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  • Articles  (891)
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  • 1
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    Single-molecule imaging reveals mechanisms of protein disruption by a DNA translocase (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-11-26
    Description: In physiological settings, nucleic-acid translocases must act on substrates occupied by other proteins, and an increasingly appreciated role of translocases is to catalyse protein displacement from RNA and DNA. However, little is known regarding the inevitable collisions that must occur, and the fate of protein obstacles and the mechanisms by which they are evicted from DNA remain unexplored. Here we sought to establish the mechanistic basis for protein displacement from DNA using RecBCD as a model system. Using nanofabricated curtains of DNA and multicolour single-molecule microscopy, we visualized collisions between a model translocase and different DNA-bound proteins in real time. We show that the DNA translocase RecBCD can disrupt core RNA polymerase, holoenzymes, stalled elongation complexes and transcribing RNA polymerases in either head-to-head or head-to-tail orientations, as well as EcoRI(E111Q), lac repressor and even nucleosomes. RecBCD did not pause during collisions and often pushed proteins thousands of base pairs before evicting them from DNA. We conclude that RecBCD overwhelms obstacles through direct transduction of chemomechanical force with no need for specific protein-protein interactions, and that proteins can be removed from DNA through active disruption mechanisms that act on a transition state intermediate as they are pushed from one nonspecific site to the next.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230117/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230117/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Finkelstein, Ilya J -- Visnapuu, Mari-Liis -- Greene, Eric C -- F32GM80864/GM/NIGMS NIH HHS/ -- GM074739/GM/NIGMS NIH HHS/ -- GM082848/GM/NIGMS NIH HHS/ -- R01 CA146940/CA/NCI NIH HHS/ -- R01 GM074739/GM/NIGMS NIH HHS/ -- R01 GM074739-01A1/GM/NIGMS NIH HHS/ -- R01 GM074739-05/GM/NIGMS NIH HHS/ -- R01 GM082848/GM/NIGMS NIH HHS/ -- R01 GM082848-01A1/GM/NIGMS NIH HHS/ -- R01 GM082848-04/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Dec 16;468(7326):983-7. doi: 10.1038/nature09561. Epub 2010 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107319" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophage lambda/genetics ; Biocatalysis ; DNA/genetics/*metabolism ; DNA, Viral/genetics/metabolism ; DNA-Binding Proteins/*metabolism ; DNA-Directed RNA Polymerases/chemistry/metabolism ; Deoxyribonuclease EcoRI/metabolism ; Escherichia coli/enzymology ; Exodeoxyribonuclease V/*metabolism ; Holoenzymes/chemistry/metabolism ; Lac Repressors/metabolism ; Microscopy, Fluorescence ; *Movement ; Nucleosomes/metabolism ; Promoter Regions, Genetic/genetics ; Protein Binding ; Quantum Dots ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Control of female gamete formation by a small RNA pathway in Arabidopsis (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-03-09
    Description: In the ovules of most sexual flowering plants female gametogenesis is initiated from a single surviving gametic cell, the functional megaspore, formed after meiosis of the somatically derived megaspore mother cell (MMC). Because some mutants and certain sexual species exhibit more than one MMC, and many others are able to form gametes without meiosis (by apomixis), it has been suggested that somatic cells in the ovule are competent to respond to a local signal likely to have an important function in determination. Here we show that the Arabidopsis protein ARGONAUTE 9 (AGO9) controls female gamete formation by restricting the specification of gametophyte precursors in a dosage-dependent, non-cell-autonomous manner. Mutations in AGO9 lead to the differentiation of multiple gametic cells that are able to initiate gametogenesis. The AGO9 protein is not expressed in the gamete lineage; instead, it is expressed in cytoplasmic foci of somatic companion cells. Mutations in SUPPRESSOR OF GENE SILENCING 3 and RNA-DEPENDENT RNA POLYMERASE 6 exhibit an identical defect to ago9 mutants, indicating that the movement of small RNA (sRNAs) silencing out of somatic companion cells is necessary for controlling the specification of gametic cells. AGO9 preferentially interacts with 24-nucleotide sRNAs derived from transposable elements (TEs), and its activity is necessary to silence TEs in female gametes and their accessory cells. Our results show that AGO9-dependent sRNA silencing is crucial to specify cell fate in the Arabidopsis ovule, and that epigenetic reprogramming in companion cells is necessary for sRNA-dependent silencing in plant gametes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613780/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613780/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Olmedo-Monfil, Vianey -- Duran-Figueroa, Noe -- Arteaga-Vazquez, Mario -- Demesa-Arevalo, Edgar -- Autran, Daphne -- Grimanelli, Daniel -- Slotkin, R Keith -- Martienssen, Robert A -- Vielle-Calzada, Jean-Philippe -- R01 GM067014/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Mar 25;464(7288):628-32. doi: 10.1038/nature08828. Epub 2010 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Grupo de Desarrollo Reproductivo y Apomixis, Laboratorio Nacional de Genomica para la Biodiversidad y Departamento de Ingenieria Genetica de Plantas, Cinvestav Irapuato CP36500 Guanajuato, Mexico.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20208518" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/genetics/growth & development/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Argonaute Proteins ; DNA Transposable Elements/genetics ; Gametogenesis, Plant/*physiology ; Gene Expression Regulation, Plant ; Gene Silencing ; Meiosis ; Molecular Sequence Data ; Mutagenesis, Insertional/genetics ; Ovule/growth & development/*metabolism ; Phenotype ; RNA, Plant/*metabolism ; RNA-Binding Proteins/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Active site remodelling accompanies thioester bond formation in the SUMO E1 (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-19
    Description: E1 enzymes activate ubiquitin (Ub) and ubiquitin-like (Ubl) proteins in two steps by carboxy-terminal adenylation and thioester bond formation to a conserved catalytic cysteine in the E1 Cys domain. The structural basis for these intermediates remains unknown. Here we report crystal structures for human SUMO E1 in complex with SUMO adenylate and tetrahedral intermediate analogues at 2.45 and 2.6 A, respectively. These structures show that side chain contacts to ATP.Mg are released after adenylation to facilitate a 130 degree rotation of the Cys domain during thioester bond formation that is accompanied by remodelling of key structural elements including the helix that contains the E1 catalytic cysteine, the crossover and re-entry loops, and refolding of two helices that are required for adenylation. These changes displace side chains required for adenylation with side chains required for thioester bond formation. Mutational and biochemical analyses indicate these mechanisms are conserved in other E1s.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866016/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866016/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Olsen, Shaun K -- Capili, Allan D -- Lu, Xuequan -- Tan, Derek S -- Lima, Christopher D -- F32 GM075695/GM/NIGMS NIH HHS/ -- F32 GM075695-03/GM/NIGMS NIH HHS/ -- R01 AI068038/AI/NIAID NIH HHS/ -- R01 AI068038-02/AI/NIAID NIH HHS/ -- R01 AI068038-03/AI/NIAID NIH HHS/ -- R01 GM065872/GM/NIGMS NIH HHS/ -- R01 GM065872-09/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- England -- Nature. 2010 Feb 18;463(7283):906-12. doi: 10.1038/nature08765.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology, Sloan-Kettering Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164921" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; *Biocatalysis ; Catalytic Domain/*physiology ; Conserved Sequence ; Crystallography, X-Ray ; Cysteine/chemistry/metabolism ; Humans ; Magnesium/metabolism ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; SUMO-1 Protein/*chemistry/*metabolism ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/metabolism ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Sulfides/*metabolism ; Ubiquitin/metabolism ; Ubiquitin-Activating Enzymes/*chemistry/*metabolism ; Ubiquitins/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-05-21
    Description: Type II topoisomerases are required for the management of DNA tangles and supercoils, and are targets of clinical antibiotics and anti-cancer agents. These enzymes catalyse the ATP-dependent passage of one DNA duplex (the transport or T-segment) through a transient, double-stranded break in another (the gate or G-segment), navigating DNA through the protein using a set of dissociable internal interfaces, or 'gates'. For more than 20 years, it has been established that a pair of dimer-related tyrosines, together with divalent cations, catalyse G-segment cleavage. Recent efforts have proposed that strand scission relies on a 'two-metal mechanism', a ubiquitous biochemical strategy that supports vital cellular processes ranging from DNA synthesis to RNA self-splicing. Here we present the structure of the DNA-binding and cleavage core of Saccharomyces cerevisiae topoisomerase II covalently linked to DNA through its active-site tyrosine at 2.5A resolution, revealing for the first time the organization of a cleavage-competent type II topoisomerase configuration. Unexpectedly, metal-soaking experiments indicate that cleavage is catalysed by a novel variation of the classic two-metal approach. Comparative analyses extend this scheme to explain how distantly-related type IA topoisomerases cleave single-stranded DNA, unifying the cleavage mechanisms for these two essential enzyme families. The structure also highlights a hitherto undiscovered allosteric relay that actuates a molecular 'trapdoor' to prevent subunit dissociation during cleavage. This connection illustrates how an indispensable chromosome-disentangling machine auto-regulates DNA breakage to prevent the aberrant formation of mutagenic and cytotoxic genomic lesions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882514/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882514/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Bryan H -- Burgin, Alex B -- Deweese, Joseph E -- Osheroff, Neil -- Berger, James M -- CA077373/CA/NCI NIH HHS/ -- GM033944/GM/NIGMS NIH HHS/ -- GM053960/GM/NIGMS NIH HHS/ -- GM08295/GM/NIGMS NIH HHS/ -- R01 CA077373/CA/NCI NIH HHS/ -- R01 CA077373-11S1/CA/NCI NIH HHS/ -- R01 CA077373-12/CA/NCI NIH HHS/ -- R01 GM033944/GM/NIGMS NIH HHS/ -- T32 CA009592/CA/NCI NIH HHS/ -- T32CA09592/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jun 3;465(7298):641-4. doi: 10.1038/nature08974.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485342" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; DNA/*chemistry/genetics/*metabolism ; DNA Topoisomerases, Type I/*chemistry/*metabolism ; DNA Topoisomerases, Type II/*chemistry/*metabolism ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Saccharomyces cerevisiae/*enzymology ; Tyrosine
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  • 5
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    Coupled chaperone action in folding and assembly of hexadecameric Rubisco (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-16
    Description: Form I Rubisco (ribulose 1,5-bisphosphate carboxylase/oxygenase), a complex of eight large (RbcL) and eight small (RbcS) subunits, catalyses the fixation of atmospheric CO(2) in photosynthesis. The limited catalytic efficiency of Rubisco has sparked extensive efforts to re-engineer the enzyme with the goal of enhancing agricultural productivity. To facilitate such efforts we analysed the formation of cyanobacterial form I Rubisco by in vitro reconstitution and cryo-electron microscopy. We show that RbcL subunit folding by the GroEL/GroES chaperonin is tightly coupled with assembly mediated by the chaperone RbcX(2). RbcL monomers remain partially unstable and retain high affinity for GroEL until captured by RbcX(2). As revealed by the structure of a RbcL(8)-(RbcX(2))(8) assembly intermediate, RbcX(2) acts as a molecular staple in stabilizing the RbcL subunits as dimers and facilitates RbcL(8) core assembly. Finally, addition of RbcS results in RbcX(2) release and holoenzyme formation. Specific assembly chaperones may be required more generally in the formation of complex oligomeric structures when folding is closely coupled to assembly.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Cuimin -- Young, Anna L -- Starling-Windhof, Amanda -- Bracher, Andreas -- Saschenbrecker, Sandra -- Rao, Bharathi Vasudeva -- Rao, Karnam Vasudeva -- Berninghausen, Otto -- Mielke, Thorsten -- Hartl, F Ulrich -- Beckmann, Roland -- Hayer-Hartl, Manajit -- England -- Nature. 2010 Jan 14;463(7278):197-202. doi: 10.1038/nature08651.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20075914" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/chemistry/metabolism ; Chaperonin 10/metabolism ; Chaperonin 60/metabolism ; Cryoelectron Microscopy ; Holoenzymes/chemistry/metabolism ; Models, Molecular ; Molecular Chaperones/chemistry/*metabolism ; Protein Binding ; *Protein Folding ; *Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Ribulose-Bisphosphate Carboxylase/*chemistry/*metabolism/ultrastructure ; Synechococcus/*chemistry/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Antagonistic coevolution accelerates molecular evolution (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-26
    Description: The Red Queen hypothesis proposes that coevolution of interacting species (such as hosts and parasites) should drive molecular evolution through continual natural selection for adaptation and counter-adaptation. Although the divergence observed at some host-resistance and parasite-infectivity genes is consistent with this, the long time periods typically required to study coevolution have so far prevented any direct empirical test. Here we show, using experimental populations of the bacterium Pseudomonas fluorescens SBW25 and its viral parasite, phage Phi2 (refs 10, 11), that the rate of molecular evolution in the phage was far higher when both bacterium and phage coevolved with each other than when phage evolved against a constant host genotype. Coevolution also resulted in far greater genetic divergence between replicate populations, which was correlated with the range of hosts that coevolved phage were able to infect. Consistent with this, the most rapidly evolving phage genes under coevolution were those involved in host infection. These results demonstrate, at both the genomic and phenotypic level, that antagonistic coevolution is a cause of rapid and divergent evolution, and is likely to be a major driver of evolutionary change within species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717453/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717453/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paterson, Steve -- Vogwill, Tom -- Buckling, Angus -- Benmayor, Rebecca -- Spiers, Andrew J -- Thomson, Nicholas R -- Quail, Mike -- Smith, Frances -- Walker, Danielle -- Libberton, Ben -- Fenton, Andrew -- Hall, Neil -- Brockhurst, Michael A -- 079643/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Mar 11;464(7286):275-8. doi: 10.1038/nature08798. Epub 2010 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biological Sciences, Biosciences Building, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20182425" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophages/genetics/*physiology ; *Biological Evolution ; *Evolution, Molecular ; Genetic Variation ; Molecular Sequence Data ; Phenotype ; Pseudomonas fluorescens/*genetics/*virology ; Selection, Genetic/genetics
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  • 7
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    Origin of the human malaria parasite Plasmodium falciparum in gorillas (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-09-25
    Description: Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here we develop a single-genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in faecal samples from wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas comprised parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla origin and not of chimpanzee, bonobo or ancient human origin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997044/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997044/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Weimin -- Li, Yingying -- Learn, Gerald H -- Rudicell, Rebecca S -- Robertson, Joel D -- Keele, Brandon F -- Ndjango, Jean-Bosco N -- Sanz, Crickette M -- Morgan, David B -- Locatelli, Sabrina -- Gonder, Mary K -- Kranzusch, Philip J -- Walsh, Peter D -- Delaporte, Eric -- Mpoudi-Ngole, Eitel -- Georgiev, Alexander V -- Muller, Martin N -- Shaw, George M -- Peeters, Martine -- Sharp, Paul M -- Rayner, Julian C -- Hahn, Beatrice H -- P30 AI 7767/AI/NIAID NIH HHS/ -- P30 AI027767/AI/NIAID NIH HHS/ -- P30 AI027767-21A1/AI/NIAID NIH HHS/ -- R01 AI058715/AI/NIAID NIH HHS/ -- R01 AI058715-06A1/AI/NIAID NIH HHS/ -- R01 AI058715-07/AI/NIAID NIH HHS/ -- R01 AI50529/AI/NIAID NIH HHS/ -- R01 I58715/PHS HHS/ -- R03 AI074778/AI/NIAID NIH HHS/ -- R03 AI074778-02/AI/NIAID NIH HHS/ -- R37 AI050529/AI/NIAID NIH HHS/ -- R37 AI050529-07/AI/NIAID NIH HHS/ -- R37 AI050529-08/AI/NIAID NIH HHS/ -- T32 AI007245/AI/NIAID NIH HHS/ -- T32 AI007245-26/AI/NIAID NIH HHS/ -- T32 GM008111/GM/NIGMS NIH HHS/ -- T32 GM008111-13/GM/NIGMS NIH HHS/ -- U19 AI 067854/AI/NIAID NIH HHS/ -- U19 AI067854/AI/NIAID NIH HHS/ -- U19 AI067854-06/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Sep 23;467(7314):420-5. doi: 10.1038/nature09442.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20864995" target="_blank"〉PubMed〈/a〉
    Keywords: Africa/epidemiology ; Animals ; Animals, Wild/classification/parasitology ; Ape Diseases/epidemiology/*parasitology/transmission ; DNA, Mitochondrial/analysis/genetics ; Evolution, Molecular ; Feces/parasitology ; Genes, Mitochondrial/genetics ; Genetic Variation/genetics ; Genome, Protozoan/genetics ; Gorilla gorilla/classification/*parasitology ; Humans ; Malaria, Falciparum/epidemiology/*parasitology/transmission/*veterinary ; Molecular Sequence Data ; Pan paniscus/parasitology ; Pan troglodytes/parasitology ; Phylogeny ; Plasmodium/classification/genetics/isolation & purification ; Plasmodium falciparum/genetics/*isolation & purification ; Prevalence ; Zoonoses/parasitology/transmission
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Genome sequence of the palaeopolyploid soybean (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-16
    Description: Soybean (Glycine max) is one of the most important crop plants for seed protein and oil content, and for its capacity to fix atmospheric nitrogen through symbioses with soil-borne microorganisms. We sequenced the 1.1-gigabase genome by a whole-genome shotgun approach and integrated it with physical and high-density genetic maps to create a chromosome-scale draft sequence assembly. We predict 46,430 protein-coding genes, 70% more than Arabidopsis and similar to the poplar genome which, like soybean, is an ancient polyploid (palaeopolyploid). About 78% of the predicted genes occur in chromosome ends, which comprise less than one-half of the genome but account for nearly all of the genetic recombination. Genome duplications occurred at approximately 59 and 13 million years ago, resulting in a highly duplicated genome with nearly 75% of the genes present in multiple copies. The two duplication events were followed by gene diversification and loss, and numerous chromosome rearrangements. An accurate soybean genome sequence will facilitate the identification of the genetic basis of many soybean traits, and accelerate the creation of improved soybean varieties.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmutz, Jeremy -- Cannon, Steven B -- Schlueter, Jessica -- Ma, Jianxin -- Mitros, Therese -- Nelson, William -- Hyten, David L -- Song, Qijian -- Thelen, Jay J -- Cheng, Jianlin -- Xu, Dong -- Hellsten, Uffe -- May, Gregory D -- Yu, Yeisoo -- Sakurai, Tetsuya -- Umezawa, Taishi -- Bhattacharyya, Madan K -- Sandhu, Devinder -- Valliyodan, Babu -- Lindquist, Erika -- Peto, Myron -- Grant, David -- Shu, Shengqiang -- Goodstein, David -- Barry, Kerrie -- Futrell-Griggs, Montona -- Abernathy, Brian -- Du, Jianchang -- Tian, Zhixi -- Zhu, Liucun -- Gill, Navdeep -- Joshi, Trupti -- Libault, Marc -- Sethuraman, Anand -- Zhang, Xue-Cheng -- Shinozaki, Kazuo -- Nguyen, Henry T -- Wing, Rod A -- Cregan, Perry -- Specht, James -- Grimwood, Jane -- Rokhsar, Dan -- Stacey, Gary -- Shoemaker, Randy C -- Jackson, Scott A -- England -- Nature. 2010 Jan 14;463(7278):178-83. doi: 10.1038/nature08670.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉HudsonAlpha Genome Sequencing Center, 601 Genome Way, Huntsville, Alabama 35806, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20075913" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/genetics ; Breeding ; Chromosomes, Plant/genetics ; Evolution, Molecular ; Gene Duplication ; Genes, Duplicate/genetics ; Genes, Plant/genetics ; Genome, Plant/*genetics ; *Genomics ; Molecular Sequence Data ; Multigene Family/genetics ; Phylogeny ; Plant Root Nodulation/genetics ; *Polyploidy ; Quantitative Trait Loci/genetics ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid/genetics ; Soybean Oil/biosynthesis ; Soybeans/*genetics ; Synteny/genetics ; Transcription Factors/genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    NINJA connects the co-repressor TOPLESS to jasmonate signalling (2010)
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    Publication Date: 2010-04-03
    Description: Jasmonoyl-isoleucine (JA-Ile) is a plant hormone that regulates a broad array of plant defence and developmental processes. JA-Ile-responsive gene expression is regulated by the transcriptional activator MYC2 that interacts physically with the jasmonate ZIM-domain (JAZ) repressor proteins. On perception of JA-Ile, JAZ proteins are degraded and JA-Ile-dependent gene expression is activated. The molecular mechanisms by which JAZ proteins repress gene expression remain unknown. Here we show that the Arabidopsis JAZ proteins recruit the Groucho/Tup1-type co-repressor TOPLESS (TPL) and TPL-related proteins (TPRs) through a previously uncharacterized adaptor protein, designated Novel Interactor of JAZ (NINJA). NINJA acts as a transcriptional repressor whose activity is mediated by a functional TPL-binding EAR repression motif. Accordingly, both NINJA and TPL proteins function as negative regulators of jasmonate responses. Our results point to TPL proteins as general co-repressors that affect multiple signalling pathways through the interaction with specific adaptor proteins. This new insight reveals how stress-related and growth-related signalling cascades use common molecular mechanisms to regulate gene expression in plants.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849182/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849182/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pauwels, Laurens -- Barbero, Gemma Fernandez -- Geerinck, Jan -- Tilleman, Sofie -- Grunewald, Wim -- Perez, Amparo Cuellar -- Chico, Jose Manuel -- Bossche, Robin Vanden -- Sewell, Jared -- Gil, Eduardo -- Garcia-Casado, Gloria -- Witters, Erwin -- Inze, Dirk -- Long, Jeff A -- De Jaeger, Geert -- Solano, Roberto -- Goossens, Alain -- R01 GM072764/GM/NIGMS NIH HHS/ -- R01 GM072764-06/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Apr 1;464(7289):788-91. doi: 10.1038/nature08854.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Systems Biology, Flanders Institute for Biotechnology (VIB), Technologiepark 927, B-9052 Gent, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20360743" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/cytology/*drug effects/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cyclopentanes/antagonists & inhibitors/*pharmacology ; Gene Expression Profiling ; Gene Expression Regulation, Plant ; Models, Biological ; Oxylipins/antagonists & inhibitors/*pharmacology ; Plants, Genetically Modified ; Protein Binding ; Repressor Proteins/genetics/*metabolism ; Signal Transduction/*drug effects ; Two-Hybrid System Techniques
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  • 10
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    Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ co-receptor (2010)
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    Publication Date: 2010-10-12
    Description: Jasmonates are a family of plant hormones that regulate plant growth, development and responses to stress. The F-box protein CORONATINE INSENSITIVE 1 (COI1) mediates jasmonate signalling by promoting hormone-dependent ubiquitylation and degradation of transcriptional repressor JAZ proteins. Despite its importance, the mechanism of jasmonate perception remains unclear. Here we present structural and pharmacological data to show that the true Arabidopsis jasmonate receptor is a complex of both COI1 and JAZ. COI1 contains an open pocket that recognizes the bioactive hormone (3R,7S)-jasmonoyl-l-isoleucine (JA-Ile) with high specificity. High-affinity hormone binding requires a bipartite JAZ degron sequence consisting of a conserved alpha-helix for COI1 docking and a loop region to trap the hormone in its binding pocket. In addition, we identify a third critical component of the jasmonate co-receptor complex, inositol pentakisphosphate, which interacts with both COI1 and JAZ adjacent to the ligand. Our results unravel the mechanism of jasmonate perception and highlight the ability of F-box proteins to evolve as multi-component signalling hubs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988090/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988090/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sheard, Laura B -- Tan, Xu -- Mao, Haibin -- Withers, John -- Ben-Nissan, Gili -- Hinds, Thomas R -- Kobayashi, Yuichi -- Hsu, Fong-Fu -- Sharon, Michal -- Browse, John -- He, Sheng Yang -- Rizo, Josep -- Howe, Gregg A -- Zheng, Ning -- P30 DK056341/DK/NIDDK NIH HHS/ -- P30 DK056341-10/DK/NIDDK NIH HHS/ -- R01 AI068718/AI/NIAID NIH HHS/ -- R01 AI068718-04/AI/NIAID NIH HHS/ -- R01 CA107134/CA/NCI NIH HHS/ -- R01 CA107134-07/CA/NCI NIH HHS/ -- R01 GM057795/GM/NIGMS NIH HHS/ -- R01 GM057795-12/GM/NIGMS NIH HHS/ -- R01AI068718/AI/NIAID NIH HHS/ -- R01GM57795/GM/NIGMS NIH HHS/ -- T32 GM07270/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Nov 18;468(7322):400-5. doi: 10.1038/nature09430. Epub 2010 Oct 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, Box 357280, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20927106" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acids/chemistry/metabolism ; Arabidopsis/chemistry/metabolism ; Arabidopsis Proteins/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Cyclopentanes/chemistry/*metabolism ; F-Box Proteins/chemistry/metabolism ; Indenes/chemistry/metabolism ; Inositol Phosphates/*metabolism ; Isoleucine/analogs & derivatives/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Oxylipins/chemistry/*metabolism ; Peptide Fragments/chemistry/metabolism ; Plant Growth Regulators/chemistry/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/*chemistry/*metabolism ; Signal Transduction
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  • 11
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    RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF (2010)
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    Publication Date: 2010-02-25
    Description: Tumours with mutant BRAF are dependent on the RAF-MEK-ERK signalling pathway for their growth. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one protomer, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation of wild-type RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178447/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178447/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poulikakos, Poulikos I -- Zhang, Chao -- Bollag, Gideon -- Shokat, Kevan M -- Rosen, Neal -- 1P01CA129243-02/CA/NCI NIH HHS/ -- 2R01EB001987/EB/NIBIB NIH HHS/ -- P01 CA129243-010002/CA/NCI NIH HHS/ -- R01 EB001987/EB/NIBIB NIH HHS/ -- U01 CA091178/CA/NCI NIH HHS/ -- U01 CA091178-01/CA/NCI NIH HHS/ -- England -- Nature. 2010 Mar 18;464(7287):427-30. doi: 10.1038/nature08902.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20179705" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Catalytic Domain ; Cell Line ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Indoles/pharmacology ; MAP Kinase Signaling System/*drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Models, Biological ; Neoplasms/drug therapy/enzymology/genetics/metabolism ; Phosphorylation ; Protein Binding ; Protein Kinase Inhibitors/metabolism/*pharmacology/therapeutic use ; Protein Multimerization ; Proto-Oncogene Proteins B-raf/antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Sulfonamides/pharmacology ; Transcriptional Activation/*drug effects ; raf Kinases/*antagonists & inhibitors/chemistry/genetics/*metabolism ; ras Proteins/genetics/metabolism
