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  • Models, Biological
  • Protein Binding
  • Nature Publishing Group (NPG)  (86)
  • American Institute of Physics (AIP)
  • Wiley
  • 2010-2014  (86)
  • 1990-1994
  • 2012  (86)
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  • 2010-2014  (86)
  • 1990-1994
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  • 1
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    Death-rate row blurs mutant flu debate (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2012 Feb 13;482(7385):289. doi: 10.1038/482289a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22337028" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Viral/analysis/immunology ; Humans ; Influenza A Virus, H5N1 Subtype/*genetics/immunology/isolation & ; purification/*pathogenicity ; Influenza, Human/epidemiology/immunology/*mortality/virology ; Models, Biological ; Poultry/virology ; Seroepidemiologic Studies ; Zoonoses/epidemiology/transmission/virology
    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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    A transcriptomic hourglass in plant embryogenesis (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-09-07
    Description: Animal and plant development starts with a constituting phase called embryogenesis, which evolved independently in both lineages. Comparative anatomy of vertebrate development--based on the Meckel-Serres law and von Baer's laws of embryology from the early nineteenth century--shows that embryos from various taxa appear different in early stages, converge to a similar form during mid-embryogenesis, and again diverge in later stages. This morphogenetic series is known as the embryonic 'hourglass', and its bottleneck of high conservation in mid-embryogenesis is referred to as the phylotypic stage. Recent analyses in zebrafish and Drosophila embryos provided convincing molecular support for the hourglass model, because during the phylotypic stage the transcriptome was dominated by ancient genes and global gene expression profiles were reported to be most conserved. Although extensively explored in animals, an embryonic hourglass has not been reported in plants, which represent the second major kingdom in the tree of life that evolved embryogenesis. Here we provide phylotranscriptomic evidence for a molecular embryonic hourglass in Arabidopsis thaliana, using two complementary approaches. This is particularly significant because the possible absence of an hourglass based on morphological features in plants suggests that morphological and molecular patterns might be uncoupled. Together with the reported developmental hourglass patterns in animals, these findings indicate convergent evolution of the molecular hourglass and a conserved logic of embryogenesis across kingdoms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Quint, Marcel -- Drost, Hajk-Georg -- Gabel, Alexander -- Ullrich, Kristian Karsten -- Bonn, Markus -- Grosse, Ivo -- England -- Nature. 2012 Oct 4;490(7418):98-101. doi: 10.1038/nature11394. Epub 2012 Sep 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Leibniz Institute of Plant Biochemistry, Department of Molecular Signal Processing, Weinberg 3, 06120 Halle (Saale), Germany. mquint@ipb-halle.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22951968" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arabidopsis/classification/*embryology/*genetics ; Brassicaceae/genetics ; Conserved Sequence/genetics ; Developmental Biology ; Drosophila/embryology/genetics ; Embryonic Development/genetics ; Evolution, Molecular ; Gene Expression Profiling ; Gene Expression Regulation, Plant/*genetics ; Genes, Plant/genetics ; Models, Biological ; Plant Development/*genetics ; Transcriptome/*genetics ; Zebrafish/embryology
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Turing centenary: Pattern formation (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reinitz, John -- England -- Nature. 2012 Feb 22;482(7386):464. doi: 10.1038/482464a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Statistics, University of Chicago, Chicago, Illinois 60637, USA. reinitz@galton.uchicago.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22358813" target="_blank"〉PubMed〈/a〉
    Keywords: Computer Simulation ; Developmental Biology/*history ; Diffusion ; History, 19th Century ; History, 20th Century ; Models, Biological ; Morphogenesis/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Visualizing molecular juggling within a B12-dependent methyltransferase complex (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-16
    Description: Derivatives of vitamin B(12) are used in methyl group transfer in biological processes as diverse as methionine synthesis in humans and CO(2) fixation in acetogenic bacteria. This seemingly straightforward reaction requires large, multimodular enzyme complexes that adopt multiple conformations to alternately activate, protect and perform catalysis on the reactive B(12) cofactor. Crystal structures determined thus far have provided structural information for only fragments of these complexes, inspiring speculation about the overall protein assembly and conformational movements inherent to activity. Here we present X-ray crystal structures of a complete 220 kDa complex that contains all enzymes responsible for B(12)-dependent methyl transfer, namely the corrinoid iron-sulphur protein and its methyltransferase from the model acetogen Moorella thermoacetica. These structures provide the first three-dimensional depiction