpha A- and alpha B-crystallin--and the ubiquitous group of 15-30-kDa heat-shock Proteins, this Family also includes two mycobacterial surface antigens and a major egg antigen of Schistosoma mansoni. Multiple small heat-shock Proteins are especially present in higher plants, where they can be distinguished in at least two classes of cytoplasmic Proteins and a chloroplast-located class. The alpha-crystallins have recently been found in many tissues outside the lens, and alpha B-crystallin, in particular, behaves in many respects like a small heat-shock Protein. The homologous sequences constitute the C-terminal halves of the Proteins and probably represent a structural domain with a more variable C-terminal extension. These domains must be responsible for the common structural and functional properties of this Protein Family. Analysis of the phylogenetic tree and comparison of the biological properties of the various Proteins in this Family suggest the following scenario for its evolution: The primordial role of the small heat-shock Protein Family must have been to cope with the destabilizing effects of stressful conditions on cellular integrity. The alpha-crystallin-like domain appears to be very stable, which makes it suitable both as a surface antigen in parasitic organisms and as a long-living lens Protein in vertebrates. It has recently been demonstrated that, like the other heat-shock Proteins, the alpha-crystallins and small heat-shock Proteins function as molecular chaperones, preventing undesired Protein-Protein interactions and assisting in refolding of denatured Proteins. Many of the small heat-shock Proteins are differentially expressed during normal development, and there is good evidence that they are involved in cytomorphological reorganizations and in degenerative diseases. In conjunction with the stabilizing, thermoprotective role of alpha-crystallins and small heat-shock Proteins, they may also be involved in signal transduction. The reversible phosphorylation of these Proteins appears to be important in this respect.
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evolution of the alpha crystallin small heat shock Protein Family
Molecular Biology and Evolution, 1993Co-Authors: W W De Jong, Jack A M Leunissen, Christina E M VoorterAbstract:Abstract The common characteristic of the alpha-crystallin/small heat-shock Protein Family is the presence of a conserved homologous sequence of 90-100 residues. Apart from the vertebrate lens Proteins--alpha A- and alpha B-crystallin--and the ubiquitous group of 15-30-kDa heat-shock Proteins, this Family also includes two mycobacterial surface antigens and a major egg antigen of Schistosoma mansoni. Multiple small heat-shock Proteins are especially present in higher plants, where they can be distinguished in at least two classes of cytoplasmic Proteins and a chloroplast-located class. The alpha-crystallins have recently been found in many tissues outside the lens, and alpha B-crystallin, in particular, behaves in many respects like a small heat-shock Protein. The homologous sequences constitute the C-terminal halves of the Proteins and probably represent a structural domain with a more variable C-terminal extension. These domains must be responsible for the common structural and functional properties of this Protein Family. Analysis of the phylogenetic tree and comparison of the biological properties of the various Proteins in this Family suggest the following scenario for its evolution: The primordial role of the small heat-shock Protein Family must have been to cope with the destabilizing effects of stressful conditions on cellular integrity. The alpha-crystallin-like domain appears to be very stable, which makes it suitable both as a surface antigen in parasitic organisms and as a long-living lens Protein in vertebrates. It has recently been demonstrated that, like the other heat-shock Proteins, the alpha-crystallins and small heat-shock Proteins function as molecular chaperones, preventing undesired Protein-Protein interactions and assisting in refolding of denatured Proteins. Many of the small heat-shock Proteins are differentially expressed during normal development, and there is good evidence that they are involved in cytomorphological reorganizations and in degenerative diseases. In conjunction with the stabilizing, thermoprotective role of alpha-crystallins and small heat-shock Proteins, they may also be involved in signal transduction. The reversible phosphorylation of these Proteins appears to be important in this respect.
Christina E M Voorter - One of the best experts on this subject based on the ideXlab platform.
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Evolution of the alpha-crystallin/small heat-shock Protein Family.