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  • 12
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    High-performance genetically targetable optical neural silencing by light-driven proton pumps (2010)
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    Publication Date: 2010-01-08
    Description: The ability to silence the activity of genetically specified neurons in a temporally precise fashion would provide the opportunity to investigate the causal role of specific cell classes in neural computations, behaviours and pathologies. Here we show that members of the class of light-driven outward proton pumps can mediate powerful, safe, multiple-colour silencing of neural activity. The gene archaerhodopsin-3 (Arch) from Halorubrum sodomense enables near-100% silencing of neurons in the awake brain when virally expressed in the mouse cortex and illuminated with yellow light. Arch mediates currents of several hundred picoamps at low light powers, and supports neural silencing currents approaching 900 pA at light powers easily achievable in vivo. Furthermore, Arch spontaneously recovers from light-dependent inactivation, unlike light-driven chloride pumps that enter long-lasting inactive states in response to light. These properties of Arch are appropriate to mediate the optical silencing of significant brain volumes over behaviourally relevant timescales. Arch function in neurons is well tolerated because pH excursions created by Arch illumination are minimized by self-limiting mechanisms to levels comparable to those mediated by channelrhodopsins or natural spike firing. To highlight how proton pump ecological and genomic diversity may support new innovation, we show that the blue-green light-drivable proton pump from the fungus Leptosphaeria maculans (Mac) can, when expressed in neurons, enable neural silencing by blue light, thus enabling alongside other developed reagents the potential for independent silencing of two neural populations by blue versus red light. Light-driven proton pumps thus represent a high-performance and extremely versatile class of 'optogenetic' voltage and ion modulator, which will broadly enable new neuroscientific, biological, neurological and psychiatric investigations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939492/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939492/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chow, Brian Y -- Han, Xue -- Dobry, Allison S -- Qian, Xiaofeng -- Chuong, Amy S -- Li, Mingjie -- Henninger, Michael A -- Belfort, Gabriel M -- Lin, Yingxi -- Monahan, Patrick E -- Boyden, Edward S -- 1K99MH085944/MH/NIMH NIH HHS/ -- DP2 OD002002/OD/NIH HHS/ -- DP2 OD002002-01/OD/NIH HHS/ -- K99 MH085944/MH/NIMH NIH HHS/ -- K99 MH085944-01/MH/NIMH NIH HHS/ -- England -- Nature. 2010 Jan 7;463(7277):98-102. doi: 10.1038/nature08652.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The MIT Media Laboratory, Synthetic Neurobiology Group, and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20054397" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/radiation effects ; Animals ; Ascomycota/metabolism/radiation effects ; Color ; Electric Conductivity ; Euryarchaeota/metabolism/radiation effects ; Genetic Engineering/*methods ; Hydrogen-Ion Concentration ; Mice ; Molecular Sequence Data ; Neocortex/cytology/physiology/radiation effects ; Neurons/*metabolism/*radiation effects ; Proton Pumps/classification/genetics/*metabolism/*radiation effects ; Rhodopsins, Microbial/antagonists & inhibitors/genetics/metabolism/radiation ; effects ; Wakefulness
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  • 13
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    Ubiquitin-like small archaeal modifier proteins (SAMPs) in Haloferax volcanii (2010)
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    Publication Date: 2010-01-08
    Description: Archaea, one of three major evolutionary lineages of life, encode proteasomes highly related to those of eukaryotes. In contrast, archaeal ubiquitin-like proteins are less conserved and not known to function in protein conjugation. This has complicated our understanding of the origins of ubiquitination and its connection to proteasomes. Here we report two small archaeal modifier proteins, SAMP1 and SAMP2, with a beta-grasp fold and carboxy-terminal diglycine motif similar to ubiquitin, that form protein conjugates in the archaeon Haloferax volcanii. The levels of SAMP-conjugates were altered by nitrogen-limitation and proteasomal gene knockout and spanned various functions including components of the Urm1 pathway. LC-MS/MS-based collision-induced dissociation demonstrated isopeptide bonds between the C-terminal glycine of SAMP2 and the epsilon-amino group of lysines from a number of protein targets and Lys 58 of SAMP2 itself, revealing poly-SAMP chains. The widespread distribution and diversity of pathways modified by SAMPylation suggest that this type of protein conjugation is central to the archaeal lineage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872088/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872088/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Humbard, Matthew A -- Miranda, Hugo V -- Lim, Jae-Min -- Krause, David J -- Pritz, Jonathan R -- Zhou, Guangyin -- Chen, Sixue -- Wells, Lance -- Maupin-Furlow, Julie A -- 1S10 RR025418-01/RR/NCRR NIH HHS/ -- P41 RR018502/RR/NCRR NIH HHS/ -- P41 RR018502-07/RR/NCRR NIH HHS/ -- R01 GM057498/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jan 7;463(7277):54-60. doi: 10.1038/nature08659.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida 32611, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20054389" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Archaeal Proteins/chemistry/*metabolism ; Gene Deletion ; Glycylglycine/metabolism ; Haloferax volcanii/genetics/metabolism ; Immunoprecipitation ; Mass Spectrometry ; Molecular Sequence Data ; Nitrogen/metabolism ; Proteasome Endopeptidase Complex/genetics/metabolism ; Sequence Alignment ; Sulfur/metabolism ; Ubiquitination ; Ubiquitins/chemistry/*metabolism
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    A redox switch in angiotensinogen modulates angiotensin release (2010)
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    Publication Date: 2010-10-12
    Description: Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 A resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 A structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024006/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024006/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Aiwu -- Carrell, Robin W -- Murphy, Michael P -- Wei, Zhenquan -- Yan, Yahui -- Stanley, Peter L D -- Stein, Penelope E -- Broughton Pipkin, Fiona -- Read, Randy J -- 082961/Wellcome Trust/United Kingdom -- BS/05/002/18361/British Heart Foundation/United Kingdom -- MC_U105663142/Medical Research Council/United Kingdom -- PG/08/041/24818/British Heart Foundation/United Kingdom -- PG/09/072/27945/British Heart Foundation/United Kingdom -- British Heart Foundation/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Nov 4;468(7320):108-11. doi: 10.1038/nature09505. Epub 2010 Oct 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK. awz20@cam.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20927107" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Angiotensinogen/blood/*chemistry/*metabolism ; Angiotensins/chemistry/*metabolism/secretion ; Blood Pressure ; Crystallography, X-Ray ; Disulfides/chemistry/metabolism ; Female ; Humans ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Oxidation-Reduction ; Oxidative Stress ; Pre-Eclampsia/blood/metabolism ; Pregnancy ; Protein Conformation ; *Protein Processing, Post-Translational ; Renin/chemistry/metabolism
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    A dicer-independent miRNA biogenesis pathway that requires Ago catalysis (2010)
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    Publication Date: 2010-04-29
    Description: The nucleolytic activity of animal Argonaute proteins is deeply conserved, despite its having no obvious role in microRNA-directed gene regulation. In mice, Ago2 (also known as Eif2c2) is uniquely required for viability, and only this family member retains catalytic competence. To investigate the evolutionary pressure to conserve Argonaute enzymatic activity, we engineered a mouse with catalytically inactive Ago2 alleles. Homozygous mutants died shortly after birth with an obvious anaemia. Examination of microRNAs and their potential targets revealed a loss of miR-451, a small RNA important for erythropoiesis. Though this microRNA is processed by Drosha (also known as Rnasen), its maturation does not require Dicer. Instead, the pre-miRNA becomes loaded into Ago and is cleaved by the Ago catalytic centre to generate an intermediate 3' end, which is then further trimmed. Our findings link the conservation of Argonaute catalysis to a conserved mechanism of microRNA biogenesis that is important for vertebrate development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995450/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995450/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheloufi, Sihem -- Dos Santos, Camila O -- Chong, Mark M W -- Hannon, Gregory J -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA013106-38/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jun 3;465(7298):584-9. doi: 10.1038/nature09092.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20424607" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Anemia/genetics/metabolism ; Animals ; Argonaute Proteins ; Base Sequence ; *Biocatalysis ; Embryo, Mammalian/embryology/metabolism ; Eukaryotic Initiation Factor-2/genetics/*metabolism ; Homozygote ; MicroRNAs/*biosynthesis ; Molecular Sequence Data ; Ribonuclease III/metabolism
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    Affinity gradients drive copper to cellular destinations (2010)
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    Publication Date: 2010-05-14
    Description: Copper is an essential trace element for eukaryotes and most prokaryotes. However, intracellular free copper must be strictly limited because of its toxic side effects. Complex systems for copper trafficking evolved to satisfy cellular requirements while minimizing toxicity. The factors driving the copper transfer between protein partners along cellular copper routes are, however, not fully rationalized. Until now, inconsistent, scattered and incomparable data on the copper-binding affinities of copper proteins have been reported. Here we determine, through a unified electrospray ionization mass spectrometry (ESI-MS)-based strategy, in an environment that mimics the cellular redox milieu, the apparent Cu(I)-binding affinities for a representative set of intracellular copper proteins involved in enzymatic redox catalysis, in copper trafficking to and within various cellular compartments, and in copper storage. The resulting thermodynamic data show that copper is drawn to the enzymes that require it by passing from one copper protein site to another, exploiting gradients of increasing copper-binding affinity. This result complements the finding that fast copper-transfer pathways require metal-mediated protein-protein interactions and therefore protein-protein specific recognition. Together with Cu,Zn-SOD1, metallothioneins have the highest affinity for copper(I), and may play special roles in the regulation of cellular copper distribution; however, for kinetic reasons they cannot demetallate copper enzymes. Our study provides the thermodynamic basis for the kinetic processes that lead to the distribution of cellular copper.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banci, Lucia -- Bertini, Ivano -- Ciofi-Baffoni, Simone -- Kozyreva, Tatiana -- Zovo, Kairit -- Palumaa, Peep -- England -- Nature. 2010 Jun 3;465(7298):645-8. doi: 10.1038/nature09018. Epub 2010 May 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Magnetic Resonance Center CERM and Department of Chemistry, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, Florence, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20463663" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Carrier Proteins/*metabolism ; Cations, Monovalent/metabolism ; Copper/isolation & purification/*metabolism ; Cyclooxygenase 2/chemistry/metabolism ; Dithiothreitol/metabolism ; Glutathione/metabolism ; Humans ; Intracellular Space/*metabolism ; Ion Transport ; Kinetics ; Ligands ; Metallothionein/metabolism ; Mitochondria, Liver ; Oxidation-Reduction ; Protein Binding ; Rats ; Spectrometry, Mass, Electrospray Ionization ; Thermodynamics
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    Structural basis of semaphorin-plexin signalling (2010)
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    Publication Date: 2010-09-30
    Description: Cell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB1(1-2)-SEMA4D(ecto) and murine PlxnA2(1-4)-Sema6A(ecto)), plus unliganded structures of PlxnA2(1-4) and Sema6A(ecto). These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed beta-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin-plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587840/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587840/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Janssen, Bert J C -- Robinson, Ross A -- Perez-Branguli, Francesc -- Bell, Christian H -- Mitchell, Kevin J -- Siebold, Christian -- Jones, E Yvonne -- 082301/Wellcome Trust/United Kingdom -- 083111/Wellcome Trust/United Kingdom -- 10976/Cancer Research UK/United Kingdom -- A10976/Cancer Research UK/United Kingdom -- A3964/Cancer Research UK/United Kingdom -- A5261/Cancer Research UK/United Kingdom -- G0700232/Medical Research Council/United Kingdom -- G0700232(82098)/Medical Research Council/United Kingdom -- G0900084/Medical Research Council/United Kingdom -- G9900061/Medical Research Council/United Kingdom -- G9900061(69203)/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Oct 28;467(7319):1118-22. doi: 10.1038/nature09468. Epub 2010 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20877282" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/chemistry/genetics/metabolism ; Binding Sites ; Cell Adhesion Molecules/*chemistry/genetics/*metabolism ; Cell Communication ; Crystallography, X-Ray ; Humans ; Ligands ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; NIH 3T3 Cells ; Nerve Tissue Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Receptors, Cell Surface/chemistry/genetics/metabolism ; Semaphorins/*chemistry/genetics/*metabolism ; *Signal Transduction ; Structure-Activity Relationship
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    Evolution of self-compatibility in Arabidopsis by a mutation in the male specificity gene (2010)
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    Publication Date: 2010-04-20
    Description: Ever since Darwin's pioneering research, the evolution of self-fertilisation (selfing) has been regarded as one of the most prevalent evolutionary transitions in flowering plants. A major mechanism to prevent selfing is the self-incompatibility (SI) recognition system, which consists of male and female specificity genes at the S-locus and SI modifier genes. Under conditions that favour selfing, mutations disabling the male recognition component are predicted to enjoy a relative advantage over those disabling the female component, because male mutations would increase through both pollen and seeds whereas female mutations would increase only through seeds. Despite many studies on the genetic basis of loss of SI in the predominantly selfing plant Arabidopsis thaliana, it remains unknown whether selfing arose through mutations in the female specificity gene (S-receptor kinase, SRK), male specificity gene (S-locus cysteine-rich protein, SCR; also known as S-locus protein 11, SP11) or modifier genes, and whether any of them rose to high frequency across large geographic regions. Here we report that a disruptive 213-base-pair (bp) inversion in the SCR gene (or its derivative haplotypes with deletions encompassing the entire SCR-A and a large portion of SRK-A) is found in 95% of European accessions, which contrasts with the genome-wide pattern of polymorphism in European A. thaliana. Importantly, interspecific crossings using Arabidopsis halleri as a pollen donor reveal that some A. thaliana accessions, including Wei-1, retain the female SI reaction, suggesting that all female components including SRK are still functional. Moreover, when the 213-bp inversion in SCR was inverted and expressed in transgenic Wei-1 plants, the functional SCR restored the SI reaction. The inversion within SCR is the first mutation disrupting SI shown to be nearly fixed in geographically wide samples, and its prevalence is consistent with theoretical predictions regarding the evolutionary advantage of mutations in male components.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsuchimatsu, Takashi -- Suwabe, Keita -- Shimizu-Inatsugi, Rie -- Isokawa, Sachiyo -- Pavlidis, Pavlos -- Stadler, Thomas -- Suzuki, Go -- Takayama, Seiji -- Watanabe, Masao -- Shimizu, Kentaro K -- England -- Nature. 2010 Apr 29;464(7293):1342-6. doi: 10.1038/nature08927. Epub 2010 Apr 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Plant Biology, University Research Priority Program in Systems Biology/Functional Genomics & Zurich-Basel Plant Science Center, University of Zurich, Zollikerstrasse 107, CH-8008 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20400945" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/chemistry/classification/*genetics/*physiology ; *Biological Evolution ; Crosses, Genetic ; Genes, Plant/*genetics ; Haplotypes/genetics ; Hybridization, Genetic/genetics ; Molecular Sequence Data ; Mutation/*genetics ; Pollen/physiology ; Pollination ; Reproduction/genetics/physiology
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    Role of a ribosome-associated E3 ubiquitin ligase in protein quality control (2010)
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    Publication Date: 2010-09-14
    Description: Messenger RNA lacking stop codons ('non-stop mRNA') can arise from errors in gene expression, and encode aberrant proteins whose accumulation could be deleterious to cellular function. In bacteria, these 'non-stop proteins' become co-translationally tagged with a peptide encoded by ssrA/tmRNA (transfer-messenger RNA), which signals their degradation by energy-dependent proteases. How eukaryotic cells eliminate non-stop proteins has remained unknown. Here we show that the Saccharomyces cerevisiae Ltn1 RING-domain-type E3 ubiquitin ligase acts in the quality control of non-stop proteins, in a process that is mechanistically distinct but conceptually analogous to that performed by ssrA: Ltn1 is predominantly associated with ribosomes, and it marks nascent non-stop proteins with ubiquitin to signal their proteasomal degradation. Ltn1-mediated ubiquitylation of non-stop proteins seems to be triggered by their stalling in ribosomes on translation through the poly(A) tail. The biological relevance of this process is underscored by the finding that loss of Ltn1 function confers sensitivity to stress caused by increased non-stop protein production. We speculate that defective protein quality control may underlie the neurodegenerative phenotype that results from mutation of the mouse Ltn1 homologue Listerin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988496/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988496/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bengtson, Mario H -- Joazeiro, Claudio A P -- R01 GM083060/GM/NIGMS NIH HHS/ -- R01 GM083060-03/GM/NIGMS NIH HHS/ -- R01GM083060/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Sep 23;467(7314):470-3. doi: 10.1038/nature09371. Epub 2010 Sep 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, The Scripps Research Institute, CB168, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20835226" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Codon, Terminator/genetics ; Mice ; Models, Biological ; Peptide Chain Termination, Translational ; Polylysine/biosynthesis/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Protein Biosynthesis/*physiology ; Ribosomes/*enzymology/*metabolism ; Saccharomyces cerevisiae/cytology/enzymology/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Stress, Physiological ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; *Ubiquitination
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    Two enzymes bound to one transfer RNA assume alternative conformations for consecutive reactions (2010)
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    Publication Date: 2010-10-01
    Description: In most bacteria and all archaea, glutamyl-tRNA synthetase (GluRS) glutamylates both tRNA(Glu) and tRNA(Gln), and then Glu-tRNA(Gln) is selectively converted to Gln-tRNA(Gln) by a tRNA-dependent amidotransferase. The mechanisms by which the two enzymes recognize their substrate tRNA(s), and how they cooperate with each other in Gln-tRNA(Gln) synthesis, remain to be determined. Here we report the formation of the 'glutamine transamidosome' from the bacterium Thermotoga maritima, consisting of tRNA(Gln), GluRS and the heterotrimeric amidotransferase GatCAB, and its crystal structure at 3.35 A resolution. The anticodon-binding body of GluRS recognizes the common features of tRNA(Gln) and tRNA(Glu), whereas the tail body of GatCAB recognizes the outer corner of the L-shaped tRNA(Gln) in a tRNA(Gln)-specific manner. GluRS is in the productive form, as its catalytic body binds to the amino-acid-acceptor arm of tRNA(Gln). In contrast, GatCAB is in the non-productive form: the catalytic body of GatCAB contacts that of GluRS and is located near the acceptor stem of tRNA(Gln), in an appropriate site to wait for the completion of Glu-tRNA(Gln) formation by GluRS. We identified the hinges between the catalytic and anticodon-binding bodies of GluRS and between the catalytic and tail bodies of GatCAB, which allow both GluRS and GatCAB to adopt the productive and non-productive forms. The catalytic bodies of the two enzymes compete for the acceptor arm of tRNA(Gln) and therefore cannot assume their productive forms simultaneously. The transition from the present glutamylation state, with the productive GluRS and the non-productive GatCAB, to the putative amidation state, with the non-productive GluRS and the productive GatCAB, requires an intermediate state with the two enzymes in their non-productive forms, for steric reasons. The proposed mechanism explains how the transamidosome efficiently performs the two consecutive steps of Gln-tRNA(Gln) formation, with a low risk of releasing the unstable intermediate Glu-tRNA(Gln).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Takuhiro -- Yokoyama, Shigeyuki -- England -- Nature. 2010 Sep 30;467(7315):612-6. doi: 10.1038/nature09411.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20882017" target="_blank"〉PubMed〈/a〉
    Keywords: Anticodon/genetics ; Biocatalysis ; Crystallography, X-Ray ; Electrophoretic Mobility Shift Assay ; Glutamate-tRNA Ligase/*chemistry/*metabolism ; Models, Molecular ; Molecular Conformation ; Nitrogenous Group Transferases/*chemistry/*metabolism ; Protein Binding ; RNA, Transfer, Gln/biosynthesis/*chemistry/*metabolism ; RNA, Transfer, Glu/chemistry/metabolism ; Staphylococcus aureus/enzymology ; Substrate Specificity ; Thermotoga maritima/*enzymology
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    The Ectocarpus genome and the independent evolution of multicellularity in brown algae (2010)
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    Publication Date: 2010-06-04
    Description: Brown algae (Phaeophyceae) are complex photosynthetic organisms with a very different evolutionary history to green plants, to which they are only distantly related. These seaweeds are the dominant species in rocky coastal ecosystems and they exhibit many interesting adaptations to these, often harsh, environments. Brown algae are also one of only a small number of eukaryotic lineages that have evolved complex multicellularity (Fig. 1). We report the 214 million base pair (Mbp) genome sequence of the filamentous seaweed Ectocarpus siliculosus (Dillwyn) Lyngbye, a model organism for brown algae, closely related to the kelps (Fig. 1). Genome features such as the presence of an extended set of light-harvesting and pigment biosynthesis genes and new metabolic processes such as halide metabolism help explain the ability of this organism to cope with the highly variable tidal environment. The evolution of multicellularity in this lineage is correlated with the presence of a rich array of signal transduction genes. Of particular interest is the presence of a family of receptor kinases, as the independent evolution of related molecules has been linked with the emergence of multicellularity in both the animal and green plant lineages. The Ectocarpus genome sequence represents an important step towards developing this organism as a model species, providing the possibility to combine genomic and genetic approaches to explore these and other aspects of brown algal biology further.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cock, J Mark -- Sterck, Lieven -- Rouze, Pierre -- Scornet, Delphine -- Allen, Andrew E -- Amoutzias, Grigoris -- Anthouard, Veronique -- Artiguenave, Francois -- Aury, Jean-Marc -- Badger, Jonathan H -- Beszteri, Bank -- Billiau, Kenny -- Bonnet, Eric -- Bothwell, John H -- Bowler, Chris -- Boyen, Catherine -- Brownlee, Colin -- Carrano, Carl J -- Charrier, Benedicte -- Cho, Ga Youn -- Coelho, Susana M -- Collen, Jonas -- Corre, Erwan -- Da Silva, Corinne -- Delage, Ludovic -- Delaroque, Nicolas -- Dittami, Simon M -- Doulbeau, Sylvie -- Elias, Marek -- Farnham, Garry -- Gachon, Claire M M -- Gschloessl, Bernhard -- Heesch, Svenja -- Jabbari, Kamel -- Jubin, Claire -- Kawai, Hiroshi -- Kimura, Kei -- Kloareg, Bernard -- Kupper, Frithjof C -- Lang, Daniel -- Le Bail, Aude -- Leblanc, Catherine -- Lerouge, Patrice -- Lohr, Martin -- Lopez, Pascal J -- Martens, Cindy -- Maumus, Florian -- Michel, Gurvan -- Miranda-Saavedra, Diego -- Morales, Julia -- Moreau, Herve -- Motomura, Taizo -- Nagasato, Chikako -- Napoli, Carolyn A -- Nelson, David R -- Nyvall-Collen, Pi -- Peters, Akira F -- Pommier, Cyril -- Potin, Philippe -- Poulain, Julie -- Quesneville, Hadi -- Read, Betsy -- Rensing, Stefan A -- Ritter, Andres -- Rousvoal, Sylvie -- Samanta, Manoj -- Samson, Gaelle -- Schroeder, Declan C -- Segurens, Beatrice -- Strittmatter, Martina -- Tonon, Thierry -- Tregear, James W -- Valentin, Klaus -- von Dassow, Peter -- Yamagishi, Takahiro -- Van de Peer, Yves -- Wincker, Patrick -- England -- Nature. 2010 Jun 3;465(7298):617-21. doi: 10.1038/nature09016.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉UPMC Universite Paris 6, The Marine Plants and Biomolecules Laboratory, UMR 7139, Station Biologique de Roscoff, Place Georges Teissier, BP74, 29682 Roscoff Cedex, France. cock@sb-roscoff.fr〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20520714" target="_blank"〉PubMed〈/a〉
    Keywords: Algal Proteins/*genetics ; Animals ; *Biological Evolution ; Eukaryota ; Evolution, Molecular ; Genome/*genetics ; Molecular Sequence Data ; Phaeophyta/*cytology/*genetics/metabolism ; Phylogeny ; Pigments, Biological/biosynthesis ; Signal Transduction/genetics
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    A novel pathway regulates memory and plasticity via SIRT1 and miR-134 (2010)
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    Publication Date: 2010-07-14
    Description: The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928875/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928875/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Jun -- Wang, Wen-Yuan -- Mao, Ying-Wei -- Graff, Johannes -- Guan, Ji-Song -- Pan, Ling -- Mak, Gloria -- Kim, Dohoon -- Su, Susan C -- Tsai, Li-Huei -- P01 AG027916/AG/NIA NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Aug 26;466(7310):1105-9. doi: 10.1038/nature09271. Epub 2010 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20622856" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain-Derived Neurotrophic Factor/metabolism ; CREB-Binding Protein/metabolism ; Electrical Synapses/genetics/pathology ; Gene Expression Regulation ; Gene Knockdown Techniques ; Long-Term Potentiation/genetics ; Male ; Memory/*physiology ; Memory Disorders/genetics/physiopathology ; Mice ; MicroRNAs/*genetics/*metabolism ; Neuronal Plasticity/*genetics ; Protein Binding ; Sequence Deletion ; Sirtuin 1/*genetics/*metabolism