of all protein modules required for the activation, protection and catalytic steps of B(12)-dependent methyl transfer. In addition, the structures capture B(12) at multiple locations between its 'resting' and catalytic positions, allowing visualization of the dramatic protein rearrangements that enable methyl transfer and identification of the trajectory for B(12) movement within the large enzyme scaffold. The structures are also presented alongside in crystallo spectroscopic data, which confirm enzymatic activity within crystals and demonstrate the largest known conformational movements of proteins in a crystalline state. Taken together, this work provides a model for the molecular juggling that accompanies turnover and helps explain why such an elaborate protein framework is required for such a simple, yet biologically essential reaction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326194/" 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/PMC3326194/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kung, Yan -- Ando, Nozomi -- Doukov, Tzanko I -- Blasiak, Leah C -- Bender, Gunes -- Seravalli, Javier -- Ragsdale, Stephen W -- Drennan, Catherine L -- GM39451/GM/NIGMS NIH HHS/ -- GM69857/GM/NIGMS NIH HHS/ -- R01 GM039451/GM/NIGMS NIH HHS/ -- R01 GM039451-25/GM/NIGMS NIH HHS/ -- R01 GM069857/GM/NIGMS NIH HHS/ -- R37 GM039451/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- T32 GM008334/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 14;484(7393):265-9. doi: 10.1038/nature10916.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, 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/22419154" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Biocatalysis ; Corrinoids/metabolism ; Crystallography, X-Ray ; Folic Acid/metabolism ; Iron-Sulfur Proteins/*chemistry/*metabolism ; Methylation ; Methyltransferases/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Moorella/chemistry/*enzymology ; Protein Multimerization ; Protein Structure, Tertiary ; Vitamin B 12/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Large-scale vortex lattice emerging from collectively moving microtubules (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-23
    Description: Spontaneous collective motion, as in some flocks of bird and schools of fish, is an example of an emergent phenomenon. Such phenomena are at present of great interest and physicists have put forward a number of theoretical results that so far lack experimental verification. In animal behaviour studies, large-scale data collection is now technologically possible, but data are still scarce and arise from observations rather than controlled experiments. Multicellular biological systems, such as bacterial colonies or tissues, allow more control, but may have many hidden variables and interactions, hindering proper tests of theoretical ideas. However, in systems on the subcellular scale such tests may be possible, particularly in in vitro experiments with only few purified components. Motility assays, in which protein filaments are driven by molecular motors grafted to a substrate in the presence of ATP, can show collective motion for high densities of motors and attached filaments. This was demonstrated recently for the actomyosin system, but a complete understanding of the mechanisms at work is still lacking. Here we report experiments in which microtubules are propelled by surface-bound dyneins. In this system it is possible to study the local interaction: we find that colliding microtubules align with each other with high probability. At high densities, this alignment results in self-organization of the microtubules, which are on average 15 microm long, into vortices with diameters of around 400 microm. Inside the vortices, the microtubules circulate both clockwise and anticlockwise. On longer timescales, the vortices form a lattice structure. The emergence of these structures, as verified by a mathematical model, is the result of the smooth, reptation-like motion of single microtubules in combination with local interactions (the nematic alignment due to collisions)--there is no need for long-range interactions. Apart from its potential relevance to cortical arrays in plant cells and other biological situations, our study provides evidence for the existence of previously unsuspected universality classes of collective motion phenomena.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sumino, Yutaka -- Nagai, Ken H -- Shitaka, Yuji -- Tanaka, Dan -- Yoshikawa, Kenichi -- Chate, Hugues -- Oiwa, Kazuhiro -- England -- Nature. 2012 Mar 21;483(7390):448-52. doi: 10.1038/nature10874.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Aichi University of Education, Aichi 448-8542, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22437613" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chlamydomonas ; Dyneins/metabolism ; Flagella ; Microtubules/*metabolism ; Models, Biological ; *Movement
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  • 6
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    Structural insight into the type-II mitochondrial NADH dehydrogenases (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-23