Molecular Biology and Evolution, 1993Co-Authors: W W De Jong, Jack A M Leunissen, Christina E M VoorterAbstract:Abstract The common characteristic of the alpha-crystallin/small heat-shock Protein Family is the presence of a conserved homologous sequence of 90-100 residues. Apart from the vertebrate lens Proteins--alpha A- and alpha B-crystallin--and the ubiquitous group of 15-30-kDa heat-shock Proteins, this Family also includes two mycobacterial surface antigens and a major egg antigen of Schistosoma mansoni. Multiple small heat-shock Proteins are especially present in higher plants, where they can be distinguished in at least two classes of cytoplasmic Proteins and a chloroplast-located class. The alpha-crystallins have recently been found in many tissues outside the lens, and alpha B-crystallin, in particular, behaves in many respects like a small heat-shock Protein. The homologous sequences constitute the C-terminal halves of the Proteins and probably represent a structural domain with a more variable C-terminal extension. These domains must be responsible for the common structural and functional properties of this Protein Family. Analysis of the phylogenetic tree and comparison of the biological properties of the various Proteins in this Family suggest the following scenario for its evolution: The primordial role of the small heat-shock Protein Family must have been to cope with the destabilizing effects of stressful conditions on cellular integrity. The alpha-crystallin-like domain appears to be very stable, which makes it suitable both as a surface antigen in parasitic organisms and as a long-living lens Protein in vertebrates. It has recently been demonstrated that, like the other heat-shock Proteins, the alpha-crystallins and small heat-shock Proteins function as molecular chaperones, preventing undesired Protein-Protein interactions and assisting in refolding of denatured Proteins. Many of the small heat-shock Proteins are differentially expressed during normal development, and there is good evidence that they are involved in cytomorphological reorganizations and in degenerative diseases. In conjunction with the stabilizing, thermoprotective role of alpha-crystallins and small heat-shock Proteins, they may also be involved in signal transduction. The reversible phosphorylation of these Proteins appears to be important in this respect.
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evolution of the alpha crystallin small heat shock Protein Family
Molecular Biology and Evolution, 1993Co-Authors: W W De Jong, Jack A M Leunissen, Christina E M VoorterAbstract:Abstract The common characteristic of the alpha-crystallin/small heat-shock Protein Family is the presence of a conserved homologous sequence of 90-100 residues. Apart from the vertebrate lens Proteins--alpha A- and alpha B-crystallin--and the ubiquitous group of 15-30-kDa heat-shock Proteins, this Family also includes two mycobacterial surface antigens and a major egg antigen of Schistosoma mansoni. Multiple small heat-shock Proteins are especially present in higher plants, where they can be distinguished in at least two classes of cytoplasmic Proteins and a chloroplast-located class. The alpha-crystallins have recently been found in many tissues outside the lens, and alpha B-crystallin, in particular, behaves in many respects like a small heat-shock Protein. The homologous sequences constitute the C-terminal halves of the Proteins and probably represent a structural domain with a more variable C-terminal extension. These domains must be responsible for the common structural and functional properties of this Protein Family. Analysis of the phylogenetic tree and comparison of the biological properties of the various Proteins in this Family suggest the following scenario for its evolution: The primordial role of the small heat-shock Protein Family must have been to cope with the destabilizing effects of stressful conditions on cellular integrity. The alpha-crystallin-like domain appears to be very stable, which makes it suitable both as a surface antigen in parasitic organisms and as a long-living lens Protein in vertebrates. It has recently been demonstrated that, like the other heat-shock Proteins, the alpha-crystallins and small heat-shock Proteins function as molecular chaperones, preventing undesired Protein-Protein interactions and assisting in refolding of denatured Proteins. Many of the small heat-shock Proteins are differentially expressed during normal development, and there is good evidence that they are involved in cytomorphological reorganizations and in degenerative diseases. In conjunction with the stabilizing, thermoprotective role of alpha-crystallins and small heat-shock Proteins, they may also be involved in signal transduction. The reversible phosphorylation of these Proteins appears to be important in this respect.