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    NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein (2010)
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    Publication Date: 2010-07-30
    Description: The post-translational methylation of alpha-amino groups was first discovered over 30 years ago on the bacterial ribosomal proteins L16 and L33 (refs 1, 2), but almost nothing is known about the function or enzymology of this modification. Several other bacterial and eukaryotic proteins have since been shown to be alpha-N-methylated. However, the Ran guanine nucleotide-exchange factor, RCC1, is the only protein for which any biological function of alpha-N-methylation has been identified. Methylation-defective mutants of RCC1 have reduced affinity for DNA and cause mitotic defects, but further characterization of this modification has been hindered by ignorance of the responsible methyltransferase. All fungal and animal N-terminally methylated proteins contain a unique N-terminal motif, Met-(Ala/Pro/Ser)-Pro-Lys, indicating that they may be targets of the same, unknown enzyme. The initiating Met is cleaved, and the exposed alpha-amino group is mono-, di- or trimethylated. Here we report the discovery of the first alpha-N-methyltransferase, which we named N-terminal RCC1 methyltransferase (NRMT). Substrate docking and mutational analysis of RCC1 defined the NRMT recognition sequence and enabled the identification of numerous new methylation targets, including SET (also known as TAF-I or PHAPII) and the retinoblastoma protein, RB. Knockdown of NRMT recapitulates the multi-spindle phenotype seen with methylation-defective RCC1 mutants, demonstrating the importance of alpha-N-methylation for normal bipolar spindle formation and chromosome segregation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939154/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939154/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tooley, Christine E Schaner -- Petkowski, Janusz J -- Muratore-Schroeder, Tara L -- Balsbaugh, Jeremy L -- Shabanowitz, Jeffrey -- Sabat, Michal -- Minor, Wladek -- Hunt, Donald F -- Macara, Ian G -- R01 GM050526/GM/NIGMS NIH HHS/ -- R01 GM050526-17/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Aug 26;466(7310):1125-8. doi: 10.1038/nature09343.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA. ces5g@virginia.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20668449" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/*metabolism ; Cell Line ; Chromosome Segregation ; Gene Knockdown Techniques ; Guanine Nucleotide Exchange Factors/*metabolism ; HeLa Cells ; Histone Chaperones/metabolism ; Humans ; Methyltransferases/chemistry/genetics/*metabolism ; Models, Molecular ; Mutation/genetics ; Nuclear Proteins/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Retinoblastoma Protein/*metabolism ; Spindle Apparatus/metabolism ; Transcription Factors/metabolism
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    Protein-protein interactions: Real-time analysis (2010)
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    Publication Date: 2010-12-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bonetta, Laura -- England -- Nature. 2010 Dec 9;468(7325):854. doi: 10.1038/468854a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21151000" target="_blank"〉PubMed〈/a〉
    Keywords: California ; Protein Binding ; Protein Interaction Mapping/*methods ; RNA, Transfer/metabolism ; Ribosomes/metabolism ; Sequence Analysis, DNA/methods ; Time Factors
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    Sequence space and the ongoing expansion of the protein universe (2010)
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    Publication Date: 2010-05-21
    Description: The need to maintain the structural and functional integrity of an evolving protein severely restricts the repertoire of acceptable amino-acid substitutions. However, it is not known whether these restrictions impose a global limit on how far homologous protein sequences can diverge from each other. Here we explore the limits of protein evolution using sequence divergence data. We formulate a computational approach to study the rate of divergence of distant protein sequences and measure this rate for ancient proteins, those that were present in the last universal common ancestor. We show that ancient proteins are still diverging from each other, indicating an ongoing expansion of the protein sequence universe. The slow rate of this divergence is imposed by the sparseness of functional protein sequences in sequence space and the ruggedness of the protein fitness landscape: approximately 98 per cent of sites cannot accept an amino-acid substitution at any given moment but a vast majority of all sites may eventually be permitted to evolve when other, compensatory, changes occur. Thus, approximately 3.5 x 10(9) yr has not been enough to reach the limit of divergent evolution of proteins, and for most proteins the limit of sequence similarity imposed by common function may not exceed that of random sequences.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Povolotskaya, Inna S -- Kondrashov, Fyodor A -- England -- Nature. 2010 Jun 17;465(7300):922-6. doi: 10.1038/nature09105. Epub 2010 May 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Bioinformatics and Genomics Programme, Centre for Genomic Regulation, Calle Dr Aiguader 88, Barcelona Biomedical Research Park Building, 08003 Barcelona, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485343" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Substitution ; Amino Acids/chemistry ; *Evolution, Molecular ; *Genetic Variation ; Molecular Sequence Data ; Mutation ; Prokaryotic Cells ; Protein Structure, Secondary ; Proteins/*chemistry ; Selection, Genetic/genetics ; Sequence Analysis, Protein ; Sequence Homology, Amino Acid
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    Self versus non-self discrimination during CRISPR RNA-directed immunity (2010)
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    Publication Date: 2010-01-15
    Description: All immune systems must distinguish self from non-self to repel invaders without inducing autoimmunity. Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci protect bacteria and archaea from invasion by phage and plasmid DNA through a genetic interference pathway. CRISPR loci are present in approximately 40% and approximately 90% of sequenced bacterial and archaeal genomes, respectively, and evolve rapidly, acquiring new spacer sequences to adapt to highly dynamic viral populations. Immunity requires a sequence match between the invasive DNA and the spacers that lie between CRISPR repeats. Each cluster is genetically linked to a subset of the cas (CRISPR-associated) genes that collectively encode 〉40 families of proteins involved in adaptation and interference. CRISPR loci encode small CRISPR RNAs (crRNAs) that contain a full spacer flanked by partial repeat sequences. CrRNA spacers are thought to identify targets by direct Watson-Crick pairing with invasive 'protospacer' DNA, but how they avoid targeting the spacer DNA within the encoding CRISPR locus itself is unknown. Here we have defined the mechanism of CRISPR self/non-self discrimination. In Staphylococcus epidermidis, target/crRNA mismatches at specific positions outside of the spacer sequence license foreign DNA for interference, whereas extended pairing between crRNA and CRISPR DNA repeats prevents autoimmunity. Hence, this CRISPR system uses the base-pairing potential of crRNAs not only to specify a target, but also to spare the bacterial chromosome from interference. Differential complementarity outside of the spacer sequence is a built-in feature of all CRISPR systems, indicating that this mechanism is a broadly applicable solution to the self/non-self dilemma that confronts all immune pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813891/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813891/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marraffini, Luciano A -- Sontheimer, Erik J -- R03 AI079722/AI/NIAID NIH HHS/ -- R03 AI079722-01A1/AI/NIAID NIH HHS/ -- England -- Nature. 2010 Jan 28;463(7280):568-71. doi: 10.1038/nature08703. Epub 2010 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, 2205 Tech Drive, Evanston, Illinois 60208, USA. marraffini@northwestern.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20072129" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/genetics ; Base Pairing/genetics ; Base Sequence ; Conserved Sequence ; DNA, Intergenic/genetics ; Molecular Sequence Data ; Mutation/genetics ; RNA, Bacterial/*genetics/metabolism ; Repetitive Sequences, Nucleic Acid/*genetics/*immunology ; Staphylococcus epidermidis/*genetics/*immunology
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    The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA (2010)
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    Publication Date: 2010-11-05
    Description: Bacteria and Archaea have developed several defence strategies against foreign nucleic acids such as viral genomes and plasmids. Among them, clustered regularly interspaced short palindromic repeats (CRISPR) loci together with cas (CRISPR-associated) genes form the CRISPR/Cas immune system, which involves partially palindromic repeats separated by short stretches of DNA called spacers, acquired from extrachromosomal elements. It was recently demonstrated that these variable loci can incorporate spacers from infecting bacteriophages and then provide immunity against subsequent bacteriophage infections in a sequence-specific manner. Here we show that the Streptococcus thermophilus CRISPR1/Cas system can also naturally acquire spacers from a self-replicating plasmid containing an antibiotic-resistance gene, leading to plasmid loss. Acquired spacers that match antibiotic-resistance genes provide a novel means to naturally select bacteria that cannot uptake and disseminate such genes. We also provide in vivo evidence that the CRISPR1/Cas system specifically cleaves plasmid and bacteriophage double-stranded DNA within the proto-spacer, at specific sites. Our data show that the CRISPR/Cas immune system is remarkably adapted to cleave invading DNA rapidly and has the potential for exploitation to generate safer microbial strains.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garneau, Josiane E -- Dupuis, Marie-Eve -- Villion, Manuela -- Romero, Dennis A -- Barrangou, Rodolphe -- Boyaval, Patrick -- Fremaux, Christophe -- Horvath, Philippe -- Magadan, Alfonso H -- Moineau, Sylvain -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2010 Nov 4;468(7320):67-71. doi: 10.1038/nature09523.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departement de biochimie, de microbiologie et de bio-informatique, Faculte des sciences et de genie, Groupe de recherche en ecologie buccale, Faculte de medecine dentaire, Felix d'Herelle Reference Center for Bacterial Viruses, Universite Laval, Quebec City, Quebec G1V 0A6, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21048762" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophages/*genetics/metabolism ; Base Sequence ; DNA, Intergenic/genetics/metabolism ; DNA, Viral/genetics/*metabolism ; Drug Resistance, Bacterial/genetics ; Genetic Loci/*genetics/*immunology ; Interspersed Repetitive Sequences/genetics ; Molecular Sequence Data ; Mutation ; Plasmids/genetics/*metabolism ; RNA, Bacterial/genetics/immunology ; Streptococcus thermophilus/genetics/*immunology/*virology
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    Orm family proteins mediate sphingolipid homeostasis (2010)
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    Publication Date: 2010-02-26
    Description: Despite the essential roles of sphingolipids both as structural components of membranes and critical signalling molecules, we have a limited understanding of how cells sense and regulate their levels. Here we reveal the function in sphingolipid metabolism of the ORM genes (known as ORMDL genes in humans)-a conserved gene family that includes ORMDL3, which has recently been identified as a potential risk factor for childhood asthma. Starting from an unbiased functional genomic approach in Saccharomyces cerevisiae, we identify Orm proteins as negative regulators of sphingolipid synthesis that form a conserved complex with serine palmitoyltransferase, the first and rate-limiting enzyme in sphingolipid production. We also define a regulatory pathway in which phosphorylation of Orm proteins relieves their inhibitory activity when sphingolipid production is disrupted. Changes in ORM gene expression or mutations to their phosphorylation sites cause dysregulation of sphingolipid metabolism. Our work identifies the Orm proteins as critical mediators of sphingolipid homeostasis and raises the possibility that sphingolipid misregulation contributes to the development of childhood asthma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877384/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877384/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Breslow, David K -- Collins, Sean R -- Bodenmiller, Bernd -- Aebersold, Ruedi -- Simons, Kai -- Shevchenko, Andrej -- Ejsing, Christer S -- Weissman, Jonathan S -- N01-HV-28179/HV/NHLBI NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- P50 GM073210-06/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Feb 25;463(7284):1048-53. doi: 10.1038/nature08787.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 1700 4th Street, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20182505" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Asthma/metabolism ; Cell Line ; Conserved Sequence ; Fatty Acids, Monounsaturated/pharmacology ; HeLa Cells ; *Homeostasis ; Humans ; Molecular Sequence Data ; *Multigene Family ; Multiprotein Complexes/chemistry/metabolism ; Phosphoric Monoester Hydrolases/genetics/metabolism ; Phosphorylation ; Protein Binding ; Saccharomyces cerevisiae/drug effects/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/classification/genetics/*metabolism ; Serine C-Palmitoyltransferase/genetics/metabolism ; Sphingolipids/biosynthesis/*metabolism
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    Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses (2010)
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    Publication Date: 2010-03-09
    Description: The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress. Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings, suggesting that the ARF-p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF-p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF-p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737736/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737736/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Delin -- Shan, Jing -- Zhu, Wei-Guo -- Qin, Jun -- Gu, Wei -- P01 CA080058/CA/NCI NIH HHS/ -- P01 CA097403/CA/NCI NIH HHS/ -- R01 CA085533/CA/NCI NIH HHS/ -- R01 CA118561/CA/NCI NIH HHS/ -- R01 CA129627/CA/NCI NIH HHS/ -- R01 CA131439/CA/NCI NIH HHS/ -- England -- Nature. 2010 Mar 25;464(7288):624-7. doi: 10.1038/nature08820. Epub 2010 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Genetics, and Department of Pathology and Cell Biology College of Physicians & Surgeons, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20208519" target="_blank"〉PubMed〈/a〉
    Keywords: ADP-Ribosylation Factors/*metabolism ; Cell Line ; Fibroblasts/metabolism ; *Gene Expression Regulation ; Humans ; Molecular Sequence Data ; Nuclear Proteins/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Stress, Physiological/*physiology ; Tumor Suppressor Protein p53/*metabolism ; U937 Cells ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
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    Ancient animal microRNAs and the evolution of tissue identity (2010)
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    Publication Date: 2010-02-02
    Description: The spectacular escalation in complexity in early bilaterian evolution correlates with a strong increase in the number of microRNAs. To explore the link between the birth of ancient microRNAs and body plan evolution, we set out to determine the ancient sites of activity of conserved bilaterian microRNA families in a comparative approach. We reason that any specific localization shared between protostomes and deuterostomes (the two major superphyla of bilaterian animals) should probably reflect an ancient specificity of that microRNA in their last common ancestor. Here, we investigate the expression of conserved bilaterian microRNAs in Platynereis dumerilii, a protostome retaining ancestral bilaterian features, in Capitella, another marine annelid, in the sea urchin Strongylocentrotus, a deuterostome, and in sea anemone Nematostella, representing an outgroup to the bilaterians. Our comparative data indicate that the oldest known animal microRNA, miR-100, and the related miR-125 and let-7 were initially active in neurosecretory cells located around the mouth. Other sets of ancient microRNAs were first present in locomotor ciliated cells, specific brain centres, or, more broadly, one of four major organ systems: central nervous system, sensory tissue, musculature and gut. These findings reveal that microRNA evolution and the establishment of tissue identities were closely coupled in bilaterian evolution. Also, they outline a minimum set of cell types and tissues that existed in the protostome-deuterostome ancestor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981144/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981144/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Christodoulou, Foteini -- Raible, Florian -- Tomer, Raju -- Simakov, Oleg -- Trachana, Kalliopi -- Klaus, Sebastian -- Snyman, Heidi -- Hannon, Gregory J -- Bork, Peer -- Arendt, Detlev -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA013106-38/CA/NCI NIH HHS/ -- P01 CA013106-39/CA/NCI NIH HHS/ -- England -- Nature. 2010 Feb 25;463(7284):1084-8. doi: 10.1038/nature08744. Epub 2010 Jan 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Biology Unit, European Molecular Biology Laboratory, D-69117 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20118916" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Annelida/anatomy & histology/cytology/genetics ; *Biological Evolution ; Brain/metabolism ; Cilia/physiology ; Conserved Sequence/genetics ; Digestive System/cytology/metabolism ; In Situ Hybridization ; MicroRNAs/*analysis/*genetics ; Molecular Sequence Data ; *Organ Specificity ; Phylogeny ; Polychaeta/*anatomy & histology/cytology/*genetics ; Sea Anemones/anatomy & histology/cytology/genetics ; Sea Urchins/anatomy & histology/cytology/genetics
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    Selective inhibition of BET bromodomains (2010)
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    Publication Date: 2010-09-28
    Description: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010259/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010259/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Filippakopoulos, Panagis -- Qi, Jun -- Picaud, Sarah -- Shen, Yao -- Smith, William B -- Fedorov, Oleg -- Morse, Elizabeth M -- Keates, Tracey -- Hickman, Tyler T -- Felletar, Ildiko -- Philpott, Martin -- Munro, Shonagh -- McKeown, Michael R -- Wang, Yuchuan -- Christie, Amanda L -- West, Nathan -- Cameron, Michael J -- Schwartz, Brian -- Heightman, Tom D -- La Thangue, Nicholas -- French, Christopher A -- Wiest, Olaf -- Kung, Andrew L -- Knapp, Stefan -- Bradner, James E -- 13058/Cancer Research UK/United Kingdom -- G0500905/Medical Research Council/United Kingdom -- G1000807/Medical Research Council/United Kingdom -- G9400953/Medical Research Council/United Kingdom -- K08 CA128972/CA/NCI NIH HHS/ -- K08 CA128972-03/CA/NCI NIH HHS/ -- T32-075762/PHS HHS/ -- Canadian Institutes of Health Research/Canada -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Dec 23;468(7327):1067-73. doi: 10.1038/nature09504. Epub 2010 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20871596" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Azirines/chemical synthesis/chemistry/*pharmacology ; Binding Sites ; Carcinoma, Squamous Cell/physiopathology ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromatin/metabolism ; Dihydropyridines/chemical synthesis/chemistry/*pharmacology ; Female ; Humans ; Mice ; Mice, Nude ; *Models, Molecular ; Molecular Sequence Data ; Nuclear Proteins/*antagonists & inhibitors/*metabolism ; Protein Binding/drug effects ; Protein Structure, Tertiary ; Recombinant Proteins/metabolism ; Sequence Alignment ; Skin Neoplasms/physiopathology ; Stereoisomerism ; Transcription Factors/*antagonists & inhibitors/*metabolism
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    eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation (2010)
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    Publication Date: 2010-05-21
    Description: In protein synthesis initiation, the eukaryotic translation initiation factor (eIF) 2 (a G protein) functions in its GTP-bound state to deliver initiator methionyl-tRNA (tRNA(i)(Met)) to the small ribosomal subunit and is necessary for protein synthesis in all cells. Phosphorylation of eIF2 [eIF2(alphaP)] is critical for translational control in diverse settings including nutrient deprivation, viral infection and memory formation. eIF5 functions in start site selection as a GTPase accelerating protein (GAP) for the eIF2.GTP.tRNA(i)(Met) ternary complex within the ribosome-bound pre-initiation complex. Here we define new regulatory functions of eIF5 in the recycling of eIF2 from its inactive eIF2.GDP state between successive rounds of translation initiation. First we show that eIF5 stabilizes the binding of GDP to eIF2 and is therefore a bi-functional protein that acts as a GDP dissociation inhibitor (GDI). We find that this activity is independent of the GAP function and identify conserved residues within eIF5 that are necessary for this role. Second we show that eIF5 is a critical component of the eIF2(alphaP) regulatory complex that inhibits the activity of the guanine-nucleotide exchange factor (GEF) eIF2B. Together our studies define a new step in the translation initiation pathway, one that is critical for normal translational controls.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875157/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875157/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jennings, Martin D -- Pavitt, Graham D -- BB/E002005/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/H010599/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BBE0020051/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2010 May 20;465(7296):378-81. doi: 10.1038/nature09003.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485439" target="_blank"〉PubMed〈/a〉
    Keywords: Basic-Leucine Zipper Transcription Factors/metabolism ; Eukaryotic Initiation Factor-2/antagonists & inhibitors/chemistry/*metabolism ; GTPase-Activating Proteins/metabolism ; Guanine Nucleotide Dissociation Inhibitors/chemistry/*metabolism ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; *Peptide Chain Initiation, Translational ; Peptide Initiation Factors/chemistry/*metabolism ; Phosphorylation ; Protein Binding ; Protein Subunits/chemistry/metabolism ; RNA, Transfer, Met/metabolism ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism
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    Network organization of the human autophagy system (2010)
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    Publication Date: 2010-06-22
    Description: Autophagy, the process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation, provides a primary route for turnover of stable and defective cellular proteins. Defects in this system are linked with numerous human diseases. Although conserved protein kinase, lipid kinase and ubiquitin-like protein conjugation subnetworks controlling autophagosome formation and cargo recruitment have been defined, our understanding of the global organization of this system is limited. Here we report a proteomic analysis of the autophagy interaction network in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 409 candidate interacting proteins with extensive connectivity among subnetworks. Many new autophagy interaction network components have roles in vesicle trafficking, protein or lipid phosphorylation and protein ubiquitination, and affect autophagosome number or flux when depleted by RNA interference. The six ATG8 orthologues in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901998/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901998/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Behrends, Christian -- Sowa, Mathew E -- Gygi, Steven P -- Harper, J Wade -- R01 AG011085/AG/NIA NIH HHS/ -- R01 AG011085-18/AG/NIA NIH HHS/ -- R01 GM054137/GM/NIGMS NIH HHS/ -- R01 GM054137-14/GM/NIGMS NIH HHS/ -- R01 GM054137-14S1/GM/NIGMS NIH HHS/ -- R01 GM054137-15/GM/NIGMS NIH HHS/ -- R01 GM070565/GM/NIGMS NIH HHS/ -- R01 GM070565-05S1/GM/NIGMS NIH HHS/ -- R01 GM095567/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jul 1;466(7302):68-76. doi: 10.1038/nature09204. Epub 2010 Jun 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20562859" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Autophagy/genetics/*physiology ; Homeostasis ; Humans ; Microfilament Proteins/genetics/metabolism ; Phagosomes ; Phosphorylation ; Protein Binding ; *Protein Interaction Mapping ; Proteomics ; RNA Interference ; Reproducibility of Results ; Ubiquitination
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    TRIM24 links a non-canonical histone signature to breast cancer (2010)
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    Publication Date: 2010-12-18
    Description: Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058826/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058826/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsai, Wen-Wei -- Wang, Zhanxin -- Yiu, Teresa T -- Akdemir, Kadir C -- Xia, Weiya -- Winter, Stefan -- Tsai, Cheng-Yu -- Shi, Xiaobing -- Schwarzer, Dirk -- Plunkett, William -- Aronow, Bruce -- Gozani, Or -- Fischle, Wolfgang -- Hung, Mien-Chie -- Patel, Dinshaw J -- Barton, Michelle Craig -- GM079641/GM/NIGMS NIH HHS/ -- GM081627/GM/NIGMS NIH HHS/ -- P01 GM081627/GM/NIGMS NIH HHS/ -- P01 GM081627-010003/GM/NIGMS NIH HHS/ -- P01 GM081627-020003/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- P30DK078392-01/DK/NIDDK NIH HHS/ -- T32 HD07325/HD/NICHD NIH HHS/ -- U54 RR025216/RR/NCRR NIH HHS/ -- UL1 TR000077/TR/NCATS NIH HHS/ -- England -- Nature. 2010 Dec 16;468(7326):927-32. doi: 10.1038/nature09542.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biomedical Sciences, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21164480" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Breast Neoplasms/*genetics/*metabolism/pathology ; Carrier Proteins/chemistry/genetics/*metabolism ; Cell Line, Tumor ; Chromatin/metabolism ; Chromatin Assembly and Disassembly ; Crystallography, X-Ray ; Estrogen Receptor alpha/metabolism ; Estrogens/metabolism ; *Gene Expression Regulation, Neoplastic/genetics ; HEK293 Cells ; Histones/chemistry/*metabolism ; Humans ; Methylation ; Protein Array Analysis ; Protein Binding ; Protein Structure, Tertiary ; Substrate Specificity ; Survival Rate
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    Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint (2010)
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    Publication Date: 2010-09-08