    Description: The single-component type-II NADH dehydrogenases (NDH-2s) serve as alternatives to the multisubunit respiratory complex I (type-I NADH dehydrogenase (NDH-1), also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) in catalysing electron transfer from NADH to ubiquinone in the mitochondrial respiratory chain. The yeast NDH-2 (Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone to maintain mitochondrial NADH/NAD(+) homeostasis. Ndi1 is a potential therapeutic agent for human diseases caused by complex I defects, particularly Parkinson's disease, because its expression restores the mitochondrial activity in animals with complex I deficiency. NDH-2s in pathogenic microorganisms are viable targets for new antibiotics. Here we solve the crystal structures of Ndi1 in its substrate-free, NADH-, ubiquinone- and NADH-ubiquinone-bound states, to help understand the catalytic mechanism of NDH-2s. We find that Ndi1 homodimerization through its carboxy-terminal domain is critical for its catalytic activity and membrane targeting. The structures reveal two ubiquinone-binding sites (UQ(I) and UQ(II)) in Ndi1. NADH and UQ(I) can bind to Ndi1 simultaneously to form a substrate-protein complex. We propose that UQ(I) interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD-UQ(I) complex to UQ(II). Together our data reveal the regulatory and catalytic mechanisms of Ndi1 and may facilitate the development or targeting of NDH-2s for potential therapeutic applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feng, Yue -- Li, Wenfei -- Li, Jian -- Wang, Jiawei -- Ge, Jingpeng -- Xu, Duo -- Liu, Yanjing -- Wu, Kaiqi -- Zeng, Qingyin -- Wu, Jia-Wei -- Tian, Changlin -- Zhou, Bing -- Yang, Maojun -- England -- Nature. 2012 Nov 15;491(7424):478-82. doi: 10.1038/nature11541. Epub 2012 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23086143" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Electron Transport Complex I/*chemistry/isolation & purification/metabolism ; Mitochondria/*enzymology ; *Models, Molecular ; NAD/chemistry ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/chemistry/enzymology ; Saccharomyces cerevisiae Proteins/*chemistry/isolation & purification/metabolism ; Ubiquinone/chemistry
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  • 7
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    The human CST complex is a terminator of telomerase activity (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-06
    Description: The lengths of human telomeres, which protect chromosome ends from degradation and end fusions, are crucial determinants of cell lifespan. During embryogenesis and in cancer, the telomerase enzyme counteracts telomeric DNA shortening. As shown in cancer cells, human telomerase binds the shelterin component TPP1 at telomeres during the S phase of the cell cycle, and adds ~60 nucleotides in a single round of extension, after which telomerase is turned off by unknown mechanisms. Here we show that the human CST (CTC1, STN1 and TEN1) complex, previously implicated in telomere protection and DNA metabolism, inhibits telomerase activity through primer sequestration and physical interaction with the protection of telomeres 1 (POT1)-TPP1 telomerase processivity factor. CST competes with POT1-TPP1 for telomeric DNA, and CST-telomeric-DNA binding increases during late S/G2 phase only on telomerase action, coinciding with telomerase shut-off. Depletion of CST allows excessive telomerase activity, promoting telomere elongation. We propose that through binding of the telomerase-extended telomere, CST limits telomerase action at individual telomeres to approximately one binding and extension event per cell cycle. Our findings define the sequence of events that occur to first enable and then terminate telomerase-mediated telomere elongation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Liuh-Yow -- Redon, Sophie -- Lingner, Joachim -- 232812/European Research Council/International -- England -- Nature. 2012 Aug 23;488(7412):540-4. doi: 10.1038/nature11269.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Federale de Lausanne, Station 19, 1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763445" target="_blank"〉PubMed〈/a〉
    Keywords: Aminopeptidases/metabolism ; Base Sequence ; Cell Line, Tumor ; DNA/genetics/metabolism ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Electrophoretic Mobility Shift Assay ; Enzyme Assays ; G2 Phase ; HEK293 Cells ; Humans ; Longevity ; Multiprotein Complexes/chemistry/genetics/*metabolism ; Protein Binding ; S Phase ; Serine Proteases/metabolism ; Telomerase/*antagonists & inhibitors/metabolism ; Telomere/genetics/metabolism ; Telomere-Binding Proteins/genetics/*metabolism
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  • 8
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    Atmospheric CO2 forces abrupt vegetation shifts locally, but not globally (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-06
    Description: It is possible that anthropogenic climate change will drive the Earth system into a qualitatively different state. Although different types of uncertainty limit our capacity to assess this risk, Earth system scientists are particularly concerned about tipping elements, large-scale components of the Earth system that can be switched into qualitatively different states by small perturbations. Despite growing evidence that tipping elements exist in the climate system, whether large-scale vegetation systems can tip into alternative states is poorly understood. Here we show that tropical grassland, savanna and forest ecosystems, areas large enough to have powerful impacts on the Earth system, are likely to shift to alternative states. Specifically, we show that increasing atmospheric CO2 concentration will force transitions to vegetation states characterized by higher biomass and/or woody-plant dominance. The timing of these critical transitions varies as a result of between-site variance in the rate of temperature increase, as well as a dependence on stochastic variation in fire severity and rainfall. We further show that the locations of bistable vegetation zones (zones where alternative vegetation states can exist) will shift as climate changes. We conclude that even though large-scale directional regime shifts in terrestrial ecosystems are likely, asynchrony in the timing of these shifts may serve to dampen, but not nullify, the shock that these changes may represent to the Earth system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Higgins, Steven I -- Scheiter, Simon -- England -- Nature. 