Ambrose L Cheung - One of the best experts on this subject based on the ideXlab platform.
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The SarA Protein Family of Staphylococcus aureus
The International Journal of Biochemistry & Cell Biology, 2007Co-Authors: Ambrose L Cheung, María Pilar Trotonda, Koren Nishina, Sandeep TamberAbstract:Staphylococcus aureus is widely appreciated as an opportunistic pathogen, primarily in hospital-related infections. However, recent reports indicate that S. aureus infections can now occur in other wise healthy individuals in the community setting. The success of this organism can be attributed to the large array of regulatory Proteins, including the SarA Protein Family, used to respond to changing microenvironments. Sequence alignment and structural data reveal that the SarA Protein Family can be divided into three subfamilies: (1) single domain Proteins; (2) double domain Proteins; (3) MarR homologs. Structural studies have also demonstrated that SarA, SarR, SarS, MgrA and thus possibly all members of this Protein Family are winged helix Proteins with minor variations. Mutagenesis studies of SarA disclose that the winged helix motifs are important for DNA binding and function. Recent progress concerning the functions and plausible mechanisms of regulation of SarA and its homologs are discussed.
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global regulation of virulence determinants in staphylococcus aureus by the sara Protein Family
Frontiers in Bioscience, 2002Co-Authors: Ambrose L Cheung, Gongyi ZhangAbstract:Abstract In S. aureus, the production of virulence determinants such as cell wall adhesins and exotoxins during the growth cycle is controlled by global regulators such as SarA and agr. Genomic scan reveals 16 two-component regulatory systems (e.g. agr and sae) as well as a Family of SarA homologs in S. aureus. We call the SarA homologs the SarA Protein Family. Many of the members in this Protein Family are either small basic Proteins (<153 residues) or two-domain Proteins in which a single domain shares sequence similarity to each of the small basic Proteins. Recent crystal structures of SarR and SarA reveal dimeric structures for these Proteins. Because of its structure and unique mode of DNA binding, SarR, and possibly other SarA Family members, may belong to a new functional class of the winged-helix Family, accommodating long stretch of DNA with bending points. Based on sequence homology, we hypothesize that the SarA Protein Family may entail homologous structures with similar DNA-binding motifs but divergent activation domains. An understanding of how these regulators interact with each other in vivo and how they sense environmental signals to control virulence gene expression (e.g. alpha-hemolysin) will be important to our eventual goal of disrupting the regulatory network.
Gongyi Zhang - One of the best experts on this subject based on the ideXlab platform.
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global regulation of virulence determinants in staphylococcus aureus by the sara Protein Family
Frontiers in Bioscience, 2002Co-Authors: Ambrose L Cheung, Gongyi ZhangAbstract:Abstract In S. aureus, the production of virulence determinants such as cell wall adhesins and exotoxins during the growth cycle is controlled by global regulators such as SarA and agr. Genomic scan reveals 16 two-component regulatory systems (e.g. agr and sae) as well as a Family of SarA homologs in S. aureus. We call the SarA homologs the SarA Protein Family. Many of the members in this Protein Family are either small basic Proteins (<153 residues) or two-domain Proteins in which a single domain shares sequence similarity to each of the small basic Proteins. Recent crystal structures of SarR and SarA reveal dimeric structures for these Proteins. Because of its structure and unique mode of DNA binding, SarR, and possibly other SarA Family members, may belong to a new functional class of the winged-helix Family, accommodating long stretch of DNA with bending points. Based on sequence homology, we hypothesize that the SarA Protein Family may entail homologous structures with similar DNA-binding motifs but divergent activation domains. An understanding of how these regulators interact with each other in vivo and how they sense environmental signals to control virulence gene expression (e.g. alpha-hemolysin) will be important to our eventual goal of disrupting the regulatory network.