    Description: Cell cycle checkpoints are implemented to safeguard the genome, avoiding the accumulation of genetic errors. Checkpoint loss results in genomic instability and contributes to the evolution of cancer. Among G1-, S-, G2- and M-phase checkpoints, genetic studies indicate the role of an intact S-phase checkpoint in maintaining genome integrity. Although the basic framework of the S-phase checkpoint in multicellular organisms has been outlined, the mechanistic details remain to be elucidated. Human chromosome-11 band-q23 translocations disrupting the MLL gene lead to poor prognostic leukaemias. Here we assign MLL as a novel effector in the mammalian S-phase checkpoint network and identify checkpoint dysfunction as an underlying mechanism of MLL leukaemias. MLL is phosphorylated at serine 516 by ATR in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCF(Skp2) E3 ligase, leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine 4 at late replication origins and inhibits the loading of CDC45 to delay DNA replication. Cells deficient in MLL showed radioresistant DNA synthesis and chromatid-type genomic abnormalities, indicative of S-phase checkpoint dysfunction. Reconstitution of Mll(-/-) (Mll also known as Mll1) mouse embryonic fibroblasts with wild-type but not S516A or DeltaSET mutant MLL rescues the S-phase checkpoint defects. Moreover, murine myeloid progenitor cells carrying an Mll-CBP knock-in allele that mimics human t(11;16) leukaemia show a severe radioresistant DNA synthesis phenotype. MLL fusions function as dominant negative mutants that abrogate the ATR-mediated phosphorylation/stabilization of wild-type MLL on damage to DNA, and thus compromise the S-phase checkpoint. Together, our results identify MLL as a key constituent of the mammalian DNA damage response pathway and show that deregulation of the S-phase checkpoint incurred by MLL translocations probably contributes to the pathogenesis of human MLL leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940944/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940944/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Han -- Takeda, Shugaku -- Kumar, Rakesh -- Westergard, Todd D -- Brown, Eric J -- Pandita, Tej K -- Cheng, Emily H-Y -- Hsieh, James J-D -- CA119008/CA/NCI NIH HHS/ -- CA123232/CA/NCI NIH HHS/ -- CA129537/CA/NCI NIH HHS/ -- R01 CA119008/CA/NCI NIH HHS/ -- R01 CA119008-01/CA/NCI NIH HHS/ -- R01 CA119008-02/CA/NCI NIH HHS/ -- R01 CA119008-03/CA/NCI NIH HHS/ -- R01 CA119008-04/CA/NCI NIH HHS/ -- R01 CA119008-05/CA/NCI NIH HHS/ -- England -- Nature. 2010 Sep 16;467(7313):343-6. doi: 10.1038/nature09350. Epub 2010 Sep 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20818375" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cell Line ; Chromatin/metabolism ; DNA Damage ; DNA Replication/physiology ; Genes, Dominant/genetics ; Genomic Instability/physiology ; Histone-Lysine N-Methyltransferase ; Histones/chemistry/metabolism ; Humans ; Leukemia/genetics ; Lysine/metabolism ; Methylation ; Mice ; Myeloid Progenitor Cells/metabolism ; Myeloid-Lymphoid Leukemia Protein/chemistry/deficiency/genetics/*metabolism ; Phosphorylation ; Phosphoserine/metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/*metabolism ; S Phase/*physiology ; S-Phase Kinase-Associated Proteins/metabolism ; Signal Transduction ; Translocation, Genetic/genetics
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    Production of p53 gene knockout rats by homologous recombination in embryonic stem cells (2010)
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    Publication Date: 2010-08-13
    Description: The use of homologous recombination to modify genes in embryonic stem (ES) cells provides a powerful means to elucidate gene function and create disease models. Application of this technology to engineer genes in rats has not previously been possible because of the absence of germline-competent ES cells in this species. We have recently established authentic rat ES cells. Here we report the generation of gene knockout rats using the ES-cell-based gene targeting technology. We designed a targeting vector to disrupt the tumour suppressor gene p53 (also known as Tp53) in rat ES cells by means of homologous recombination. p53 gene-targeted rat ES cells can be routinely generated. Furthermore, the p53 gene-targeted mutation in the rat ES-cell genome can transmit through the germ line via ES-cell rat chimaeras to create p53 gene knockout rats. The rat is the most widely used animal model in biological research. The establishment of gene targeting technology in rat ES cells, in combination with advances in genomics and the vast amount of research data on physiology and pharmacology in this species, now provide a powerful new platform for the study of human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937076/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tong, Chang -- Li, Ping -- Wu, Nancy L -- Yan, Youzhen -- Ying, Qi-Long -- 1R01 RR025881/RR/NCRR NIH HHS/ -- R01 OD010926/OD/NIH HHS/ -- R01 RR025881/RR/NCRR NIH HHS/ -- R01 RR025881-01A2/RR/NCRR NIH HHS/ -- England -- Nature. 2010 Sep 9;467(7312):211-3. doi: 10.1038/nature09368. Epub 2010 Aug 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20703227" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Culture Techniques ; Embryo, Mammalian/cytology ; Embryonic Stem Cells/*cytology ; Female ; Gene Knockout Techniques/*methods ; *Genes, p53 ; Germ-Line Mutation ; Male ; Mice ; Molecular Sequence Data ; Rats/*genetics ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Recombination, Genetic
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    Protein-protein interactions: Interactome under construction (2010)
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    Publication Date: 2010-12-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bonetta, Laura -- England -- Nature. 2010 Dec 9;468(7325):851-4. doi: 10.1038/468851a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21150998" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/diagnosis/metabolism/pathology ; Computational Biology ; Databases, Factual/trends ; False Negative Reactions ; False Positive Reactions ; Genes, Reporter ; Humans ; Immunoprecipitation ; Mass Spectrometry ; Protein Array Analysis ; Protein Binding ; Protein Interaction Mapping/*methods/*trends ; Proteome/genetics/metabolism ; Two-Hybrid System Techniques
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    Genome-wide measurement of RNA secondary structure in yeast (2010)
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    Publication Date: 2010-09-03
    Description: The structures of RNA molecules are often important for their function and regulation, yet there are no experimental techniques for genome-scale measurement of RNA structure. Here we describe a novel strategy termed parallel analysis of RNA structure (PARS), which is based on deep sequencing fragments of RNAs that were treated with structure-specific enzymes, thus providing simultaneous in vitro profiling of the secondary structure of thousands of RNA species at single nucleotide resolution. We apply PARS to profile the secondary structure of the messenger RNAs (mRNAs) of the budding yeast Saccharomyces cerevisiae and obtain structural profiles for over 3,000 distinct transcripts. Analysis of these profiles reveals several RNA structural properties of yeast transcripts, including the existence of more secondary structure over coding regions compared with untranslated regions, a three-nucleotide periodicity of secondary structure across coding regions and an anti-correlation between the efficiency with which an mRNA is translated and the structure over its translation start site. PARS is readily applicable to other organisms and to profiling RNA structure in diverse conditions, thus enabling studies of the dynamics of secondary structure at a genomic scale.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847670/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847670/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kertesz, Michael -- Wan, Yue -- Mazor, Elad -- Rinn, John L -- Nutter, Robert C -- Chang, Howard Y -- Segal, Eran -- R01 HG004361/HG/NHGRI NIH HHS/ -- R01HG004361/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Sep 2;467(7311):103-7. doi: 10.1038/nature09322.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20811459" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; *Genetic Techniques ; Genome-Wide Association Study ; Molecular Sequence Data ; *Nucleic Acid Conformation ; RNA, Fungal/*chemistry ; RNA, Messenger/*chemistry ; Saccharomyces cerevisiae/*chemistry/*genetics ; Transcription, Genetic
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    Drug discovery: Pulled from a protein's embrace (2010)
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    Publication Date: 2010-07-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jorgensen, William L -- England -- Nature. 2010 Jul 1;466(7302):42-3. doi: 10.1038/466042a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20596009" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; *Computer-Aided Design ; Drug Design ; Drug Discovery/*methods ; Enzyme Inhibitors/*chemistry/*metabolism ; Flavonoids/chemistry/metabolism ; Ligands ; Luteolin/chemistry/metabolism ; Molecular Dynamics Simulation ; Plasmodium falciparum ; Protein Binding ; Protozoan Proteins/chemistry/metabolism ; Thermodynamics
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    Pyruvate kinase M2 is a phosphotyrosine-binding protein (2008)
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    Publication Date: 2008-03-14
    Description: Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Christofk, Heather R -- Vander Heiden, Matthew G -- Wu, Ning -- Asara, John M -- Cantley, Lewis C -- R01 GM056203/GM/NIGMS NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- England -- Nature. 2008 Mar 13;452(7184):181-6. doi: 10.1038/nature06667.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337815" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Site ; Animals ; Catalysis ; Cell Line ; Cell Proliferation/drug effects ; Cells/drug effects/metabolism ; HeLa Cells ; Humans ; Lysine/metabolism ; Models, Molecular ; Peptide Library ; Phosphotyrosine/*metabolism ; Protein Binding ; Proteomics ; Pyruvate Kinase/antagonists & inhibitors/*metabolism ; Substrate Specificity
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    Hierarchical structure and the prediction of missing links in networks (2008)
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    Publication Date: 2008-05-03
    Description: Networks have in recent years emerged as an invaluable tool for describing and quantifying complex systems in many branches of science. Recent studies suggest that networks often exhibit hierarchical organization, in which vertices divide into groups that further subdivide into groups of groups, and so forth over multiple scales. In many cases the groups are found to correspond to known functional units, such as ecological niches in food webs, modules in biochemical networks (protein interaction networks, metabolic networks or genetic regulatory networks) or communities in social networks. Here we present a general technique for inferring hierarchical structure from network data and show that the existence of hierarchy can simultaneously explain and quantitatively reproduce many commonly observed topological properties of networks, such as right-skewed degree distributions, high clustering coefficients and short path lengths. We further show that knowledge of hierarchical structure can be used to predict missing connections in partly known networks with high accuracy, and for more general network structures than competing techniques. Taken together, our results suggest that hierarchy is a central organizing principle of complex networks, capable of offering insight into many network phenomena.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clauset, Aaron -- Moore, Cristopher -- Newman, M E J -- England -- Nature. 2008 May 1;453(7191):98-101. doi: 10.1038/nature06830.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Computer Science, University of New Mexico, Albuquerque, New Mexico 87131, USA. aaronc@santafe.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18451861" target="_blank"〉PubMed〈/a〉
    Keywords: *Algorithms ; Biosynthetic Pathways ; Food Chain ; Gene Regulatory Networks ; Metabolic Networks and Pathways ; *Models, Biological ; *Probability ; Protein Binding ; Sensitivity and Specificity ; Social Behavior
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    Structural basis for gibberellin recognition by its receptor GID1 (2008)
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    Publication Date: 2008-11-28
    Description: Gibberellins (GAs) are phytohormones essential for many developmental processes in plants. A nuclear GA receptor, GIBBERELLIN INSENSITIVE DWARF1 (GID1), has a primary structure similar to that of the hormone-sensitive lipases (HSLs). Here we analyse the crystal structure of Oryza sativa GID1 (OsGID1) bound with GA(4) and GA(3) at 1.9 A resolution. The overall structure of both complexes shows an alpha/beta-hydrolase fold similar to that of HSLs except for an amino-terminal lid. The GA-binding pocket corresponds to the substrate-binding site of HSLs. On the basis of the OsGID1 structure, we mutagenized important residues for GA binding and examined their binding activities. Almost all of them showed very little or no activity, confirming that the residues revealed by structural analysis are important for GA binding. The replacement of Ile 133 with Leu or Val-residues corresponding to those of the lycophyte Selaginella moellendorffii GID1s-caused an increase in the binding affinity for GA(34), a 2beta-hydroxylated GA(4). These observations indicate that GID1 originated from HSL and was further modified to have higher affinity and more strict selectivity for bioactive GAs by adapting the amino acids involved in GA binding in the course of plant evolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shimada, Asako -- Ueguchi-Tanaka, Miyako -- Nakatsu, Toru -- Nakajima, Masatoshi -- Naoe, Youichi -- Ohmiya, Hiroko -- Kato, Hiroaki -- Matsuoka, Makoto -- England -- Nature. 2008 Nov 27;456(7221):520-3. doi: 10.1038/nature07546.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Bioscience and Biotechnology Center, Nagoya University, Nagoya, Aichi 464-8601, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19037316" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Gibberellins/*chemistry/*metabolism ; Hydrolases/chemistry/metabolism ; Hydroxylation ; Models, Molecular ; Oryza/*chemistry/genetics/metabolism ; Plant Growth Regulators/*chemistry/*metabolism ; Plant Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Conformation ; Substrate Specificity ; Two-Hybrid System Techniques
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    BAX activation is initiated at a novel interaction site (2008)
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    Publication Date: 2008-10-25
    Description: BAX is a pro-apoptotic protein of the BCL-2 family that is stationed in the cytosol until activated by a diversity of stress stimuli to induce cell death. Anti-apoptotic proteins such as BCL-2 counteract BAX-mediated cell death. Although an interaction site that confers survival functionality has been defined for anti-apoptotic proteins, an activation site has not been identified for BAX, rendering its explicit trigger mechanism unknown. We previously developed stabilized alpha-helix of BCL-2 domains (SAHBs) that directly initiate BAX-mediated mitochondrial apoptosis. Here we demonstrate by NMR analysis that BIM SAHB binds BAX at an interaction site that is distinct from the canonical binding groove characterized for anti-apoptotic proteins. The specificity of the human BIM-SAHB-BAX interaction is highlighted by point mutagenesis that disrupts functional activity, confirming that BAX activation is initiated at this novel structural location. Thus, we have now defined a BAX interaction site for direct activation, establishing a new target for therapeutic modulation of apoptosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597110/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597110/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gavathiotis, Evripidis -- Suzuki, Motoshi -- Davis, Marguerite L -- Pitter, Kenneth -- Bird, Gregory H -- Katz, Samuel G -- Tu, Ho-Chou -- Kim, Hyungjin -- Cheng, Emily H-Y -- Tjandra, Nico -- Walensky, Loren D -- 5P01CA92625/CA/NCI NIH HHS/ -- 5R01CA125562/CA/NCI NIH HHS/ -- 5R01CA50239/CA/NCI NIH HHS/ -- K99 HL095929/HL/NHLBI NIH HHS/ -- K99 HL095929-01A1/HL/NHLBI NIH HHS/ -- K99 HL095929-02/HL/NHLBI NIH HHS/ -- R00 HL095929/HL/NHLBI NIH HHS/ -- R01 CA050239/CA/NCI NIH HHS/ -- R01 CA125562/CA/NCI NIH HHS/ -- R01 CA125562-02/CA/NCI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2008 Oct 23;455(7216):1076-81. doi: 10.1038/nature07396.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric Oncology and the Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18948948" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Apoptosis ; Apoptosis Regulatory Proteins/chemistry/metabolism ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Cell Line ; *Gene Expression Regulation ; Humans ; Membrane Proteins/chemistry/metabolism ; Mice ; Mutagenesis, Site-Directed ; Mutation/genetics ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Proto-Oncogene Proteins/chemistry/metabolism ; Sequence Alignment ; bcl-2-Associated X Protein/chemistry/*metabolism
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    NUMB controls p53 tumour suppressor activity (2008)
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    Publication Date: 2008-01-04
    Description: NUMB is a cell fate determinant, which, by asymmetrically partitioning at mitosis, controls cell fate choices by antagonising the activity of the plasma membrane receptor of the NOTCH family. NUMB is also an endocytic protein, and the NOTCH-NUMB counteraction has been linked to this function. There might be, however, additional functions of NUMB, as witnessed by its proposed role as a tumour suppressor in breast cancer. Here we describe a previously unknown function for human NUMB as a regulator of tumour protein p53 (also known as TP53). NUMB enters in a tricomplex with p53 and the E3 ubiquitin ligase HDM2 (also known as MDM2), thereby preventing ubiquitination and degradation of p53. This results in increased p53 protein levels and activity, and in regulation of p53-dependent phenotypes. In breast cancers there is frequent loss of NUMB expression. We show that, in primary breast tumour cells, this event causes decreased p53 levels and increased chemoresistance. In breast cancers, loss of NUMB expression causes increased activity of the receptor NOTCH. Thus, in these cancers, a single event-loss of NUMB expression-determines activation of an oncogene (NOTCH) and attenuation of the p53 tumour suppressor pathway. Biologically, this results in an aggressive tumour phenotype, as witnessed by findings that NUMB-defective breast tumours display poor prognosis. Our results uncover a previously unknown tumour suppressor circuitry.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Colaluca, Ivan N -- Tosoni, Daniela -- Nuciforo, Paolo -- Senic-Matuglia, Francesca -- Galimberti, Viviana -- Viale, Giuseppe -- Pece, Salvatore -- Di Fiore, Pier Paolo -- England -- Nature. 2008 Jan 3;451(7174):76-80. doi: 10.1038/nature06412.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IFOM, the FIRC Institute for Molecular Oncology Foundation, Via Adamello 16, 20139, Milan, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18172499" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/genetics/metabolism/pathology ; Cell Line, Tumor ; Cells, Cultured ; DNA Damage ; Drug Resistance, Neoplasm ; Gene Silencing ; Humans ; Membrane Proteins/deficiency/genetics/*metabolism ; Nerve Tissue Proteins/deficiency/genetics/*metabolism ; Prognosis ; Protein Binding ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/*metabolism ; Ubiquitination
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    Proteasome subunit Rpn13 is a novel ubiquitin receptor (2008)
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    Publication Date: 2008-05-24
    Description: Proteasomal receptors that recognize ubiquitin chains attached to substrates are key mediators of selective protein degradation in eukaryotes. Here we report the identification of a new ubiquitin receptor, Rpn13/ARM1, a known component of the proteasome. Rpn13 binds ubiquitin through a conserved amino-terminal region termed the pleckstrin-like receptor for ubiquitin (Pru) domain, which binds K48-linked diubiquitin with an affinity of approximately 90 nM. Like proteasomal ubiquitin receptor Rpn10/S5a, Rpn13 also binds ubiquitin-like (UBL) domains of UBL-ubiquitin-associated (UBA) proteins. In yeast, a synthetic phenotype results when specific mutations of the ubiquitin binding sites of Rpn10 and Rpn13 are combined, indicating functional linkage between these ubiquitin receptors. Because Rpn13 is also the proteasomal receptor for Uch37, a deubiquitinating enzyme, our findings suggest a coupling of chain recognition and disassembly at the proteasome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839886/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839886/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Husnjak, Koraljka -- Elsasser, Suzanne -- Zhang, Naixia -- Chen, Xiang -- Randles, Leah -- Shi, Yuan -- Hofmann, Kay -- Walters, Kylie J -- Finley, Daniel -- Dikic, Ivan -- CA097004/CA/NCI NIH HHS/ -- GM008700/GM/NIGMS NIH HHS/ -- GM043601/GM/NIGMS NIH HHS/ -- R01 CA097004/CA/NCI NIH HHS/ -- R01 CA097004-05/CA/NCI NIH HHS/ -- R01 CA097004-06A1/CA/NCI NIH HHS/ -- R37 GM043601/GM/NIGMS NIH HHS/ -- R37 GM043601-17/GM/NIGMS NIH HHS/ -- T32 GM008700/GM/NIGMS NIH HHS/ -- T32 GM008700-09/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 May 22;453(7194):481-8. doi: 10.1038/nature06926.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18497817" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites/genetics ; Cell Adhesion Molecules/chemistry/genetics/metabolism ; Humans ; Membrane Glycoproteins/chemistry/genetics/metabolism ; Mice ; Molecular Sequence Data ; Mutation/genetics ; Phenotype ; Proteasome Endopeptidase Complex/*chemistry/genetics/*metabolism ; Protein Subunits/chemistry/genetics/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism ; Ubiquitin/*metabolism
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    Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants (2008)
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    Publication Date: 2008-05-16
    Description: The potential impact of pandemic influenza makes effective measures to limit the spread and morbidity of virus infection a public health priority. Antiviral drugs are seen as essential requirements for control of initial influenza outbreaks caused by a new virus, and in pre-pandemic plans there is a heavy reliance on drug stockpiles. The principal target for these drugs is a virus surface glycoprotein, neuraminidase, which facilitates the release of nascent virus and thus the spread of infection. Oseltamivir (Tamiflu) and zanamivir (Relenza) are two currently used neuraminidase inhibitors that were developed using knowledge of the enzyme structure. It has been proposed that the closer such inhibitors resemble the natural substrate, the less likely they are to select drug-resistant mutant viruses that retain viability. However, there have been reports of drug-resistant mutant selection in vitro and from infected humans. We report here the enzymatic properties and crystal structures of neuraminidase mutants from H5N1-infected patients that explain the molecular basis of resistance. Our results show that these mutants are resistant to oseltamivir but still strongly inhibited by zanamivir owing to an altered hydrophobic pocket in the active site of the enzyme required for oseltamivir binding. Together with recent reports of the viability and pathogenesis of H5N1 (ref. 7) and H1N1 (ref. 8) viruses with neuraminidases carrying these mutations, our results indicate that it would be prudent for pandemic stockpiles of oseltamivir to be augmented by additional antiviral drugs, including zanamivir.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Collins, Patrick J -- Haire, Lesley F -- Lin, Yi Pu -- Liu, Junfeng -- Russell, Rupert J -- Walker, Philip A -- Skehel, John J -- Martin, Stephen R -- Hay, Alan J -- Gamblin, Steven J -- MC_U117512711/Medical Research Council/United Kingdom -- MC_U117512723/Medical Research Council/United Kingdom -- MC_U117570592/Medical Research Council/United Kingdom -- MC_U117584222/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2008 Jun 26;453(7199):1258-61. doi: 10.1038/nature06956. Epub 2008 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18480754" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; *Drug Resistance, Viral ; Enzyme Inhibitors/chemistry/metabolism/pharmacology ; Humans ; Influenza A Virus, H1N1 Subtype/drug effects/enzymology/genetics ; Influenza A Virus, H5N1 Subtype/*drug effects/*enzymology/genetics ; Influenza, Human/virology ; Kinetics ; Models, Molecular ; Molecular Conformation ; Mutation/*genetics ; Neuraminidase/antagonists & inhibitors/*chemistry/*genetics/metabolism ; Oseltamivir/chemistry/metabolism/*pharmacology ; Protein Binding ; Zanamivir/pharmacology
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    Identification of the sex genes in an early diverged fungus (2008)
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    Publication Date: 2008-01-11
    Description: Sex determination in fungi is controlled by a small, specialized region of the genome in contrast to the large sex-specific chromosomes of animals and some plants. Different gene combinations reside at these mating-type (MAT) loci and confer sexual identity; invariably they encode homeodomain, alpha-box, or high mobility group (HMG)-domain transcription factors. So far, MAT loci have been characterized from a single monophyletic clade of fungi, the Dikarya (the ascomycetes and basidiomycetes), and the ancestral state and evolutionary history of these loci have remained a mystery. Mating in the basal members of the kingdom has been less well studied, and even their precise taxonomic inter-relationships are still obscure. Here we apply bioinformatic and genetic mapping to identify the sex-determining (sex) region in Phycomyces blakesleeanus (Zygomycota), which represents an early branch within the fungi. Each sex allele contains a single gene that encodes an HMG-domain protein, implicating the HMG-domain proteins as an earlier form of fungal MAT loci. Additionally, one allele also contains a copy of a unique, chromosome-specific repetitive element, suggesting a generalized mechanism for the earliest steps in the evolution of sex determination and sex chromosome structure in eukaryotes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Idnurm, Alexander -- Walton, Felicia J -- Floyd, Anna -- Heitman, Joseph -- England -- Nature. 2008 Jan 10;451(7175):193-6. doi: 10.1038/nature06453.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18185588" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; Chromosomes, Fungal/genetics ; Computational Biology ; Fertility/genetics ; Fungal Proteins/chemistry/genetics ; Fungi/classification/*genetics ; Genes, Fungal/*genetics ; Genes, Mating Type, Fungal/genetics ; HMG-Box Domains ; Heterozygote ; High Mobility Group Proteins/chemistry/genetics ; Molecular Sequence Data ; *Phylogeny ; Recombination, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; *Sex ; *Sex Determination Processes
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    Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery (2008)
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    Publication Date: 2008-07-11
    Description: Polo-like kinase-1 (PLK1) is an essential mitotic kinase regulating multiple aspects of the cell division process. Activation of PLK1 requires phosphorylation of a conserved threonine residue (Thr 210) in the T-loop of the PLK1 kinase domain, but the kinase responsible for this has not yet been affirmatively identified. Here we show that in human cells PLK1 activation occurs several hours before entry into mitosis, and requires aurora A (AURKA, also known as STK6)-dependent phosphorylation of Thr 210. We find that aurora A can directly phosphorylate PLK1 on Thr 210, and that activity of aurora A towards PLK1 is greatly enhanced by Bora (also known as C13orf34 and FLJ22624), a known cofactor for aurora A (ref. 7). We show that Bora/aurora-A-dependent phosphorylation is a prerequisite for PLK1 to promote mitotic entry after a checkpoint-dependent arrest. Importantly, expression of a PLK1-T210D phospho-mimicking mutant partially overcomes the requirement for aurora A in checkpoint recovery. Taken together, these data demonstrate that the initial activation of PLK1 is a primary function of aurora A.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Macurek, Libor -- Lindqvist, Arne -- Lim, Dan -- Lampson, Michael A -- Klompmaker, Rob -- Freire, Raimundo -- Clouin, Christophe -- Taylor, Stephen S -- Yaffe, Michael B -- Medema, Rene H -- CA112967/CA/NCI NIH HHS/ -- GM-60594/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 4;455(7209):119-23. doi: 10.1038/nature07185. Epub 2008 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18615013" target="_blank"〉PubMed〈/a〉
    Keywords: Aurora Kinase A ; Aurora Kinases ; Cell Cycle/*physiology ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line ; DNA Damage ; Enzyme Activation ; Humans ; Mitosis ; Molecular Sequence Data ; Phosphorylation ; Phosphothreonine/metabolism ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Proto-Oncogene Proteins/genetics/*metabolism ; Time Factors
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    Type IV collagens regulate BMP signalling in Drosophila (2008)
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    Publication Date: 2008-08-15