2012 Aug 9;488(7410):209-12. doi: 10.1038/nature11238.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut fur Physische Geographie, Goethe Universitat Frankfurt am Main, 60438 Frankfurt am Main, Germany. higgins@em.uni-frankfurt.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763447" target="_blank"〉PubMed〈/a〉
    Keywords: Africa ; Atmosphere/*chemistry ; Biomass ; Carbon/metabolism ; Carbon Dioxide/analysis/*metabolism ; Climate Change/*statistics & numerical data ; *Ecosystem ; Fires ; Geography ; History, 19th Century ; History, 20th Century ; History, 21st Century ; Hot Temperature ; Models, Biological ; Photosynthesis/physiology ; Poaceae/growth & development/metabolism ; Probability ; Rain ; Stochastic Processes ; Time Factors ; Trees/*growth & development/metabolism ; Wood
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  • 9
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    Telomerase RNA biogenesis involves sequential binding by Sm and Lsm complexes (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-27
    Description: In most eukaryotes, the progressive loss of chromosome-terminal DNA sequences is counteracted by the enzyme telomerase, a reverse transcriptase that uses part of an RNA subunit as template to synthesize telomeric repeats. Many cancer cells express high telomerase activity, and mutations in telomerase subunits are associated with degenerative syndromes including dyskeratosis congenita and aplastic anaemia. The therapeutic value of altering telomerase activity thus provides ample impetus to study the biogenesis and regulation of this enzyme in human cells and model systems. We have previously identified a precursor of the fission yeast telomerase RNA subunit (TER1) and demonstrated that the mature 3'-end is generated by the spliceosome in a single cleavage reaction akin to the first step of splicing. Directly upstream and partly overlapping with the spliceosomal cleavage site is a putative binding site for Sm proteins. Sm and like-Sm (LSm) proteins belong to an ancient family of RNA-binding proteins represented in all three domains of life. Members of this family form ring complexes on specific sets of target RNAs and have critical roles in their biogenesis, function and turnover. Here we demonstrate that the canonical Sm ring and the Lsm2-8 complex sequentially associate with fission yeast TER1. The Sm ring binds to the TER1 precursor, stimulates spliceosomal cleavage and promotes the hypermethylation of the 5'-cap by Tgs1. Sm proteins are then replaced by the Lsm2-8 complex, which promotes the association with the catalytic subunit and protects the mature 3'-end of TER1 from exonucleolytic degradation. Our findings define the sequence of events that occur during telomerase biogenesis and characterize roles for Sm and Lsm complexes as well as for the methylase Tgs1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326189/" 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/PMC3326189/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tang, Wen -- Kannan, Ram -- Blanchette, Marco -- Baumann, Peter -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 25;484(7393):260-4. doi: 10.1038/nature10924.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Kansas City, Missouri 64110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22446625" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Chromosomes, Fungal/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Methyltransferases/metabolism ; Multiprotein Complexes/chemistry/*metabolism ; Protein Binding ; RNA/*biosynthesis/genetics ; RNA Splicing ; RNA, Fungal/genetics/metabolism ; RNA-Binding Proteins/*metabolism ; Schizosaccharomyces/enzymology/*genetics/*metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Spliceosomes/*metabolism ; Telomerase/*biosynthesis/genetics ; Telomere/genetics/metabolism ; tRNA Methyltransferases/metabolism
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    Ubiquitin chain conformation regulates recognition and activity of interacting proteins (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-12-04