    Description: Dorsal-ventral patterning in vertebrate and invertebrate embryos is mediated by a conserved system of secreted proteins that establishes a bone morphogenetic protein (BMP) gradient. Although the Drosophila embryonic Decapentaplegic (Dpp) gradient has served as a model to understand how morphogen gradients are established, no role for the extracellular matrix has been previously described. Here we show that type IV collagen extracellular matrix proteins bind Dpp and regulate its signalling in both the Drosophila embryo and ovary. We provide evidence that the interaction between Dpp and type IV collagen augments Dpp signalling in the embryo by promoting gradient formation, yet it restricts the signalling range in the ovary through sequestration of the Dpp ligand. Together, these results identify a critical function of type IV collagens in modulating Dpp in the extracellular space during Drosophila development. On the basis of our findings that human type IV collagen binds BMP4, we predict that this role of type IV collagens will be conserved.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiaomeng -- Harris, Robin E -- Bayston, Laura J -- Ashe, Hilary L -- BBS/B/11672/Biotechnology and Biological Sciences Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2008 Sep 4;455(7209):72-7. doi: 10.1038/nature07214.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18701888" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Body Patterning ; Bone Morphogenetic Proteins/genetics/*metabolism ; Cell Count ; Collagen Type IV/genetics/*metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/embryology/genetics/*metabolism ; Female ; Male ; Ovary/cytology/metabolism ; Protein Binding ; *Signal Transduction ; Transforming Growth Factor beta/genetics/metabolism
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    Translational control of intron splicing in eukaryotes (2008)
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    Publication Date: 2008-01-19
    Description: Most eukaryotic genes are interrupted by non-coding introns that must be accurately removed from pre-messenger RNAs to produce translatable mRNAs. Splicing is guided locally by short conserved sequences, but genes typically contain many potential splice sites, and the mechanisms specifying the correct sites remain poorly understood. In most organisms, short introns recognized by the intron definition mechanism cannot be efficiently predicted solely on the basis of sequence motifs. In multicellular eukaryotes, long introns are recognized through exon definition and most genes produce multiple mRNA variants through alternative splicing. The nonsense-mediated mRNA decay (NMD) pathway may further shape the observed sets of variants by selectively degrading those containing premature termination codons, which are frequently produced in mammals. Here we show that the tiny introns of the ciliate Paramecium tetraurelia are under strong selective pressure to cause premature termination of mRNA translation in the event of intron retention, and that the same bias is observed among the short introns of plants, fungi and animals. By knocking down the two P. tetraurelia genes encoding UPF1, a protein that is crucial in NMD, we show that the intrinsic efficiency of splicing varies widely among introns and that NMD activity can significantly reduce the fraction of unspliced mRNAs. The results suggest that, independently of alternative splicing, species with large intron numbers universally rely on NMD to compensate for suboptimal splicing efficiency and accuracy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jaillon, Olivier -- Bouhouche, Khaled -- Gout, Jean-Francois -- Aury, Jean-Marc -- Noel, Benjamin -- Saudemont, Baptiste -- Nowacki, Mariusz -- Serrano, Vincent -- Porcel, Betina M -- Segurens, Beatrice -- Le Mouel, Anne -- Lepere, Gersende -- Schachter, Vincent -- Betermier, Mireille -- Cohen, Jean -- Wincker, Patrick -- Sperling, Linda -- Duret, Laurent -- Meyer, Eric -- England -- Nature. 2008 Jan 17;451(7176):359-62. doi: 10.1038/nature06495.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genoscope (CEA), 2 rue Gaston Cremieux CP5706, 91057 Evry, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18202663" target="_blank"〉PubMed〈/a〉
    Keywords: *Alternative Splicing ; Animals ; Base Sequence ; Codon, Terminator/genetics ; Computational Biology ; Eukaryotic Cells/*metabolism ; Expressed Sequence Tags ; Genes, Protozoan/genetics ; Introns/*genetics ; Molecular Sequence Data ; Paramecium/*genetics ; *Protein Biosynthesis ; Protozoan Proteins/genetics/metabolism ; RNA Interference ; RNA Stability ; RNA, Protozoan/genetics/metabolism
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    Neuroscience: a complex in psychosis (2008)
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    Publication Date: 2008-03-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Snyder, Solomon H -- England -- Nature. 2008 Mar 6;452(7183):38-9. doi: 10.1038/452038a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18322519" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/metabolism ; Humans ; Mice ; Protein Binding ; Psychotic Disorders/drug therapy/*metabolism ; Receptor, Serotonin, 5-HT2A/deficiency/*metabolism ; Receptors, Metabotropic Glutamate/agonists/antagonists & inhibitors/*metabolism ; Schizophrenia/metabolism
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    Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes (2008)
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    Publication Date: 2008-04-12
    Description: RNA interference (RNAi) is a mechanism by which double-stranded RNAs (dsRNAs) suppress specific transcripts in a sequence-dependent manner. dsRNAs are processed by Dicer to 21-24-nucleotide small interfering RNAs (siRNAs) and then incorporated into the argonaute (Ago) proteins. Gene regulation by endogenous siRNAs has been observed only in organisms possessing RNA-dependent RNA polymerase (RdRP). In mammals, where no RdRP activity has been found, biogenesis and function of endogenous siRNAs remain largely unknown. Here we show, using mouse oocytes, that endogenous siRNAs are derived from naturally occurring dsRNAs and have roles in the regulation of gene expression. By means of deep sequencing, we identify a large number of both approximately 25-27-nucleotide Piwi-interacting RNAs (piRNAs) and approximately 21-nucleotide siRNAs corresponding to messenger RNAs or retrotransposons in growing oocytes. piRNAs are bound to Mili and have a role in the regulation of retrotransposons. siRNAs are exclusively mapped to retrotransposons or other genomic regions that produce transcripts capable of forming dsRNA structures. Inverted repeat structures, bidirectional transcription and antisense transcripts from various loci are sources of the dsRNAs. Some precursor transcripts of siRNAs are derived from expressed pseudogenes, indicating that one role of pseudogenes is to adjust the level of the founding source mRNA through RNAi. Loss of Dicer or Ago2 results in decreased levels of siRNAs and increased levels of retrotransposon and protein-coding transcripts complementary to the siRNAs. Thus, the RNAi pathway regulates both protein-coding transcripts and retrotransposons in mouse oocytes. Our results reveal a role for endogenous siRNAs in mammalian oocytes and show that organisms lacking RdRP activity can produce functional endogenous siRNAs from naturally occurring dsRNAs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watanabe, Toshiaki -- Totoki, Yasushi -- Toyoda, Atsushi -- Kaneda, Masahiro -- Kuramochi-Miyagawa, Satomi -- Obata, Yayoi -- Chiba, Hatsune -- Kohara, Yuji -- Kono, Tomohiro -- Nakano, Toru -- Surani, M Azim -- Sakaki, Yoshiyuki -- Sasaki, Hiroyuki -- England -- Nature. 2008 May 22;453(7194):539-43. doi: 10.1038/nature06908. Epub 2008 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima 411-8540, Japan. toshwata@lab.nig.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18404146" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; Eukaryotic Initiation Factor-2/deficiency/genetics/metabolism ; Female ; Gene Expression Regulation, Developmental ; Gene Library ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Oocytes/growth & development/*metabolism ; Polymerase Chain Reaction ; Pseudogenes/genetics ; *RNA Interference ; RNA, Double-Stranded/*genetics/*metabolism ; RNA, Messenger/*genetics/metabolism ; RNA, Small Interfering/*genetics/*metabolism ; Retroelements/genetics ; Ribonuclease III/deficiency/genetics/metabolism
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    Localization and functionality of microsporidian iron-sulphur cluster assembly proteins (2008)
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    Publication Date: 2008-03-04
    Description: Microsporidia are highly specialized obligate intracellular parasites of other eukaryotes (including humans) that show extreme reduction at the molecular, cellular and biochemical level. Although microsporidia have long been considered as early branching eukaryotes that lack mitochondria, they have recently been shown to contain a tiny mitochondrial remnant called a mitosome. The function of the mitosome is unknown, because microsporidians lack the genes for canonical mitochondrial functions, such as aerobic respiration and haem biosynthesis. However, microsporidial genomes encode several components of the mitochondrial iron-sulphur (Fe-S) cluster assembly machinery. Here we provide experimental insights into the metabolic function and localization of these proteins. We cloned, functionally characterized and localized homologues of several central mitochondrial Fe-S cluster assembly components for the microsporidians Encephalitozoon cuniculi and Trachipleistophora hominis. Several microsporidial proteins can functionally replace their yeast counterparts in Fe-S protein biogenesis. In E. cuniculi, the iron (frataxin) and sulphur (cysteine desulphurase, Nfs1) donors and the scaffold protein (Isu1) co-localize with mitochondrial Hsp70 to the mitosome, consistent with it being the functional site for Fe-S cluster biosynthesis. In T. hominis, mitochondrial Hsp70 and the essential sulphur donor (Nfs1) are still in the mitosome, but surprisingly the main pools of Isu1 and frataxin are cytosolic, creating a conundrum of how these key components of Fe-S cluster biosynthesis coordinate their function. Together, our studies identify the essential biosynthetic process of Fe-S protein assembly as a key function of microsporidian mitosomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldberg, Alina V -- Molik, Sabine -- Tsaousis, Anastasios D -- Neumann, Karina -- Kuhnke, Grit -- Delbac, Frederic -- Vivares, Christian P -- Hirt, Robert P -- Lill, Roland -- Embley, T Martin -- England -- Nature. 2008 Apr 3;452(7187):624-8. doi: 10.1038/nature06606. Epub 2008 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cell and Molecular Biosciences, The Catherine Cookson Building, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18311129" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cloning, Molecular ; Fungal Proteins/genetics/*metabolism ; HSP70 Heat-Shock Proteins/genetics/metabolism ; Iron-Binding Proteins/genetics/metabolism ; Iron-Sulfur Proteins/*biosynthesis/genetics/metabolism ; Microsporidia/cytology/genetics/*metabolism ; Mitochondria/metabolism ; Molecular Sequence Data ; Protein Transport ; Rabbits ; Saccharomyces cerevisiae/cytology/genetics/metabolism
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    Biochemistry: Cells enforce an ion curtain (2008)
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    Publication Date: 2008-10-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berks, Ben C -- England -- Nature. 2008 Oct 23;455(7216):1043-4. doi: 10.1038/4551043a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18948937" target="_blank"〉PubMed〈/a〉
    Keywords: Cytoplasm/metabolism ; Metals/*metabolism ; Periplasm/metabolism ; Periplasmic Proteins/*metabolism ; Protein Binding ; Protein Folding ; Protein Transport ; Synechocystis/metabolism
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    Antigenic variation in Giardia lamblia is regulated by RNA interference (2008)
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    Publication Date: 2008-12-17
    Description: Giardia lamblia (also called Giardia intestinalis) is one of the most common intestinal parasites of humans. To evade the host's immune response, Giardia undergoes antigenic variation-a process that allows the parasite to develop chronic and recurrent infections. From a repertoire of approximately 190 variant-specific surface protein (VSP)-coding genes, Giardia expresses only one VSP on the surface of each parasite at a particular time, but spontaneously switches to a different VSP by unknown mechanisms. Here we show that regulation of VSP expression involves a system comprising RNA-dependent RNA polymerase, Dicer and Argonaute, known components of the RNA interference machinery. Clones expressing a single surface antigen efficiently transcribe several VSP genes but only accumulate transcripts encoding the VSP to be expressed. Detection of antisense RNAs corresponding to the silenced VSP genes and small RNAs from the silenced but not for the expressed vsp implicate the RNA interference pathway in antigenic variation. Remarkably, silencing of Dicer and RNA-dependent RNA polymerase leads to a change from single to multiple VSP expression in individual parasites.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Prucca, Cesar G -- Slavin, Ileana -- Quiroga, Rodrigo -- Elias, Eliana V -- Rivero, Fernando D -- Saura, Alicia -- Carranza, Pedro G -- Lujan, Hugo D -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Dec 11;456(7223):750-4. doi: 10.1038/nature07585.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratorio de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad Catolica de Cordoba, Cordoba X5004ASK, Argentina.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19079052" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Antigenic Variation/*genetics/immunology ; Antigens, Protozoan/*genetics/immunology ; Antigens, Surface/*genetics/immunology ; *Gene Expression Regulation ; Gene Knockdown Techniques ; Giardia lamblia/*genetics/immunology ; Molecular Sequence Data ; Protozoan Proteins/genetics/immunology ; *RNA Interference ; RNA, Protozoan/metabolism ; Ribonuclease III/metabolism
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    Innate immunity and intestinal microbiota in the development of Type 1 diabetes (2008)
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    Publication Date: 2008-09-23
    Description: Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T-cell-mediated destruction of insulin-producing beta-cells. Its incidence has increased during the past several decades in developed countries, suggesting that changes in the environment (including the human microbial environment) may influence disease pathogenesis. The incidence of spontaneous T1D in non-obese diabetic (NOD) mice can be affected by the microbial environment in the animal housing facility or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products. Here we show that specific pathogen-free NOD mice lacking MyD88 protein (an adaptor for multiple innate immune receptors that recognize microbial stimuli) do not develop T1D. The effect is dependent on commensal microbes because germ-free MyD88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free MyD88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates T1D. We also find that MyD88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free MyD88-negative NOD donors attenuates T1D in germ-free NOD recipients. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying T1D predisposition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574766/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574766/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Li -- Ley, Ruth E -- Volchkov, Pavel Yu -- Stranges, Peter B -- Avanesyan, Lia -- Stonebraker, Austin C -- Hu, Changyun -- Wong, F Susan -- Szot, Gregory L -- Bluestone, Jeffrey A -- Gordon, Jeffrey I -- Chervonsky, Alexander V -- DK063452/DK/NIDDK NIH HHS/ -- DK30292/DK/NIDDK NIH HHS/ -- DK42086/DK/NIDDK NIH HHS/ -- DK45735/DK/NIDDK NIH HHS/ -- DK70977/DK/NIDDK NIH HHS/ -- P30 DK042086/DK/NIDDK NIH HHS/ -- P30 DK042086-16/DK/NIDDK NIH HHS/ -- P30 DK045735/DK/NIDDK NIH HHS/ -- P30 DK045735-10/DK/NIDDK NIH HHS/ -- P30 DK045735-119006/DK/NIDDK NIH HHS/ -- P30 DK056341/DK/NIDDK NIH HHS/ -- P30 DK056341-07/DK/NIDDK NIH HHS/ -- P30 DK056341-08/DK/NIDDK NIH HHS/ -- P30 DK063720/DK/NIDDK NIH HHS/ -- P30 DK063720-01/DK/NIDDK NIH HHS/ -- P30 DK63720/DK/NIDDK NIH HHS/ -- R01 DK030292/DK/NIDDK NIH HHS/ -- R01 DK030292-24/DK/NIDDK NIH HHS/ -- R01 DK070977/DK/NIDDK NIH HHS/ -- R01 DK070977-04/DK/NIDDK NIH HHS/ -- R21 DK063452/DK/NIDDK NIH HHS/ -- R21 DK063452-02/DK/NIDDK NIH HHS/ -- R37 AI046643/AI/NIAID NIH HHS/ -- R37 AI046643-10/AI/NIAID NIH HHS/ -- R37 AI46643/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Oct 23;455(7216):1109-13. doi: 10.1038/nature07336. Epub 2008 Sep 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18806780" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteria/classification/genetics/*immunology/isolation & purification ; CD8-Positive T-Lymphocytes/immunology ; Diabetes Mellitus, Type 1/genetics/*immunology/*microbiology ; Female ; Immunity, Innate/genetics/*immunology ; Interferon-gamma/immunology ; Intestines/*microbiology ; Islets of Langerhans/pathology ; Male ; Mice ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Molecular Sequence Data ; Myeloid Differentiation Factor 88/genetics ; Phylogeny ; Specific Pathogen-Free Organisms ; Time Factors
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    Prolyl 4-hydroxylation regulates Argonaute 2 stability (2008)
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    Publication Date: 2008-08-12
    Description: Human Argonaute (Ago) proteins are essential components of the RNA-induced silencing complexes (RISCs). Argonaute 2 (Ago2) has a P-element-induced wimpy testis (PIWI) domain, which folds like RNase H and is responsible for target RNA cleavage in RNA interference. Proteins such as Dicer, TRBP, MOV10, RHA, RCK/p54 and KIAA1093 associate with Ago proteins and participate in small RNA processing, RISC loading and localization of Ago proteins in the cytoplasmic messenger RNA processing bodies. However, mechanisms that regulate RNA interference remain obscure. Here we report physical interactions between Ago2 and the alpha-(P4H-alpha(I)) and beta-(P4H-beta) subunits of the type I collagen prolyl-4-hydroxylase (C-P4H(I)). Mass spectrometric analysis identified hydroxylation of the endogenous Ago2 at proline 700. In vitro, both Ago2 and Ago4 seem to be more efficiently hydroxylated than Ago1 and Ago3 by recombinant human C-P4H(I). Importantly, human cells depleted of P4H-alpha(I) or P4H-beta by short hairpin RNA and P4H-alpha(I) null mouse embryonic fibroblast cells showed reduced stability of Ago2 and impaired short interfering RNA programmed RISC activity. Furthermore, mutation of proline 700 to alanine also resulted in destabilization of Ago2, thus linking Ago2 P700 and hydroxylation at this residue to its stability regulation. These findings identify hydroxylation as a post-translational modification important for Ago2 stability and effective RNA interference.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661850/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661850/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qi, Hank H -- Ongusaha, Pat P -- Myllyharju, Johanna -- Cheng, Dongmei -- Pakkanen, Outi -- Shi, Yujiang -- Lee, Sam W -- Peng, Junmin -- Shi, Yang -- AG025688/AG/NIA NIH HHS/ -- GM53874/GM/NIGMS NIH HHS/ -- R01 GM053874/GM/NIGMS NIH HHS/ -- R01 GM053874-15/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 18;455(7211):421-4. doi: 10.1038/nature07186. Epub 2008 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School, New Research Building 854, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18690212" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; Enzyme Stability ; Eukaryotic Initiation Factor-2/*chemistry/genetics/*metabolism ; HeLa Cells ; Humans ; Hydroxylation ; Mice ; MicroRNAs/genetics ; Proline/*metabolism ; Protein Binding ; Protein Subunits ; RNA-Induced Silencing Complex/genetics/metabolism
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    Control of segment number in vertebrate embryos (2008)
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    Publication Date: 2008-06-20
    Description: The vertebrate body axis is subdivided into repeated segments, best exemplified by the vertebrae that derive from embryonic somites. The number of somites is precisely defined for any given species but varies widely from one species to another. To determine the mechanism controlling somite number, we have compared somitogenesis in zebrafish, chicken, mouse and corn snake embryos. Here we present evidence that in all of these species a similar 'clock-and-wavefront' mechanism operates to control somitogenesis; in all of them, somitogenesis is brought to an end through a process in which the presomitic mesoderm, having first increased in size, gradually shrinks until it is exhausted, terminating somite formation. In snake embryos, however, the segmentation clock rate is much faster relative to developmental rate than in other amniotes, leading to a greatly increased number of smaller-sized somites.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gomez, Celine -- Ozbudak, Ertugrul M -- Wunderlich, Joshua -- Baumann, Diana -- Lewis, Julian -- Pourquie, Olivier -- Cancer Research UK/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Jul 17;454(7202):335-9. doi: 10.1038/nature07020. Epub 2008 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18563087" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Body Patterning/genetics ; Chick Embryo/*embryology ; Gene Expression Regulation, Developmental ; Mice/*embryology ; Molecular Sequence Data ; Snakes/*embryology ; Somites/*embryology ; Time Factors ; Zebrafish/*embryology
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    A peptide deformylase-ribosome complex reveals mechanism of nascent chain processing (2008)
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    Publication Date: 2008-02-22
    Description: Messenger-RNA-directed protein synthesis is accomplished by the ribosome. In eubacteria, this complex process is initiated by a specialized transfer RNA charged with formylmethionine (tRNA(fMet)). The amino-terminal formylated methionine of all bacterial nascent polypeptides blocks the reactive amino group to prevent unfavourable side-reactions and to enhance the efficiency of translation initiation. The first enzymatic factor that processes nascent chains is peptide deformylase (PDF); it removes this formyl group as polypeptides emerge from the ribosomal tunnel and before the newly synthesized proteins can adopt their native fold, which may bury the N terminus. Next, the N-terminal methionine is excised by methionine aminopeptidase. Bacterial PDFs are metalloproteases sharing a conserved N-terminal catalytic domain. All Gram-negative bacteria, including Escherichia coli, possess class-1 PDFs characterized by a carboxy-terminal alpha-helical extension. Studies focusing on PDF as a target for antibacterial drugs have not revealed the mechanism of its co-translational mode of action despite indications in early work that it co-purifies with ribosomes. Here we provide biochemical evidence that E. coli PDF interacts directly with the ribosome via its C-terminal extension. Crystallographic analysis of the complex between the ribosome-interacting helix of PDF and the ribosome at 3.7 A resolution reveals that the enzyme orients its active site towards the ribosomal tunnel exit for efficient co-translational processing of emerging nascent chains. Furthermore, we have found that the interaction of PDF with the ribosome enhances cell viability. These results provide the structural basis for understanding the coupling between protein synthesis and enzymatic processing of nascent chains, and offer insights into the interplay of PDF with the ribosome-associated chaperone trigger factor.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bingel-Erlenmeyer, Rouven -- Kohler, Rebecca -- Kramer, Gunter -- Sandikci, Arzu -- Antolic, Snjezana -- Maier, Timm -- Schaffitzel, Christiane -- Wiedmann, Brigitte -- Bukau, Bernd -- Ban, Nenad -- England -- Nature. 2008 Mar 6;452(7183):108-11. doi: 10.1038/nature06683. Epub 2008 Feb 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18288106" target="_blank"〉PubMed〈/a〉
    Keywords: Amidohydrolases/*chemistry/deficiency/genetics/*metabolism ; Amino Acid Sequence ; Arabinose/metabolism ; Binding Sites ; Crystallography, X-Ray ; Escherichia coli/*enzymology/genetics/growth & development/metabolism ; Genetic Complementation Test ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; N-Formylmethionine/metabolism ; Peptidylprolyl Isomerase/metabolism ; Protein Binding ; *Protein Biosynthesis ; *Protein Processing, Post-Translational ; Protein Structure, Secondary ; RNA, Transfer, Met/genetics/metabolism ; Ribosome Subunits/chemistry/metabolism ; Ribosomes/*chemistry/*metabolism
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    Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex (2008)
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    Publication Date: 2008-07-04
    Description: Neurotrophins (NTs) are important regulators for the survival, differentiation and maintenance of different peripheral and central neurons. NTs bind to two distinct classes of glycosylated receptor: the p75 neurotrophin receptor (p75(NTR)) and tyrosine kinase receptors (Trks). Whereas p75(NTR) binds to all NTs, the Trk subtypes are specific for each NT. The question of whether NTs stimulate p75(NTR) by inducing receptor homodimerization is still under debate. Here we report the 2.6-A resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75(NTR). In contrast to the previously reported asymmetric complex structure, which contains a dimer of nerve growth factor (NGF) bound to a single ectodomain of deglycosylated p75(NTR) (ref. 3), we show that NT-3 forms a central homodimer around which two glycosylated p75(NTR) molecules bind symmetrically. Symmetrical binding occurs along the NT-3 interfaces, resulting in a 2:2 ligand-receptor cluster. A comparison of the symmetrical and asymmetric structures reveals significant differences in ligand-receptor interactions and p75(NTR) conformations. Biochemical experiments indicate that both NT-3 and NGF bind to p75(NTR) with 2:2 stoichiometry in solution, whereas the 2:1 complexes are the result of artificial deglycosylation. We therefore propose that the symmetrical 2:2 complex reflects a native state of p75(NTR) activation at the cell surface. These results provide a model for NTs-p75(NTR) recognition and signal generation, as well as insights into coordination between p75(NTR) and Trks.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gong, Yong -- Cao, Peng -- Yu, Hong-jun -- Jiang, Tao -- England -- Nature. 2008 Aug 7;454(7205):789-93. doi: 10.1038/nature07089. Epub 2008 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18596692" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Crystallography, X-Ray ; Dimerization ; Glycosylation ; Humans ; Ligands ; Models, Molecular ; Neurotrophin 3/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Receptor, Nerve Growth Factor/*chemistry/genetics/*metabolism ; Spodoptera
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    Identification of a serotonin/glutamate receptor complex implicated in psychosis (2008)
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    Publication Date: 2008-02-26
    Description: The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743172/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743172/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gonzalez-Maeso, Javier -- Ang, Rosalind L -- Yuen, Tony -- Chan, Pokman -- Weisstaub, Noelia V -- Lopez-Gimenez, Juan F -- Zhou, Mingming -- Okawa, Yuuya -- Callado, Luis F -- Milligan, Graeme -- Gingrich, Jay A -- Filizola, Marta -- Meana, J Javier -- Sealfon, Stuart C -- G9811527/Medical Research Council/United Kingdom -- P01 DA012923/DA/NIDA NIH HHS/ -- P01 DA012923-06A10004/DA/NIDA NIH HHS/ -- T32 DA007135/DA/NIDA NIH HHS/ -- T32 DA007135-25S1/DA/NIDA NIH HHS/ -- T32 GM062754/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Mar 6;452(7183):93-7. doi: 10.1038/nature06612. Epub 2008 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. javier.maeso@mssm.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18297054" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/cytology/metabolism ; Cell Line ; Cells, Cultured ; Down-Regulation ; Hallucinogens/metabolism/pharmacology ; Humans ; Mice ; Models, Molecular ; Multiprotein Complexes/chemistry/genetics/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Psychotic Disorders/drug therapy/genetics/*metabolism ; Receptor, Serotonin, 5-HT2A/analysis/deficiency/genetics/*metabolism ; Receptors, Metabotropic Glutamate/analysis/antagonists & ; inhibitors/genetics/*metabolism ; Schizophrenia/metabolism ; Signal Transduction/drug effects ; Up-Regulation
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    A new class of anthelmintics effective against drug-resistant nematodes (2008)
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    Publication Date: 2008-03-14
    Description: Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaminsky, Ronald -- Ducray, Pierre -- Jung, Martin -- Clover, Ralph -- Rufener, Lucien -- Bouvier, Jacques -- Weber, Sandra Schorderet -- Wenger, Andre -- Wieland-Berghausen, Susanne -- Goebel, Thomas -- Gauvry, Noelle -- Pautrat, Francois -- Skripsky, Thomas -- Froelich, Olivier -- Komoin-Oka, Clarisse -- Westlund, Bethany -- Sluder, Ann -- Maser, Pascal -- England -- Nature. 2008 Mar 13;452(7184):176-80. doi: 10.1038/nature06722.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Centre de Recherche Sante Animale, CH-1566 St Aubin (FR), Switzerland. ronald.kaminsky@novartis.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337814" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Amino Acid Sequence ; Aminoacetonitrile/adverse effects/*analogs & ; derivatives/pharmacokinetics/*pharmacology ; Animals ; Anthelmintics/chemistry/*classification/pharmacokinetics/*pharmacology ; Caenorhabditis elegans/drug effects/genetics/metabolism ; Caenorhabditis elegans Proteins/chemistry/genetics/metabolism ; Cattle ; Cattle Diseases/drug therapy/parasitology ; *Drug Resistance/genetics ; Larva/drug effects/genetics ; Molecular Sequence Data ; Nematoda/*drug effects/genetics/physiology ; Parasitic Diseases, Animal/drug therapy/*parasitology ; Receptors, Nicotinic/chemistry/genetics/metabolism ; Sheep/parasitology ; Sheep Diseases/drug therapy/parasitology
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    An endogenous small interfering RNA pathway in Drosophila (2008)
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    Publication Date: 2008-05-09
    Description: Drosophila endogenous small RNAs are categorized according to their mechanisms of biogenesis and the Argonaute protein to which they bind. MicroRNAs are a class of ubiquitously expressed RNAs of approximately 22 nucleotides in length, which arise from structured precursors through the action of Drosha-Pasha and Dicer-1-Loquacious complexes. These join Argonaute-1 to regulate gene expression. A second endogenous small RNA class, the Piwi-interacting RNAs, bind Piwi proteins and suppress transposons. Piwi-interacting RNAs are restricted to the gonad, and at least a subset of these arises by Piwi-catalysed cleavage of single-stranded RNAs. Here we show that Drosophila generates a third small RNA class, endogenous small interfering RNAs, in both gonadal and somatic tissues. Production of these RNAs requires Dicer-2, but a subset depends preferentially on Loquacious rather than the canonical Dicer-2 partner, R2D2 (ref. 14). Endogenous small interfering RNAs arise both from convergent transcription units and from structured genomic loci in a tissue-specific fashion. They predominantly join Argonaute-2 and have the capacity, as a class, to target both protein-coding genes and mobile elements. These observations expand the repertoire of small RNAs in Drosophila, adding a class that blurs distinctions based on known biogenesis mechanisms and functional roles.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895258/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895258/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Czech, Benjamin -- Malone, Colin D -- Zhou, Rui -- Stark, Alexander -- Schlingeheyde, Catherine -- Dus, Monica -- Perrimon, Norbert -- Kellis, Manolis -- Wohlschlegel, James A -- Sachidanandam, Ravi -- Hannon, Gregory J -- Brennecke, Julius -- U01 HG004264/HG/NHGRI NIH HHS/ -- U01 HG004264-02/HG/NHGRI NIH HHS/ -- U54 HG004555/HG/NHGRI NIH HHS/ -- U54 HG004555-01/HG/NHGRI NIH HHS/ -- U54 HG004570/HG/NHGRI NIH HHS/ -- U54 HG004570-01/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Jun 5;453(7196):798-802. doi: 10.1038/nature07007. Epub 2008 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18463631" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; Cell Line ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/cytology/enzymology/*genetics/metabolism ; Protein Binding ; RNA Helicases/metabolism ; *RNA Interference ; RNA, Small Interfering/biosynthesis/genetics/*metabolism ; RNA-Binding Proteins/metabolism ; RNA-Induced Silencing Complex/genetics/metabolism ; Retroelements/genetics ; Ribonuclease III
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    Drosophila endogenous small RNAs bind to Argonaute 2 in somatic cells (2008)
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    Publication Date: 2008-05-09
    Description: RNA silencing is a conserved mechanism in which small RNAs trigger various forms of sequence-specific gene silencing by guiding Argonaute complexes to target RNAs by means of base pairing. RNA silencing is thought to have evolved as a form of nucleic-acid-based immunity to inactivate viruses and transposable elements. Although the activity of transposable elements in animals has been thought largely to be restricted to the germ line, recent studies have shown that they may also actively transpose in somatic cells, creating somatic mosaicism in animals. In the Drosophila germ line, Piwi-interacting RNAs arise from repetitive intergenic elements including retrotransposons by a Dicer-independent pathway and function through the Piwi subfamily of Argonautes to ensure silencing of retrotransposons. Here we show that, in cultured Drosophila S2 cells, Argonaute 2 (AGO2), an AGO subfamily member of Argonautes, associates with endogenous small RNAs of 20-22 nucleotides in length, which we have collectively named endogenous short interfering RNAs (esiRNAs). esiRNAs can be divided into two groups: one that mainly corresponds to a subset of retrotransposons, and the other that arises from stem-loop structures. esiRNAs are produced in a Dicer-2-dependent manner from distinctive genomic loci, are modified at their 3' ends and can direct AGO2 to cleave target RNAs. Mutations in Dicer-2 caused an increase in retrotransposon transcripts. Together, our findings indicate that different types of small RNAs and Argonautes are used to repress retrotransposons in germline and somatic cells in Drosophila.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kawamura, Yoshinori -- Saito, Kuniaki -- Kin, Taishin -- Ono, Yukiteru -- Asai, Kiyoshi -- Sunohara, Takafumi -- Okada, Tomoko N -- Siomi, Mikiko C -- Siomi, Haruhiko -- England -- Nature. 2008 Jun 5;453(7196):793-7. doi: 10.1038/nature06938. Epub 2008 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18463636" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; Cell Line ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*cytology/enzymology/genetics/*metabolism ; Eukaryotic Initiation Factors ; Germ Cells/metabolism ; Mosaicism ; Polymerase Chain Reaction ; Protein Binding ; RNA Helicases/genetics/metabolism ; RNA Interference ; RNA, Small Interfering/genetics/*metabolism ; RNA-Induced Silencing Complex/*metabolism ; Retroelements/genetics ; Ribonuclease III
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    Life without RNase P (2008)
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    Publication Date: 2008-05-03
    Description: The universality of ribonuclease P (RNase P), the ribonucleoprotein essential for transfer RNA (tRNA) 5' maturation, is challenged in the archaeon Nanoarchaeum equitans. Neither extensive computational analysis of the genome nor biochemical tests in cell extracts revealed the existence of this enzyme. Here we show that the conserved placement of its tRNA gene promoters allows the synthesis of leaderless tRNAs, whose presence was verified by the observation of 5' triphosphorylated mature tRNA species. Initiation of tRNA gene transcription requires a purine, which coincides with the finding that tRNAs with a cytosine in position 1 display unusually extended 5' termini with an extra purine residue. These tRNAs were shown to be substrates for their cognate aminoacyl-tRNA synthetases. These findings demonstrate how nature can cope with the loss of the universal and supposedly ancient RNase P through genomic rearrangement at tRNA genes under the pressure of genome condensation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Randau, Lennart -- Schroder, Imke -- Soll, Dieter -- England -- Nature. 2008 May 1;453(7191):120-3. doi: 10.1038/nature06833.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520-8114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18451863" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acyl-tRNA Synthetases/metabolism ; Aminoacylation ; Base Sequence ; *Evolution, Molecular ; Gene Deletion ; Genes, Archaeal/*genetics ; Models, Biological ; Molecular Sequence Data ; Nanoarchaeota/cytology/enzymology/*genetics ; Phosphorylation ; Promoter Regions, Genetic/*genetics ; RNA, Archaeal/*genetics/metabolism ; RNA, Transfer/*genetics/metabolism ; Ribonuclease P/*deficiency/metabolism ; Substrate Specificity ; Transcription, Genetic/genetics
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    A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex (2009)
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    Publication Date: 2009-01-14
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340503/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340503/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kelly, Bernard T -- McCoy, Airlie J -- Spate, Kira -- Miller, Sharon E -- Evans, Philip R -- Honing, Stefan -- Owen, David J -- 090909/Wellcome Trust/United Kingdom -- MC_U105178845/Medical Research Council/United Kingdom -- England -- Nature. 2008 Dec 18;456(7224):976-79. doi: 10.1038/nature07422.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19140243" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Protein Complex 2/*chemistry/genetics/*metabolism ; Amino Acid Motifs ; Animals ; Antigens, CD4/*chemistry/*metabolism ; Binding Sites ; Conserved Sequence ; *Endocytosis ; Humans ; Leucine/*metabolism ; Mice ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry/genetics/metabolism ; Rats
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    Multimodal warning signals for a multiple predator world (2008)
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    Publication Date: 2008-09-05
    Description: Aposematism is an anti-predator defence, dependent on a predator's ability to associate unprofitable prey with a prey-borne signal. Multimodal signals should vary in efficacy according to the sensory systems of different predators; however, until now, the impact of multiple predator classes on the evolution of these signals had not been investigated. Here, using a community-level molecular phylogeny to generate phylogenetically independent contrasts, we show that warning signals of tiger moths vary according to the seasonal and daily activity patterns of birds and bats-predators with divergent sensory capacities. Many tiger moths advertise chemical defence using conspicuous colouration and/or ultrasonic clicks. During spring, when birds are active and bats less so, we found that tiger moths did not produce ultrasonic clicks. Throughout both spring and summer, tiger moths most active during the day were visually conspicuous. Those species emerging later in the season produced ultrasonic clicks; those that were most nocturnal were visually cryptic. Our results indicate that selective pressures from multiple predator classes have distinct roles in the evolution of multimodal warning displays now effective against a single predator class. We also suggest that the evolution of acoustic warning signals may lack the theoretical difficulties associated with the origination of conspicuous colouration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ratcliffe, John M -- Nydam, Marie L -- England -- Nature. 2008 Sep 4;455(7209):96-9. doi: 10.1038/nature07087.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Sound Communication, Institute of Biology, University of Southern Denmark, DK-5230 Odense M, Denmark. jmr@biology.sdu.dk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18769439" target="_blank"〉PubMed〈/a〉
    Keywords: *Animal Communication ; Animals ; Bayes Theorem ; Birds/*physiology ; Chiroptera/*physiology ; Circadian Rhythm ; Color ; Cues ; Molecular Sequence Data ; Moths/genetics/*physiology ; Ontario ; Phylogeny ; Pigmentation/*physiology ; Predatory Behavior/*physiology ; Seasons ; Ultrasonics
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    Apoptosis: Stabbed in the BAX (2008)
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    Publication Date: 2008-10-25
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242476/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242476/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Green, Douglas R -- Chipuk, Jerry E -- F32 CA101444/CA/NCI NIH HHS/ -- R01 AI040646/AI/NIAID NIH HHS/ -- R01 AI040646-14/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Oct 23;455(7216):1047-9. doi: 10.1038/4551047a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18948940" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Apoptosis ; Apoptosis Regulatory Proteins/*metabolism ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Membrane Proteins/*metabolism ; Mitochondrial Membranes/*metabolism ; Models, Molecular ; Permeability ; Protein Binding ; Proto-Oncogene Proteins/*metabolism ; bcl-2-Associated X Protein/chemistry/*metabolism
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    Networks: teasing out the missing links (2008)
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    Publication Date: 2008-05-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Redner, Sid -- England -- Nature. 2008 May 1;453(7191):47-8. doi: 10.1038/453047a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18451851" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Friends ; Internet ; *Models, Biological ; *Probability ; Protein Binding ; Saccharomyces cerevisiae/metabolism ; Schools ; Sensitivity and Specificity ; Social Behavior ; United States
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    Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960 (2008)
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    Publication Date: 2008-10-04
    Description: Human immunodeficiency virus type 1 (HIV-1) sequences that pre-date the recognition of AIDS are critical to defining the time of origin and the timescale of virus evolution. A viral sequence from 1959 (ZR59) is the oldest known HIV-1 infection. Other historically documented sequences, important calibration points to convert evolutionary distance into time, are lacking, however; ZR59 is the only one sampled before 1976. Here we report the amplification and characterization of viral sequences from a Bouin's-fixed paraffin-embedded lymph node biopsy specimen obtained in 1960 from an adult female in Leopoldville, Belgian Congo (now Kinshasa, Democratic Republic of the Congo (DRC)), and we use them to conduct the first comparative evolutionary genetic study of early pre-AIDS epidemic HIV-1 group M viruses. Phylogenetic analyses position this viral sequence (DRC60) closest to the ancestral node of subtype A (excluding A2). Relaxed molecular clock analyses incorporating DRC60 and ZR59 date the most recent common ancestor of the M group to near the beginning of the twentieth century. The sizeable genetic distance between DRC60 and ZR59 directly demonstrates that diversification of HIV-1 in west-central Africa occurred long before the recognized AIDS pandemic. The recovery of viral gene sequences from decades-old paraffin-embedded tissues opens the door to a detailed palaeovirological investigation of the evolutionary history of HIV-1 that is not accessible by other methods.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682493/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682493/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Worobey, Michael -- Gemmel, Marlea -- Teuwen, Dirk E -- Haselkorn, Tamara -- Kunstman, Kevin -- Bunce, Michael -- Muyembe, Jean-Jacques -- Kabongo, Jean-Marie M -- Kalengayi, Raphael M -- Van Marck, Eric -- Gilbert, M Thomas P -- Wolinsky, Steven M -- R21 AI065371/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Oct 2;455(7213):661-4. doi: 10.1038/nature07390.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona 85721, USA. worobey@email.arizona.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18833279" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Canada ; Democratic Republic of the Congo/epidemiology ; *Evolution, Molecular ; Female ; Genetic Variation/*genetics ; HIV Infections/*epidemiology/pathology/*virology ; HIV-1/classification/*genetics/*isolation & purification ; History, 20th Century ; Humans ; Male ; Microtomy ; Molecular Sequence Data ; Paraffin Embedding ; Phylogeny ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA
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    DBC1 is a negative regulator of SIRT1 (2008)
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    Publication Date: 2008-02-01
    Description: The NAD-dependent protein deacetylase Sir2 (silent information regulator 2) regulates lifespan in several organisms. SIRT1, the mammalian orthologue of yeast Sir2, participates in various cellular functions and possibly tumorigenesis. Whereas the cellular functions of SIRT1 have been extensively investigated, less is known about the regulation of SIRT1 activity. Here we show that Deleted in Breast Cancer-1 (DBC1), initially cloned from a region (8p21) homozygously deleted in breast cancers, forms a stable complex with SIRT1. DBC1 directly interacts with SIRT1 and inhibits SIRT1 activity in vitro and in vivo. Downregulation of DBC1 expression potentiates SIRT1-dependent inhibition of apoptosis induced by genotoxic stress. Our results shed new light on the regulation of SIRT1 and have important implications in understanding the molecular mechanism of ageing and cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Ja-Eun -- Chen, Junjie -- Lou, Zhenkun -- England -- Nature. 2008 Jan 31;451(7178):583-6. doi: 10.1038/nature06500.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18235501" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/genetics/*metabolism ; Aging ; Apoptosis/drug effects ; Catalytic Domain ; Cell Line ; Down-Regulation ; Etoposide/pharmacology ; Humans ; Immunoprecipitation ; Leucine Zippers ; Mutagens/pharmacology ; Protein Binding ; Protein Interaction Mapping ; Sirtuin 1 ; Sirtuins/*antagonists & inhibitors/chemistry/genetics/*metabolism
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    Role for perinuclear chromosome tethering in maintenance of genome stability (2008)
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    Publication Date: 2008-11-11
    Description: Repetitive DNA sequences, which constitute half the genome in some organisms, often undergo homologous recombination. This can instigate genomic instability resulting from a gain or loss of DNA. Assembly of DNA into silent chromatin is generally thought to serve as a mechanism ensuring repeat stability by limiting access to the recombination machinery. Consistent with this notion is the observation, in the budding yeast Saccharomyces cerevisiae, that stability of the highly repetitive ribosomal DNA (rDNA) sequences requires a Sir2-containing chromatin silencing complex that also inhibits transcription from foreign promoters and transposons inserted within the repeats by a process called rDNA silencing. Here we describe a protein network that stabilizes rDNA repeats of budding yeast by means of interactions between rDNA-associated silencing proteins and two proteins of the inner nuclear membrane (INM). Deletion of either the INM or silencing proteins reduces perinuclear rDNA positioning, disrupts the nucleolus-nucleoplasm boundary, induces the formation of recombination foci, and destabilizes the repeats. In addition, artificial targeting of rDNA repeats to the INM suppresses the instability observed in cells lacking an rDNA-associated silencing protein that is typically required for peripheral tethering of the repeats. Moreover, in contrast to Sir2 and its associated nucleolar factors, the INM proteins are not required for rDNA silencing, indicating that Sir2-dependent silencing is not sufficient to inhibit recombination within the rDNA locus. These findings demonstrate a role for INM proteins in the perinuclear localization of chromosomes and show that tethering to the nuclear periphery is required for the stability of rDNA repeats. The INM proteins studied here are conserved and have been implicated in chromosome organization in metazoans. Our results therefore reveal an ancient mechanism in which interactions between INM proteins and chromosomal proteins ensure genome stability.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596277/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596277/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mekhail, Karim -- Seebacher, Jan -- Gygi, Steven P -- Moazed, Danesh -- R01 GM079535/GM/NIGMS NIH HHS/ -- R01 GM079535-02/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Dec 4;456(7222):667-70. doi: 10.1038/nature07460. Epub 2008 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18997772" target="_blank"〉PubMed〈/a〉
    Keywords: Chromosomal Position Effects ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosome Positioning ; Chromosomes, Fungal/genetics/*metabolism ; DNA, Ribosomal/*genetics/metabolism ; Gene Expression Regulation, Fungal ; *Gene Silencing ; Genomic Instability/*genetics ; Nuclear Envelope/chemistry/genetics/*metabolism ; Protein Binding ; Recombination, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Saccharomyces cerevisiae/*cytology/*genetics
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    Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B (2008)
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    Publication Date: 2008-07-29
    Description: Epac proteins are activated by binding of the second messenger cAMP and then act as guanine nucleotide exchange factors for Rap proteins. The Epac proteins are involved in the regulation of cell adhesion and insulin secretion. Here we have determined the structure of Epac2 in complex with a cAMP analogue (Sp-cAMPS) and RAP1B by X-ray crystallography and single particle electron microscopy. The structure represents the cAMP activated state of the Epac2 protein with the RAP1B protein trapped in the course of the exchange reaction. Comparison with the inactive conformation reveals that cAMP binding causes conformational changes that allow the cyclic nucleotide binding domain to swing from a position blocking the Rap binding site towards a docking site at the Ras exchange motif domain.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rehmann, Holger -- Arias-Palomo, Ernesto -- Hadders, Michael A -- Schwede, Frank -- Llorca, Oscar -- Bos, Johannes L -- England -- Nature. 2008 Sep 4;455(7209):124-7. doi: 10.1038/nature07187. Epub 2008 Jul 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiological Chemistry, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. h.rehmann@UMCutrecht.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18660803" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Binding Sites ; Carrier Proteins/*chemistry/*metabolism/ultrastructure ; Crystallography, X-Ray ; Cyclic AMP/*analogs & derivatives/chemistry/metabolism ; Enzyme Activation ; Guanine Nucleotide Exchange Factors/*chemistry/*metabolism/ultrastructure ; Humans ; Mice ; Microscopy, Electron ; Models, Molecular ; Protein Binding ; Protein Conformation ; Thionucleotides/*chemistry/*metabolism ; rap GTP-Binding Proteins/chemistry/*metabolism/ultrastructure
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    Structural biology: Enzyme knocked for a loop (2008)
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    Publication Date: 2008-11-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mellgren, Ronald L -- England -- Nature. 2008 Nov 20;456(7220):337-8. doi: 10.1038/456337a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19020611" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Calcium/metabolism ; Calcium-Binding Proteins/*chemistry/*metabolism ; Calpain/*antagonists & inhibitors/chemistry/*metabolism ; *Catalytic Domain ; Crystallography, X-Ray ; Models, Molecular ; Peptide Fragments/chemistry/metabolism ; Protein Binding ; Protein Multimerization ; Rats
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    Control of chromosome stability by the beta-TrCP-REST-Mad2 axis (2008)
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    Publication Date: 2008-03-21
    Description: REST/NRSF (repressor-element-1-silencing transcription factor/neuron-restrictive silencing factor) negatively regulates the transcription of genes containing RE1 sites. REST is expressed in non-neuronal cells and stem/progenitor neuronal cells, in which it inhibits the expression of neuron-specific genes. Overexpression of REST is frequently found in human medulloblastomas and neuroblastomas, in which it is thought to maintain the stem character of tumour cells. Neural stem cells forced to express REST and c-Myc fail to differentiate and give rise to tumours in the mouse cerebellum. Expression of a splice variant of REST that lacks the carboxy terminus has been associated with neuronal tumours and small-cell lung carcinomas, and a frameshift mutant (REST-FS), which is also truncated at the C terminus, has oncogenic properties. Here we show, by using an unbiased screen, that REST is an interactor of the F-box protein beta-TrCP. REST is degraded by means of the ubiquitin ligase SCF(beta-TrCP) during the G2 phase of the cell cycle to allow transcriptional derepression of Mad2, an essential component of the spindle assembly checkpoint. The expression in cultured cells of a stable REST mutant, which is unable to bind beta-TrCP, inhibited Mad2 expression and resulted in a phenotype analogous to that observed in Mad2(+/-) cells. In particular, we observed defects that were consistent with faulty activation of the spindle checkpoint, such as shortened mitosis, premature sister-chromatid separation, chromosome bridges and mis-segregation in anaphase, tetraploidy, and faster mitotic slippage in the presence of a spindle inhibitor. An indistinguishable phenotype was observed by expressing the oncogenic REST-FS mutant, which does not bind beta-TrCP. Thus, SCF(beta-TrCP)-dependent degradation of REST during G2 permits the optimal activation of the spindle checkpoint, and consequently it is required for the fidelity of mitosis. The high levels of REST or its truncated variants found in certain human tumours may contribute to cellular transformation by promoting genomic instability.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707768/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707768/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guardavaccaro, Daniele -- Frescas, David -- Dorrello, N Valerio -- Peschiaroli, Angelo -- Multani, Asha S -- Cardozo, Timothy -- Lasorella, Anna -- Iavarone, Antonio -- Chang, Sandy -- Hernando, Eva -- Pagano, Michele -- R01 GM057587/GM/NIGMS NIH HHS/ -- R01 GM057587-10/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 20;452(7185):365-9. doi: 10.1038/nature06641.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18354482" target="_blank"〉PubMed〈/a〉
    Keywords: Calcium-Binding Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line ; *Chromosomal Instability ; G2 Phase ; Gene Expression Regulation ; Genomic Instability ; Humans ; Mad2 Proteins ; Mitosis ; Protein Binding ; Repressor Proteins/genetics/*metabolism ; SKP Cullin F-Box Protein Ligases/metabolism ; Spindle Apparatus/physiology ; Transcription Factors/genetics/*metabolism ; beta-Transducin Repeat-Containing Proteins/deficiency/genetics/*metabolism
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    The Phaeodactylum genome reveals the evolutionary history of diatom genomes (2008)
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    Publication Date: 2008-10-17
    Description: Diatoms are photosynthetic secondary endosymbionts found throughout marine and freshwater environments, and are believed to be responsible for around one-fifth of the primary productivity on Earth. The genome sequence of the marine centric diatom Thalassiosira pseudonana was recently reported, revealing a wealth of information about diatom biology. Here we report the complete genome sequence of the pennate diatom Phaeodactylum tricornutum and compare it with that of T. pseudonana to clarify evolutionary origins, functional significance and ubiquity of these features throughout diatoms. In spite of the fact that the pennate and centric lineages have only been diverging for 90 million years, their genome structures are dramatically different and a substantial fraction of genes ( approximately 40%) are not shared by these representatives of the two lineages. Analysis of molecular divergence compared with yeasts and metazoans reveals rapid rates of gene diversification in diatoms. Contributing factors include selective gene family expansions, differential losses and gains of genes and introns, and differential mobilization of transposable elements. Most significantly, we document the presence of hundreds of genes from bacteria. More than 300 of these gene transfers are found in both diatoms, attesting to their ancient origins, and many are likely to provide novel possibilities for metabolite management and for perception of environmental signals. These findings go a long way towards explaining the incredible diversity and success of the diatoms in contemporary oceans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bowler, Chris -- Allen, Andrew E -- Badger, Jonathan H -- Grimwood, Jane -- Jabbari, Kamel -- Kuo, Alan -- Maheswari, Uma -- Martens, Cindy -- Maumus, Florian -- Otillar, Robert P -- Rayko, Edda -- Salamov, Asaf -- Vandepoele, Klaas -- Beszteri, Bank -- Gruber, Ansgar -- Heijde, Marc -- Katinka, Michael -- Mock, Thomas -- Valentin, Klaus -- Verret, Frederic -- Berges, John A -- Brownlee, Colin -- Cadoret, Jean-Paul -- Chiovitti, Anthony -- Choi, Chang Jae -- Coesel, Sacha -- De Martino, Alessandra -- Detter, J Chris -- Durkin, Colleen -- Falciatore, Angela -- Fournet, Jerome -- Haruta, Miyoshi -- Huysman, Marie J J -- Jenkins, Bethany D -- Jiroutova, Katerina -- Jorgensen, Richard E -- Joubert, Yolaine -- Kaplan, Aaron -- Kroger, Nils -- Kroth, Peter G -- La Roche, Julie -- Lindquist, Erica -- Lommer, Markus -- Martin-Jezequel, Veronique -- Lopez, Pascal J -- Lucas, Susan -- Mangogna, Manuela -- McGinnis, Karen -- Medlin, Linda K -- Montsant, Anton -- Oudot-Le Secq, Marie-Pierre -- Napoli, Carolyn -- Obornik, Miroslav -- Parker, Micaela Schnitzler -- Petit, Jean-Louis -- Porcel, Betina M -- Poulsen, Nicole -- Robison, Matthew -- Rychlewski, Leszek -- Rynearson, Tatiana A -- Schmutz, Jeremy -- Shapiro, Harris -- Siaut, Magali -- Stanley, Michele -- Sussman, Michael R -- Taylor, Alison R -- Vardi, Assaf -- von Dassow, Peter -- Vyverman, Wim -- Willis, Anusuya -- Wyrwicz, Lucjan S -- Rokhsar, Daniel S -- Weissenbach, Jean -- Armbrust, E Virginia -- Green, Beverley R -- Van de Peer, Yves -- Grigoriev, Igor V -- England -- Nature. 2008 Nov 13;456(7219):239-44. doi: 10.1038/nature07410. Epub 2008 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS UMR8186, Department of Biology, Ecole Normale Superieure, 46 rue d'Ulm, 75005 Paris, France. cbowler@biologie.ens.fr〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18923393" target="_blank"〉PubMed〈/a〉
    Keywords: DNA, Algal/analysis ; Diatoms/*genetics ; *Evolution, Molecular ; Genes, Bacterial/genetics ; Genome/*genetics ; Molecular Sequence Data ; Protein Structure, Tertiary ; Sequence Homology, Amino Acid ; Signal Transduction
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    A PtdIns4,5P2-regulated nuclear poly(A) polymerase controls expression of select mRNAs (2008)
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    Publication Date: 2008-02-22
    Description: Phosphoinositides are a family of lipid signalling molecules that regulate many cellular functions in eukaryotes. Phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2), the central component in the phosphoinositide signalling circuitry, is generated primarily by type I phosphatidylinositol 4-phosphate 5-kinases (PIPKIalpha, PIPKIbeta and PIPKIgamma). In addition to functions in the cytosol, phosphoinositides are present in the nucleus, where they modulate several functions; however, the mechanism by which they directly regulate nuclear functions remains unknown. PIPKIs regulate cellular functions through interactions with protein partners, often PtdIns4,5P2 effectors, that target PIPKIs to discrete subcellular compartments, resulting in the spatial and temporal generation of PtdIns4,5P2 required for the regulation of specific signalling pathways. Therefore, to determine roles for nuclear PtdIns4,5P2 we set out to identify proteins that interacted with the nuclear PIPK, PIPKIalpha. Here we show that PIPKIalpha co-localizes at nuclear speckles and interacts with a newly identified non-canonical poly(A) polymerase, which we have termed Star-PAP (nuclear speckle targeted PIPKIalpha regulated-poly(A) polymerase) and that the activity of Star-PAP can be specifically regulated by PtdIns4,5P2. Star-PAP and PIPKIalpha function together in a complex to control the expression of select mRNAs, including the transcript encoding the key cytoprotective enzyme haem oxygenase-1 (refs 8, 9) and other oxidative stress response genes by regulating the 3'-end formation of their mRNAs. Taken together, the data demonstrate a model by which phosphoinositide signalling works in tandem with complement pathways to regulate the activity of Star-PAP and the subsequent biosynthesis of its target mRNA. The results reveal a mechanism for the integration of nuclear phosphoinositide signals and a method for regulating gene expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mellman, David L -- Gonzales, Michael L -- Song, Chunhua -- Barlow, Christy A -- Wang, Ping -- Kendziorski, Christina -- Anderson, Richard A -- R01 GM051968/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Feb 21;451(7181):1013-7. doi: 10.1038/nature06666.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular and Cellular Pharmacology, University of Wisconsin Medical School, University of Wisconsin-Madison, 1300 University Avenue, Madison, Wisconsin 53706, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18288197" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Nucleus/enzymology/genetics/*metabolism ; Heme Oxygenase-1/genetics ; Humans ; Mice ; Multiprotein Complexes/metabolism ; Oxidative Stress/genetics ; Phosphatidylinositol 4,5-Diphosphate ; Phosphatidylinositol Phosphates/*metabolism ; Phosphotransferases (Alcohol Group Acceptor)/deficiency/genetics/metabolism ; Polynucleotide Adenylyltransferase/chemistry/deficiency/genetics/*metabolism ; Protein Binding ; *RNA 3' End Processing ; RNA, Messenger/genetics/metabolism ; Substrate Specificity ; Transcription, Genetic
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    Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions (2008)
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    Publication Date: 2008-05-09
    Description: The architecture of human chromosomes in interphase nuclei is still largely unknown. Microscopy studies have indicated that specific regions of chromosomes are located in close proximity to the nuclear lamina (NL). This has led to the idea that certain genomic elements may be attached to the NL, which may contribute to the spatial organization of chromosomes inside the nucleus. However, sequences in the human genome that interact with the NL in vivo have not been identified. Here we construct a high-resolution map of the interaction sites of the entire genome with NL components in human fibroblasts. This map shows that genome-lamina interactions occur through more than 1,300 sharply defined large domains 0.1-10 megabases in size. These lamina-associated domains (LADs) are typified by low gene-expression levels, indicating that LADs represent a repressive chromatin environment. The borders of LADs are demarcated by the insulator protein CTCF, by promoters that are oriented away from LADs, or by CpG islands, suggesting possible mechanisms of LAD confinement. Taken together, these results demonstrate that the human genome is divided into large, discrete domains that are units of chromosome organization within the nucleus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guelen, Lars -- Pagie, Ludo -- Brasset, Emilie -- Meuleman, Wouter -- Faza, Marius B -- Talhout, Wendy -- Eussen, Bert H -- de Klein, Annelies -- Wessels, Lodewyk -- de Laat, Wouter -- van Steensel, Bas -- England -- Nature. 2008 Jun 12;453(7197):948-51. doi: 10.1038/nature06947. Epub 2008 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18463634" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Chromatin/genetics/metabolism ; *Chromosome Positioning ; Chromosomes, Human/genetics/*metabolism ; CpG Islands/genetics ; DNA-Binding Proteins/metabolism ; Fibroblasts ; Genome, Human ; Humans ; Lamin Type B/metabolism ; Nuclear Lamina/chemistry/*metabolism ; Promoter Regions, Genetic/genetics ; Protein Binding ; Repressor Proteins/metabolism
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    Heterochromatin links to centromeric protection by recruiting shugoshin (2008)
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    Publication Date: 2008-08-22
    Description: The centromere of a chromosome is composed mainly of two domains, a kinetochore assembling core centromere and peri-centromeric heterochromatin regions. The crucial role of centromeric heterochromatin is still unknown, because even in simpler unicellular organisms such as the fission yeast Schizosaccharomyces pombe, the heterochromatin protein Swi6 (HP1 homologue) has several functions at centromeres, including silencing gene expression and recombination, enriching cohesin, promoting kinetochore assembly, and, ultimately, preventing erroneous microtubule attachment to the kinetochores. Here we show that the requirement of heterochromatin for mitotic chromosome segregation is largely replaced by forcibly enriching cohesin at centromeres in fission yeast. However, this enrichment of cohesin is not sufficient to replace the meiotic requirement for heterochromatin. We find that the heterochromatin protein Swi6 associates directly with meiosis-specific shugoshin Sgo1, a protector of cohesin at centromeres. A point mutation of Sgo1 (V242E), which abolishes the interaction with Swi6, impairs the centromeric localization and function of Sgo1. The forced centromeric localization of Sgo1 restores proper meiotic chromosome segregation in swi6 cells. We also show that the direct link between HP1 and shugoshin is conserved in human cells. Taken together, our findings suggest that the recruitment of shugoshin is the important primary role for centromeric heterochromatin in ensuring eukaryotic chromosome segregation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yamagishi, Yuya -- Sakuno, Takeshi -- Shimura, Mari -- Watanabe, Yoshinori -- England -- Nature. 2008 Sep 11;455(7210):251-5. doi: 10.1038/nature07217.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Tokyo 113-0032, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18716626" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/*metabolism ; Centromere/*metabolism ; Chromosomal Proteins, Non-Histone/*metabolism ; Chromosome Segregation ; Heterochromatin/*metabolism ; Humans ; Meiosis ; Mitosis ; Protein Binding ; Protein Transport ; Schizosaccharomyces/genetics/metabolism ; Schizosaccharomyces pombe Proteins/*metabolism
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    Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA (2008)
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    Publication Date: 2008-04-25
    Description: Escherichia coli AlkB and its human homologues ABH2 and ABH3 repair DNA/RNA base lesions by using a direct oxidative dealkylation mechanism. ABH2 has the primary role of guarding mammalian genomes against 1-meA damage by repairing this lesion in double-stranded DNA (dsDNA), whereas AlkB and ABH3 preferentially repair single-stranded DNA (ssDNA) lesions and can repair damaged bases in RNA. Here we show the first crystal structures of AlkB-dsDNA and ABH2-dsDNA complexes, stabilized by a chemical cross-linking strategy. This study reveals that AlkB uses an unprecedented base-flipping mechanism to access the damaged base: it squeezes together the two bases flanking the flipped-out one to maintain the base stack, explaining the preference of AlkB for repairing ssDNA lesions over dsDNA ones. In addition, the first crystal structure of ABH2, presented here, provides a structural basis for designing inhibitors of this human DNA repair protein.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587245/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587245/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Cai-Guang -- Yi, Chengqi -- Duguid, Erica M -- Sullivan, Christopher T -- Jian, Xing -- Rice, Phoebe A -- He, Chuan -- GM071440/GM/NIGMS NIH HHS/ -- R01 GM071440/GM/NIGMS NIH HHS/ -- R01 GM071440-03/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Apr 24;452(7190):961-5. doi: 10.1038/nature06889.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18432238" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/analogs & derivatives/metabolism ; Binding Sites ; Cross-Linking Reagents/chemistry ; Crystallography, X-Ray ; DNA/chemistry/*metabolism ; DNA Damage ; DNA Repair ; DNA Repair Enzymes/*chemistry/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; Dioxygenases/*chemistry/*metabolism ; Escherichia coli Proteins/*chemistry/*metabolism ; Humans ; Mixed Function Oxygenases/*chemistry/*metabolism ; Models, Molecular ; Protein Binding ; RNA/*metabolism
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    Cell biology: SUMO (2008)
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    Publication Date: 2008-04-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meulmeester, Erik -- Melchior, Frauke -- England -- Nature. 2008 Apr 10;452(7188):709-11. doi: 10.1038/452709a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18401402" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Eukaryotic Cells/metabolism ; History, 20th Century ; Humans ; Protein Binding ; Small Ubiquitin-Related Modifier Proteins/history/*metabolism ; Substrate Specificity ; Viruses/metabolism
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    SMAD proteins control DROSHA-mediated microRNA maturation (2008)
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    Publication Date: 2008-06-13
    Description: MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases, such as cardiovascular disorders and cancer; however, the stimuli and processes regulating miRNA biogenesis are largely unknown. The transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) family of growth factors orchestrates fundamental biological processes in development and in the homeostasis of adult tissues, including the vasculature. Here we show that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is mediated by miR-21. miR-21 downregulates PDCD4 (programmed cell death 4), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signalling promotes a rapid increase in expression of mature miR-21 through a post-transcriptional step, promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR-21 (pre-miR-21) by the DROSHA (also known as RNASEN) complex. TGF-beta- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. The shared cofactor SMAD4 is not required for this process. Thus, regulation of miRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signalling pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653422/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653422/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davis, Brandi N -- Hilyard, Aaron C -- Lagna, Giorgio -- Hata, Akiko -- HD042149/HD/NICHD NIH HHS/ -- HL082854/HL/NHLBI NIH HHS/ -- HL086572/HL/NHLBI NIH HHS/ -- R01 HD042149/HD/NICHD NIH HHS/ -- R01 HD042149-05/HD/NICHD NIH HHS/ -- R01 HL082854/HL/NHLBI NIH HHS/ -- R01 HL082854-03/HL/NHLBI NIH HHS/ -- R21 HL086572/HL/NHLBI NIH HHS/ -- R21 HL086572-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2008 Jul 3;454(7200):56-61. doi: 10.1038/nature07086. Epub 2008 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18548003" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/metabolism ; Bone Morphogenetic Protein 4 ; Bone Morphogenetic Proteins/metabolism/pharmacology ; Breast Neoplasms/genetics ; Cell Line ; Cercopithecus aethiops ; DEAD-box RNA Helicases/metabolism ; Gene Expression Regulation/drug effects ; Humans ; Ligands ; Mice ; MicroRNAs/biosynthesis/*metabolism ; Muscle, Smooth/metabolism ; Phenotype ; Protein Binding ; *RNA Processing, Post-Transcriptional ; RNA-Binding Proteins/metabolism ; Ribonuclease III/*metabolism ; Signal Transduction/drug effects ; Smad Proteins/*metabolism ; Transforming Growth Factor beta/metabolism/pharmacology
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    SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin (2008)
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    Publication Date: 2008-03-14
    Description: The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein, but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646112/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646112/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Michishita, Eriko -- McCord, Ronald A -- Berber, Elisabeth -- Kioi, Mitomu -- Padilla-Nash, Hesed -- Damian, Mara -- Cheung, Peggie -- Kusumoto, Rika -- Kawahara, Tiara L A -- Barrett, J Carl -- Chang, Howard Y -- Bohr, Vilhelm A -- Ried, Thomas -- Gozani, Or -- Chua, Katrin F -- K08 AG028961/AG/NIA NIH HHS/ -- K08 AG028961-03/AG/NIA NIH HHS/ -- R01 AG028867/AG/NIA NIH HHS/ -- R01 AG028867-03/AG/NIA NIH HHS/ -- R01 GM079641/GM/NIGMS NIH HHS/ -- R01 GM079641-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Mar 27;452(7186):492-6. doi: 10.1038/nature06736. Epub 2008 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337721" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Cell Aging/genetics ; Cell Line ; Chromatin/genetics/*metabolism ; DNA Replication ; Exodeoxyribonucleases/metabolism ; Fibroblasts ; Histone Deacetylases/deficiency/genetics/*metabolism ; Histones/chemistry/metabolism ; Humans ; Lysine/metabolism ; Phenotype ; Protein Binding ; RecQ Helicases/metabolism ; Sirtuins/deficiency/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Werner Syndrome/genetics
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    FCA does not bind abscisic acid (2008)
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    Publication Date: 2008-12-17
    Description: The RNA-binding protein FCA promotes flowering in Arabidopsis. Razem et al. reported that FCA is also a receptor for the phytohormone abscisic acid (ABA). However, we find that FCA does not bind ABA, suggesting that the quality of the proteins assayed and the sensitivity of the ABA-binding assay have led Razem et al. to erroneous conclusions. Because similar assays have been used to characterize other ABA receptors, our results indicate that the ABA-binding properties of these proteins should be carefully re-evaluated and that alternative ABA receptors are likely to be discovered.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Risk, Joanna M -- Macknight, Richard C -- Day, Catherine L -- England -- Nature. 2008 Dec 11;456(7223):E5-6. doi: 10.1038/nature07646.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biochemistry Department, University of Otago, Dunedin 9054, New Zealand. catherine.day@otago.ac.nz.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19078995" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*metabolism ; Arabidopsis/*metabolism ; Arabidopsis Proteins/*metabolism ; Protein Binding ; RNA-Binding Proteins/*metabolism ; mRNA Cleavage and Polyadenylation Factors/metabolism
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    Structural biology: Modelling collagen diseases (2008)
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    Publication Date: 2008-06-20
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760068/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760068/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brodsky, Barbara -- Baum, Jean -- R01 GM045302/GM/NIGMS NIH HHS/ -- R01 GM045302-14A2/GM/NIGMS NIH HHS/ -- R01 GM060048/GM/NIGMS NIH HHS/ -- R01 GM060048-29/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Jun 19;453(7198):998-9. doi: 10.1038/453998a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18563144" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Collagen Type I/*chemistry/*genetics/metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Osteogenesis Imperfecta/genetics/metabolism ; Peptides/chemistry/genetics/metabolism ; Structure-Activity Relationship
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    A molecular framework for light and gibberellin control of cell elongation (2008)
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    Publication Date: 2008-01-25
    Description: Cell elongation during seedling development is antagonistically regulated by light and gibberellins (GAs). Light induces photomorphogenesis, leading to inhibition of hypocotyl growth, whereas GAs promote etiolated growth, characterized by increased hypocotyl elongation. The mechanism underlying this antagonistic interaction remains unclear. Here we report on the central role of the Arabidopsis thaliana nuclear transcription factor PIF4 (encoded by PHYTOCHROME INTERACTING FACTOR 4) in the positive control of genes mediating cell elongation and show that this factor is negatively regulated by the light photoreceptor phyB (ref. 4) and by DELLA proteins that have a key repressor function in GA signalling. Our results demonstrate that PIF4 is destabilized by phyB in the light and that DELLAs block PIF4 transcriptional activity by binding the DNA-recognition domain of this factor. We show that GAs abrogate such repression by promoting DELLA destabilization, and therefore cause a concomitant accumulation of free PIF4 in the nucleus. Consistent with this model, intermediate hypocotyl lengths were observed in transgenic plants over-accumulating both DELLAs and PIF4. Destabilization of this factor by phyB, together with its inactivation by DELLAs, constitutes a protein interaction framework that explains how plants integrate both light and GA signals to optimize growth and development in response to changing environments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Lucas, Miguel -- Daviere, Jean-Michel -- Rodriguez-Falcon, Mariana -- Pontin, Mariela -- Iglesias-Pedraz, Juan Manuel -- Lorrain, Severine -- Fankhauser, Christian -- Blazquez, Miguel Angel -- Titarenko, Elena -- Prat, Salome -- England -- Nature. 2008 Jan 24;451(7177):480-4. doi: 10.1038/nature06520.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departamento de Genetica Molecular de Plantas, Centro Nacional de Biotecnologia-CSIC, Campus Univ. Autonoma de Madrid, Cantoblanco. c/ Darwin 3, 28049 Madrid, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18216857" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/cytology/*drug effects/metabolism/*radiation effects ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; Basic Helix-Loop-Helix Transcription Factors/chemistry/genetics/metabolism ; Cell Shape/*drug effects/*radiation effects ; Cell Size/drug effects/radiation effects ; DNA, Plant/metabolism ; Gibberellins/*pharmacology ; Hypocotyl/genetics/growth & development/metabolism ; *Light ; Nuclear Proteins/chemistry/genetics/metabolism ; Phytochrome B/genetics/metabolism ; Plant Leaves/metabolism ; Protein Binding ; Seedlings/metabolism ; Signal Transduction/drug effects ; Tobacco/metabolism ; Triazoles/pharmacology ; Two-Hybrid System Techniques
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    Molecular biology: The Bloom's complex mousetrap (2008)
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    Publication Date: 2008-11-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brosh, Robert M Jr -- England -- Nature. 2008 Nov 27;456(7221):453-4. doi: 10.1038/456453a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19037304" target="_blank"〉PubMed〈/a〉
    Keywords: Bloom Syndrome/*genetics/*physiopathology ; DNA Helicases/genetics/*metabolism ; DNA, Cruciform/genetics ; Fanconi Anemia/genetics ; *Genomic Instability ; Humans ; Multiprotein Complexes/chemistry/genetics/*metabolism ; Protein Binding ; RecQ Helicases ; Sister Chromatid Exchange/genetics
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    An internal thermal sensor controlling temperature preference in Drosophila (2008)
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    Publication Date: 2008-06-13
    Description: Animals from flies to humans are able to distinguish subtle gradations in temperature and show strong temperature preferences. Animals move to environments of optimal temperature and some manipulate the temperature of their surroundings, as humans do using clothing and shelter. Despite the ubiquitous influence of environmental temperature on animal behaviour, the neural circuits and strategies through which animals select a preferred temperature remain largely unknown. Here we identify a small set of warmth-activated anterior cell (AC) neurons located in the Drosophila brain, the function of which is critical for preferred temperature selection. AC neuron activation occurs just above the fly's preferred temperature and depends on dTrpA1, an ion channel that functions as a molecular sensor of warmth. Flies that selectively express dTrpA1 in the AC neurons select normal temperatures, whereas flies in which dTrpA1 function is reduced or eliminated choose warmer temperatures. This internal warmth-sensing pathway promotes avoidance of slightly elevated temperatures and acts together with a distinct pathway for cold avoidance to set the fly's preferred temperature. Thus, flies select a preferred temperature by using a thermal sensing pathway tuned to trigger avoidance of temperatures that deviate even slightly from the preferred temperature. This provides a potentially general strategy for robustly selecting a narrow temperature range optimal for survival.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730888/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730888/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamada, Fumika N -- Rosenzweig, Mark -- Kang, Kyeongjin -- Pulver, Stefan R -- Ghezzi, Alfredo -- Jegla, Timothy J -- Garrity, Paul A -- P01 NS044232/NS/NINDS NIH HHS/ -- P01 NS044232-060002/NS/NINDS NIH HHS/ -- P01 NS044232-070002/NS/NINDS NIH HHS/ -- P30 NS045713/NS/NINDS NIH HHS/ -- P30 NS045713-069006/NS/NINDS NIH HHS/ -- P30 NS045713S10/NS/NINDS NIH HHS/ -- R01 EY013874/EY/NEI NIH HHS/ -- R01 EY013874-06/EY/NEI NIH HHS/ -- R01 EY13874/EY/NEI NIH HHS/ -- R01 MH067284/MH/NIMH NIH HHS/ -- R01 MH067284-05/MH/NIMH NIH HHS/ -- RR16780/RR/NCRR NIH HHS/ -- England -- Nature. 2008 Jul 10;454(7201):217-20. doi: 10.1038/nature07001. Epub 2008 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Center for Behavioral Genomics, Volen Center for Complex Systems, Biology Department, Brandeis University MS-008, 415 South Street, Waltham, Massachusetts 02454, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18548007" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Avoidance Learning ; Body Temperature ; Choice Behavior/*physiology ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/growth & development/*physiology ; Female ; Larva ; Molecular Sequence Data ; Neurons/metabolism ; Oocytes/metabolism ; TRPC Cation Channels/genetics/*metabolism ; *Temperature ; Xenopus laevis
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    The draft genome of the transgenic tropical fruit tree papaya (Carica papaya Linnaeus) (2008)
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    Publication Date: 2008-04-25
    Description: Papaya, a fruit crop cultivated in tropical and subtropical regions, is known for its nutritional benefits and medicinal applications. Here we report a 3x draft genome sequence of 'SunUp' papaya, the first commercial virus-resistant transgenic fruit tree to be sequenced. The papaya genome is three times the size of the Arabidopsis genome, but contains fewer genes, including significantly fewer disease-resistance gene analogues. Comparison of the five sequenced genomes suggests a minimal angiosperm gene set of 13,311. A lack of recent genome duplication, atypical of other angiosperm genomes sequenced so far, may account for the smaller papaya gene number in most functional groups. Nonetheless, striking amplifications in gene number within particular functional groups suggest roles in the evolution of tree-like habit, deposition and remobilization of starch reserves, attraction of seed dispersal agents, and adaptation to tropical daylengths. Transgenesis at three locations is closely associated with chloroplast insertions into the nuclear genome, and with topoisomerase I recognition sites. Papaya offers numerous advantages as a system for fruit-tree functional genomics, and this draft genome sequence provides the foundation for revealing the basis of Carica's distinguishing morpho-physiological, medicinal and nutritional properties.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836516/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836516/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ming, Ray -- Hou, Shaobin -- Feng, Yun -- Yu, Qingyi -- Dionne-Laporte, Alexandre -- Saw, Jimmy H -- Senin, Pavel -- Wang, Wei -- Ly, Benjamin V -- Lewis, Kanako L T -- Salzberg, Steven L -- Feng, Lu -- Jones, Meghan R -- Skelton, Rachel L -- Murray, Jan E -- Chen, Cuixia -- Qian, Wubin -- Shen, Junguo -- Du, Peng -- Eustice, Moriah -- Tong, Eric -- Tang, Haibao -- Lyons, Eric -- Paull, Robert E -- Michael, Todd P -- Wall, Kerr -- Rice, Danny W -- Albert, Henrik -- Wang, Ming-Li -- Zhu, Yun J -- Schatz, Michael -- Nagarajan, Niranjan -- Acob, Ricelle A -- Guan, Peizhu -- Blas, Andrea -- Wai, Ching Man -- Ackerman, Christine M -- Ren, Yan -- Liu, Chao -- Wang, Jianmei -- Wang, Jianping -- Na, Jong-Kuk -- Shakirov, Eugene V -- Haas, Brian -- Thimmapuram, Jyothi -- Nelson, David -- Wang, Xiyin -- Bowers, John E -- Gschwend, Andrea R -- Delcher, Arthur L -- Singh, Ratnesh -- Suzuki, Jon Y -- Tripathi, Savarni -- Neupane, Kabi -- Wei, Hairong -- Irikura, Beth -- Paidi, Maya -- Jiang, Ning -- Zhang, Wenli -- Presting, Gernot -- Windsor, Aaron -- Navajas-Perez, Rafael -- Torres, Manuel J -- Feltus, F Alex -- Porter, Brad -- Li, Yingjun -- Burroughs, A Max -- Luo, Ming-Cheng -- Liu, Lei -- Christopher, David A -- Mount, Stephen M -- Moore, Paul H -- Sugimura, Tak -- Jiang, Jiming -- Schuler, Mary A -- Friedman, Vikki -- Mitchell-Olds, Thomas -- Shippen, Dorothy E -- dePamphilis, Claude W -- Palmer, Jeffrey D -- Freeling, Michael -- Paterson, Andrew H -- Gonsalves, Dennis -- Wang, Lei -- Alam, Maqsudul -- R01 GM083873/GM/NIGMS NIH HHS/ -- R01 GM083873-05/GM/NIGMS NIH HHS/ -- R01 LM006845/LM/NLM NIH HHS/ -- R01 LM006845-08/LM/NLM NIH HHS/ -- England -- Nature. 2008 Apr 24;452(7190):991-6. doi: 10.1038/nature06856.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hawaii Agriculture Research Center, Aiea, Hawaii 96701, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18432245" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/genetics ; Carica/*genetics ; Contig Mapping ; Databases, Genetic ; Genes, Plant/genetics ; Genome, Plant/*genetics ; Molecular Sequence Data ; Plants, Genetically Modified/genetics ; Sequence Alignment ; Sequence Analysis, DNA ; Transcription Factors/genetics ; Tropical Climate
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    Neurodegeneration: a question of balance (2008)
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    Publication Date: 2008-04-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thompson, Leslie Michels -- England -- Nature. 2008 Apr 10;452(7188):707-8. doi: 10.1038/452707a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18401401" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxin-1 ; Ataxins ; Humans ; Mice ; Multiprotein Complexes/chemistry/metabolism ; Nerve Tissue Proteins/chemistry/genetics/*metabolism ; Nuclear Proteins/chemistry/genetics/*metabolism ; Peptides/genetics/*metabolism ; Protein Binding ; Protein Structure, Quaternary ; Repressor Proteins/metabolism ; Spinocerebellar Ataxias/genetics/*metabolism/pathology ; *Trinucleotide Repeat Expansion/genetics
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    Negative feedback that improves information transmission in yeast signalling (2008)
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    Publication Date: 2008-12-17
    Description: Haploid Saccharomyces cerevisiae yeast cells use a prototypic cell signalling system to transmit information about the extracellular concentration of mating pheromone secreted by potential mating partners. The ability of cells to respond distinguishably to different pheromone concentrations depends on how much information about pheromone concentration the system can transmit. Here we show that the mitogen-activated protein kinase Fus3 mediates fast-acting negative feedback that adjusts the dose response of the downstream system response to match the dose response of receptor-ligand binding. This 'dose-response alignment', defined by a linear relationship between receptor occupancy and downstream response, can improve the fidelity of information transmission by making downstream responses corresponding to different receptor occupancies more distinguishable and reducing amplification of stochastic noise during signal transmission. We also show that one target of the feedback is a previously uncharacterized signal-promoting function of the regulator of G-protein signalling protein Sst2. Our work suggests that negative feedback is a general mechanism used in signalling systems to align dose responses and thereby increase the fidelity of information transmission.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716709/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716709/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Richard C -- Pesce, C Gustavo -- Colman-Lerner, Alejandro -- Lok, Larry -- Pincus, David -- Serra, Eduard -- Holl, Mark -- Benjamin, Kirsten -- Gordon, Andrew -- Brent, Roger -- P50 HG002370/HG/NHGRI NIH HHS/ -- P50 HG002370-01A1/HG/NHGRI NIH HHS/ -- P50 HG002370-01A1S1/HG/NHGRI NIH HHS/ -- P50 HG002370-02/HG/NHGRI NIH HHS/ -- P50 HG002370-03/HG/NHGRI NIH HHS/ -- P50 HG002370-03S1/HG/NHGRI NIH HHS/ -- P50 HG002370-04/HG/NHGRI NIH HHS/ -- P50 HG002370-04S1/HG/NHGRI NIH HHS/ -- P50 HG002370-05/HG/NHGRI NIH HHS/ -- P50 HG002370-05S1/HG/NHGRI NIH HHS/ -- P50 HG02370/HG/NHGRI NIH HHS/ -- R01 GM097479/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Dec 11;456(7223):755-61. doi: 10.1038/nature07513.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Sciences Institute, 2168 Shattuck Avenue, Berkeley, California 94704, USA. ryu@molsci.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19079053" target="_blank"〉PubMed〈/a〉
    Keywords: Dose-Response Relationship, Drug ; Feedback, Physiological/*physiology ; GTPase-Activating Proteins/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Pheromones/*metabolism/pharmacology ; Protein Binding ; Saccharomyces cerevisiae/drug effects/metabolism/*physiology ; Saccharomyces cerevisiae Proteins/*metabolism ; *Signal Transduction/drug effects
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-22
    Description: Investigation of the human antibody response to influenza virus infection has been largely limited to serology, with relatively little analysis at the molecular level. The 1918 H1N1 influenza virus pandemic was the most severe of the modern era. Recent work has recovered the gene sequences of this unusual strain, so that the 1918 pandemic virus could be reconstituted to display its unique virulence phenotypes. However, little is known about adaptive immunity to this virus. We took advantage of the 1918 virus sequencing and the resultant production of recombinant 1918 haemagglutinin (HA) protein antigen to characterize at the clonal level neutralizing antibodies induced by natural exposure of survivors to the 1918 pandemic virus. Here we show that of the 32 individuals tested that were born in or before 1915, each showed seroreactivity with the 1918 virus, nearly 90 years after the pandemic. Seven of the eight donor samples tested had circulating B cells that secreted antibodies that bound the 1918 HA. We isolated B cells from subjects and generated five monoclonal antibodies that showed potent neutralizing activity against 1918 virus from three separate donors. These antibodies also cross-reacted with the genetically similar HA of a 1930 swine H1N1 influenza strain, but did not cross-react with HAs of more contemporary human influenza viruses. The antibody genes had an unusually high degree of somatic mutation. The antibodies bound to the 1918 HA protein with high affinity, had exceptional virus-neutralizing potency and protected mice from lethal infection. Isolation of viruses that escaped inhibition suggested that the antibodies recognize classical antigenic sites on the HA surface. Thus, these studies demonstrate that survivors of the 1918 influenza pandemic possess highly functional, virus-neutralizing antibodies to this uniquely virulent virus, and that humans can sustain circulating B memory cells to viruses for many decades after exposure-well into the tenth decade of life.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848880/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848880/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Xiaocong -- Tsibane, Tshidi -- McGraw, Patricia A -- House, Frances S -- Keefer, Christopher J -- Hicar, Mark D -- Tumpey, Terrence M -- Pappas, Claudia -- Perrone, Lucy A -- Martinez, Osvaldo -- Stevens, James -- Wilson, Ian A -- Aguilar, Patricia V -- Altschuler, Eric L -- Basler, Christopher F -- Crowe, James E Jr -- AI057158/AI/NIAID NIH HHS/ -- AI42266/AI/NIAID NIH HHS/ -- CA55896/CA/NCI NIH HHS/ -- P01 AI058113/AI/NIAID NIH HHS/ -- R01 AI048677/AI/NIAID NIH HHS/ -- R01 AI048677-04/AI/NIAID NIH HHS/ -- U19 AI057229/AI/NIAID NIH HHS/ -- U19 AI62623/AI/NIAID NIH HHS/ -- U54 AI057157/AI/NIAID NIH HHS/ -- U54 AI057157-019002/AI/NIAID NIH HHS/ -- U54 AI57158/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Sep 25;455(7212):532-6. doi: 10.1038/nature07231. Epub 2008 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18716625" target="_blank"〉PubMed〈/a〉
    Keywords: Aged, 80 and over ; Animals ; Antibodies, Monoclonal/genetics/immunology/isolation & purification ; Antibodies, Viral/genetics/*immunology/*isolation & purification ; B-Lymphocytes/*immunology ; Cell Line ; Cross Reactions/immunology ; *Disease Outbreaks/history ; Dogs ; Female ; History, 20th Century ; Humans ; Influenza A Virus, H1N1 Subtype/genetics/*immunology/physiology ; Influenza, Human/*immunology/virology ; Kinetics ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Neutralization Tests ; *Survival
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    Concerted multi-pronged attack by calpastatin to occlude the catalytic cleft of heterodimeric calpains (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-11-21
    Description: The Ca(2+)-dependent cysteine proteases, calpains, regulate cell migration, cell death, insulin secretion, synaptic function and muscle homeostasis. Their endogenous inhibitor, calpastatin, consists of four inhibitory repeats, each of which neutralizes an activated calpain with exquisite specificity and potency. Despite the physiological importance of this interaction, the structural basis of calpain inhibition by calpastatin is unknown. Here we report the 3.0 A structure of Ca(2+)-bound m-calpain in complex with the first calpastatin repeat, both from rat, revealing the mechanism of exclusive specificity. The structure highlights the complexity of calpain activation by Ca(2+), illustrating key residues in a peripheral domain that serve to stabilize the protease core on Ca(2+) binding. Fully activated calpain binds ten Ca(2+) atoms, resulting in several conformational changes allowing recognition by calpastatin. Calpain inhibition is mediated by the intimate contact with three critical regions of calpastatin. Two regions target the penta-EF-hand domains of calpain and the third occupies the substrate-binding cleft, projecting a loop around the active site thiol to evade proteolysis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847431/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847431/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moldoveanu, Tudor -- Gehring, Kalle -- Green, Douglas R -- P01 CA069381/CA/NCI NIH HHS/ -- P01 CA069381-140010/CA/NCI NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 AI040646/AI/NIAID NIH HHS/ -- R01 AI040646-14/AI/NIAID NIH HHS/ -- R01 AI044828/AI/NIAID NIH HHS/ -- R01 AI044828-12/AI/NIAID NIH HHS/ -- R01 AI047891/AI/NIAID NIH HHS/ -- R01 AI047891-12/AI/NIAID NIH HHS/ -- R37 GM052735/GM/NIGMS NIH HHS/ -- R37 GM052735-19/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Nov 20;456(7220):404-8. doi: 10.1038/nature07353.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19020622" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Calcium/metabolism ; Calcium-Binding Proteins/*chemistry/genetics/*metabolism ; Calpain/antagonists & inhibitors/*chemistry/*metabolism ; *Catalytic Domain ; Crystallography, X-Ray ; EF Hand Motifs ; Enzyme Activation ; Protein Binding ; Protein Multimerization ; Protein Processing, Post-Translational ; Rats ; Structure-Activity Relationship ; Substrate Specificity
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    Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-12-05
    Description: Species-specific recognition between the egg extracellular matrix (zona pellucida) and sperm is the first, crucial step of mammalian fertilization. Zona pellucida filament components ZP3 and ZP2 act as sperm receptors, and mice lacking either of the corresponding genes produce oocytes without a zona pellucida and are completely infertile. Like their counterparts in the vitelline envelope of non-mammalian eggs and many other secreted eukaryotic proteins, zona pellucida subunits polymerize using a 'zona pellucida (ZP) domain' module, whose conserved amino-terminal part (ZP-N) was suggested to constitute a domain of its own. No atomic structure has been reported for ZP domain proteins, and there is no structural information on any conserved vertebrate protein that is essential for fertilization and directly involved in egg-sperm binding. Here we describe the 2.3 angstrom (A) resolution structure of the ZP-N fragment of mouse primary sperm receptor ZP3. The ZP-N fold defines a new immunoglobulin superfamily subtype with a beta-sheet extension characterized by an E' strand and an invariant tyrosine residue implicated in polymerization. The structure strongly supports the presence of ZP-N repeats within the N-terminal region of ZP2 and other vertebrate zona pellucida/vitelline envelope proteins, with implications for overall egg coat architecture, the post-fertilization block to polyspermy and speciation. Moreover, it provides an important framework for understanding human diseases caused by mutations in ZP domain proteins and developing new methods of non-hormonal contraception.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Monne, Magnus -- Han, Ling -- Schwend, Thomas -- Burendahl, Sofia -- Jovine, Luca -- G0500367/Medical Research Council/United Kingdom -- England -- Nature. 2008 Dec 4;456(7222):653-7. doi: 10.1038/nature07599.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Karolinska Institutet, Department of Biosciences and Nutrition, Halsovagen 7, SE-141 57 Huddinge, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052627" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; CHO Cells ; Conserved Sequence ; Cricetinae ; Cricetulus ; Crystallization ; Crystallography, X-Ray ; Egg Proteins/*chemistry/genetics/*metabolism ; Female ; Male ; Membrane Glycoproteins/*chemistry/genetics/*metabolism ; Mice ; Models, Molecular ; Molecular Sequence Data ; Ovum/*chemistry/*metabolism ; Peptide Fragments/chemistry/genetics/metabolism ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Cell Surface/*chemistry/genetics/*metabolism ; Repetitive Sequences, Amino Acid ; Spermatozoa/metabolism
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    Escape from adaptive conflict after duplication in an anthocyanin pathway gene (2008)
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    Publication Date: 2008-07-03
    Description: Gene duplications have been recognized as an important source of evolutionary innovation and adaptation since at least Haldane, and their varying fates may partly explain the vast disparity in observed genome sizes. The expected fates of most gene duplications involve primarily non-adaptive substitutions leading to either non-functionalization of one duplicate copy or subfunctionalization, neither of which yields novel function. A significant evolutionary problem is thus elucidating the mechanisms of adaptive evolutionary change leading to evolutionary novelty. Currently, the most widely recognized adaptive process involving gene duplication is neo-functionalization (NEO-F), in which one copy undergoes directional selection to perform a novel function after duplication. An alternative, but understudied, adaptive fate that has been proposed is escape from adaptive conflict (EAC), in which a single-copy gene is selected to perform a novel function while maintaining its ancestral function. This gene is constrained from improving either novel or ancestral function because of detrimental pleiotropic effects on the other function. After duplication, one copy is free to improve novel function, whereas the other is selected to improve ancestral function. Here we first present two criteria that can be used to distinguish NEO-F from EAC. Using both tests for positive selection and assays of enzyme function, we then demonstrate that adaptive evolutionary change in a duplicated gene of the anthocyanin biosynthetic pathway in morning glories (Ipomoea) is best interpreted as EAC. Finally, we argue that this phenomenon likely occurs more often than has been previously believed and may thus represent an important mechanism in generating evolutionary novelty.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Des Marais, David L -- Rausher, Mark D -- England -- Nature. 2008 Aug 7;454(7205):762-5. doi: 10.1038/nature07092. Epub 2008 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology and University Program in Genetics and Genomics, Box 90338, Duke University, Durham, North Carolina 27708-0338, USA. dld3@duke.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18594508" target="_blank"〉PubMed〈/a〉
    Keywords: Alcohol Oxidoreductases/*genetics/metabolism ; Anthocyanins/*biosynthesis/metabolism ; Convolvulaceae/enzymology/*genetics ; *Evolution, Molecular ; *Gene Duplication ; Genes, Duplicate/*genetics ; Ipomoea/enzymology/genetics ; Models, Genetic ; Molecular Sequence Data ; Phylogeny ; Solanaceae/enzymology/genetics
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    RNA interference screen for human genes associated with West Nile virus infection (2008)
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    Publication Date: 2008-08-12
    Description: West Nile virus (WNV), and related flaviviruses such as tick-borne encephalitis, Japanese encephalitis, yellow fever and dengue viruses, constitute a significant global human health problem. However, our understanding of the molecular interaction of such flaviviruses with mammalian host cells is limited. WNV encodes only 10 proteins, implying that it may use many cellular proteins for infection. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticulum, and exits along the secretory pathway. RNA interference (RNAi) presents a powerful forward genetics approach to dissect virus-host cell interactions. Here we report the identification of 305 host proteins that affect WNV infection, using a human-genome-wide RNAi screen. Functional clustering of the genes revealed a complex dependence of this virus on host cell physiology, requiring a wide variety of molecules and cellular pathways for successful infection. We further demonstrate a requirement for the ubiquitin ligase CBLL1 in WNV internalization, a post-entry role for the endoplasmic-reticulum-associated degradation pathway in viral infection, and the monocarboxylic acid transporter MCT4 as a viral replication resistance factor. By extending this study to dengue virus, we show that flaviviruses have both overlapping and unique interaction strategies with host cells. This study provides a comprehensive molecular portrait of WNV-human cell interactions that forms a model for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136529/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136529/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krishnan, Manoj N -- Ng, Aylwin -- Sukumaran, Bindu -- Gilfoy, Felicia D -- Uchil, Pradeep D -- Sultana, Hameeda -- Brass, Abraham L -- Adametz, Rachel -- Tsui, Melody -- Qian, Feng -- Montgomery, Ruth R -- Lev, Sima -- Mason, Peter W -- Koski, Raymond A -- Elledge, Stephen J -- Xavier, Ramnik J -- Agaisse, Herve -- Fikrig, Erol -- AI062773/AI/NIAID NIH HHS/ -- AI07526/AI/NIAID NIH HHS/ -- N01 AI500031/AI/NIAID NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- R01 AI032947/AI/NIAID NIH HHS/ -- R01 AI041440/AI/NIAID NIH HHS/ -- R01 AI062773/AI/NIAID NIH HHS/ -- R01 AI062773-01A1/AI/NIAID NIH HHS/ -- U01 AI070343/AI/NIAID NIH HHS/ -- U01 AI070343-04/AI/NIAID NIH HHS/ -- U54 AI057156/AI/NIAID NIH HHS/ -- U54 AI057156-01/AI/NIAID NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- U54 AI057159-01/AI/NIAID NIH HHS/ -- U54AI057159/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Sep 11;455(7210):242-5. doi: 10.1038/nature07207.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticutt 06520-8031, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18690214" target="_blank"〉PubMed〈/a〉
    Keywords: Computational Biology ; Dengue Virus/physiology ; Endoplasmic Reticulum/metabolism ; Gene Expression Profiling ; Genome, Human ; Hiv ; HeLa Cells ; Humans ; Immunity/genetics ; Monocarboxylic Acid Transporters/deficiency/genetics/metabolism ; Muscle Proteins/deficiency/genetics/metabolism ; Protein Binding ; *RNA Interference ; Ubiquitin-Protein Ligases/deficiency/genetics/metabolism ; Ubiquitination/genetics ; Vesiculovirus ; Virus Replication ; West Nile Fever/*genetics/*virology ; West Nile virus/*physiology
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    Biodiversity and biogeography of phages in modern stromatolites and thrombolites (2008)
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    Publication Date: 2008-03-04
    Description: Viruses, and more particularly phages (viruses that infect bacteria), represent one of the most abundant living entities in aquatic and terrestrial environments. The biogeography of phages has only recently been investigated and so far reveals a cosmopolitan distribution of phage genetic material (or genotypes). Here we address this cosmopolitan distribution through the analysis of phage communities in modern microbialites, the living representatives of one of the most ancient life forms on Earth. On the basis of a comparative metagenomic analysis of viral communities associated with marine (Highborne Cay, Bahamas) and freshwater (Pozas Azules II and Rio Mesquites, Mexico) microbialites, we show that some phage genotypes are geographically restricted. The high percentage of unknown sequences recovered from the three metagenomes (〉97%), the low percentage similarities with sequences from other environmental viral (n = 42) and microbial (n = 36) metagenomes, and the absence of viral genotypes shared among microbialites indicate that viruses are genetically unique in these environments. Identifiable sequences in the Highborne Cay metagenome were dominated by single-stranded DNA microphages that were not detected in any other samples examined, including sea water, fresh water, sediment, terrestrial, extreme, metazoan-associated and marine microbial mats. Finally, a marine signature was present in the phage community of the Pozas Azules II microbialites, even though this environment has not been in contact with the ocean for tens of millions of years. Taken together, these results prove that viruses in modern microbialites display biogeographical variability and suggest that they may be derived from an ancient community.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Desnues, Christelle -- Rodriguez-Brito, Beltran -- Rayhawk, Steve -- Kelley, Scott -- Tran, Tuong -- Haynes, Matthew -- Liu, Hong -- Furlan, Mike -- Wegley, Linda -- Chau, Betty -- Ruan, Yijun -- Hall, Dana -- Angly, Florent E -- Edwards, Robert A -- Li, Linlin -- Thurber, Rebecca Vega -- Reid, R Pamela -- Siefert, Janet -- Souza, Valeria -- Valentine, David L -- Swan, Brandon K -- Breitbart, Mya -- Rohwer, Forest -- England -- Nature. 2008 Mar 20;452(7185):340-3. doi: 10.1038/nature06735. Epub 2008 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, San Diego State University, San Diego, California 92182, USA. cdesnues@yahoo.fr〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18311127" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophages/classification/genetics/*isolation & purification/*physiology ; Bahamas ; *Biodiversity ; Capsid/chemistry ; Computational Biology ; DNA, Viral/analysis/genetics ; *Ecosystem ; Fresh Water/microbiology/virology ; Genome, Viral/genetics ; Genomics ; *Geography ; Geologic Sediments/microbiology/virology ; Mexico ; Molecular Sequence Data ; Phylogeny ; Proteome/metabolism ; Seawater/microbiology/virology ; *Water Microbiology
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    NLRX1 is a regulator of mitochondrial antiviral immunity (2008)
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    Publication Date: 2008-01-18
    Description: The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection. MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moore, Chris B -- Bergstralh, Daniel T -- Duncan, Joseph A -- Lei, Yu -- Morrison, Thomas E -- Zimmermann, Albert G -- Accavitti-Loper, Mary A -- Madden, Victoria J -- Sun, Lijun -- Ye, Zhengmao -- Lich, John D -- Heise, Mark T -- Chen, Zhijian -- Ting, Jenny P-Y -- England -- Nature. 2008 Jan 31;451(7178):573-7. doi: 10.1038/nature06501. Epub 2008 Jan 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology-Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18200010" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/antagonists & inhibitors/metabolism ; Animals ; Cell Line ; Cloning, Molecular ; Computational Biology ; Humans ; Interferon-beta/biosynthesis/genetics/metabolism ; Mice ; Mitochondria/*immunology/*metabolism ; Mitochondrial Membranes/metabolism ; Mitochondrial Proteins/genetics/*metabolism ; NF-kappa B/metabolism ; Protein Binding ; Protein Transport ; RNA, Small Interfering/genetics/metabolism ; Signal Transduction ; Virus Replication ; Viruses/*immunology
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    Negative regulation of the deacetylase SIRT1 by DBC1 (2008)
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    Publication Date: 2008-02-01
    Description: SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation; we and others previously found that SIRT1 promotes cell survival by deacetylating p53 (refs 4-6). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1alpha directly modulate metabolic responses. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866287/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866287/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Wenhui -- Kruse, Jan-Philipp -- Tang, Yi -- Jung, Sung Yun -- Qin, Jun -- Gu, Wei -- R01 CA085533/CA/NCI NIH HHS/ -- R01 CA098821/CA/NCI NIH HHS/ -- R01 CA098821-06A1/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jan 31;451(7178):587-90. doi: 10.1038/nature06515.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Genetics, and Department of Pathology College of Physicians and Surgeons, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18235502" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Adaptor Proteins, Signal Transducing/deficiency/genetics/*metabolism ; Apoptosis ; Cell Line, Tumor ; Humans ; Immunoprecipitation ; Protein Binding ; RNA Interference ; RNA, Small Interfering/genetics/metabolism ; Sirtuin 1 ; Sirtuins/*antagonists & inhibitors/deficiency/genetics/*metabolism ; Transcriptional Activation ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    Identification of ALK as a major familial neuroblastoma predisposition gene (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-08-30
    Description: Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672043/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672043/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mosse, Yael P -- Laudenslager, Marci -- Longo, Luca -- Cole, Kristina A -- Wood, Andrew -- Attiyeh, Edward F -- Laquaglia, Michael J -- Sennett, Rachel -- Lynch, Jill E -- Perri, Patrizia -- Laureys, Genevieve -- Speleman, Frank -- Kim, Cecilia -- Hou, Cuiping -- Hakonarson, Hakon -- Torkamani, Ali -- Schork, Nicholas J -- Brodeur, Garrett M -- Tonini, Gian P -- Rappaport, Eric -- Devoto, Marcella -- Maris, John M -- K08 CA111733/CA/NCI NIH HHS/ -- K08 CA111733-04/CA/NCI NIH HHS/ -- K08-111733/PHS HHS/ -- R01 CA078545/CA/NCI NIH HHS/ -- R01 CA078545-09/CA/NCI NIH HHS/ -- R01 CA124709/CA/NCI NIH HHS/ -- R01-CA78454/CA/NCI NIH HHS/ -- R01-CA87847/CA/NCI NIH HHS/ -- U10 CA098543/CA/NCI NIH HHS/ -- U10 CA098543-06/CA/NCI NIH HHS/ -- England -- Nature. 2008 Oct 16;455(7215):930-5. doi: 10.1038/nature07261. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724359" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Line, Tumor ; Child ; Chromosomes, Human, Pair 2/genetics ; Female ; Gene Dosage ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease/*genetics ; Germ-Line Mutation/genetics ; Humans ; Male ; Models, Molecular ; Molecular Sequence Data ; Mutation/*genetics ; Neuroblastoma/*enzymology/*genetics ; Pedigree ; Phosphorylation ; Protein Structure, Tertiary ; Protein-Tyrosine Kinases/chemistry/deficiency/*genetics ; Receptor Protein-Tyrosine Kinases
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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