    Description: Mechanisms of protein recognition have been extensively studied for single-domain proteins, but are less well characterized for dynamic multidomain systems. Ubiquitin chains represent a biologically important multidomain system that requires recognition by structurally diverse ubiquitin-interacting proteins. Ubiquitin chain conformations in isolation are often different from conformations observed in ubiquitin-interacting protein complexes, indicating either great dynamic flexibility or extensive chain remodelling upon binding. Using single-molecule fluorescence resonance energy transfer, we show that Lys 63-, Lys 48- and Met 1-linked diubiquitin exist in several distinct conformational states in solution. Lys 63- and Met 1-linked diubiquitin adopt extended 'open' and more compact 'closed' conformations, and ubiquitin-binding domains and deubiquitinases (DUBs) select pre-existing conformations. By contrast, Lys 48-linked diubiquitin adopts predominantly compact conformations. DUBs directly recognize existing conformations, but may also remodel ubiquitin chains to hydrolyse the isopeptide bond. Disruption of the Lys 48-diubiquitin interface changes conformational dynamics and affects DUB activity. Hence, conformational equilibria in ubiquitin chains provide an additional layer of regulation in the ubiquitin system, and distinct conformations observed in differently linked polyubiquitin may contribute to the specificity of ubiquitin-interacting proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605796/" 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/PMC3605796/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ye, Yu -- Blaser, Georg -- Horrocks, Mathew H -- Ruedas-Rama, Maria J -- Ibrahim, Shehu -- Zhukov, Alexander A -- Orte, Angel -- Klenerman, David -- Jackson, Sophie E -- Komander, David -- 092096/Wellcome Trust/United Kingdom -- BB/F00219X/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105192732/Medical Research Council/United Kingdom -- U.1051.03.019.00001.01(92732)/Medical Research Council/United Kingdom -- U105192732/Medical Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):266-70. doi: 10.1038/nature11722. Epub 2012 Dec 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Protein and Nucleic Acids Chemistry, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201676" target="_blank"〉PubMed〈/a〉
    Keywords: Fluorescence Resonance Energy Transfer ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; Ubiquitin/*chemistry/*metabolism
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    A unifying model for mTORC1-mediated regulation of mRNA translation (2012)
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    Publication Date: 2012-05-04
    Description: The mTOR complex 1 (mTORC1) kinase nucleates a pathway that promotes cell growth and proliferation and is the target of rapamycin, a drug with many clinical uses. mTORC1 regulates messenger RNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how mTORC1 differentially controls the translation of specific mRNAs. Here we use high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR inhibitor Torin 1, which, unlike rapamycin, fully inhibits mTORC1 (ref. 2). Our data reveal a surprisingly simple model of the mRNA features and mechanisms that confer mTORC1-dependent translation control. The subset of mRNAs that are specifically regulated by mTORC1 consists almost entirely of transcripts with established 5' terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1 and Ybx1, with previously unrecognized TOP or related TOP-like motifs that we identified. We find no evidence to support proposals that mTORC1 preferentially regulates mRNAs with increased 5' untranslated region length or complexity. mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown. Remarkably, loss of just the 4E-BP family of translational repressors, arguably the best characterized mTORC1 substrates, is sufficient to render TOP and TOP-like mRNA translation resistant to Torin 1. The 4E-BPs inhibit translation initiation by interfering with the interaction between the cap-binding protein eIF4E and eIF4G1. Loss of this interaction diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other mRNAs, explaining why mTOR inhibition selectively suppresses their translation. Our results clarify the translational program controlled by mTORC1 and identify 4E-BPs and eIF4G1 as its master effectors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347774/" 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/PMC3347774/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thoreen, Carson C -- Chantranupong, Lynne -- Keys, Heather R -- Wang, Tim -- Gray, Nathanael S -- Sabatini, David M -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA103866-08/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 2;485(7396):109-13. doi: 10.1038/nature11083.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana Farber Cancer Institute, 250 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22552098" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/genetics ; Animals ; Base Sequence ; Cell Line, Tumor ; Eukaryotic Initiation Factor-4E/metabolism ; Eukaryotic Initiation Factor-4G/metabolism ; *Gene Expression Regulation/drug effects ; Humans ; Male ; Mice ; *Models, Biological ; Multiprotein Complexes ; Naphthyridines/pharmacology ; Nucleotide Motifs ; Phosphorylation ; Prostatic Neoplasms/genetics/pathology ; Protein Binding ; *Protein Biosynthesis/drug effects ; Proteins/antagonists & inhibitors/*metabolism ; RNA, Messenger/genetics/metabolism ; Ribosomes/metabolism ; TOR Serine-Threonine Kinases
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    Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes (2012)
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    Publication Date: 2012-11-13
    Description: Chromatin-remodelling complexes (CRCs) mobilize nucleosomes to mediate the access of DNA-binding factors to their sites in vivo. These CRCs contain a catalytic subunit that bears an ATPase/DNA-translocase domain and flanking regions that bind nucleosomal epitopes. A central question is whether and how these flanking regions regulate ATP hydrolysis or the coupling of hydrolysis to DNA translocation, to affect nucleosome-sliding efficiency. ISWI-family CRCs contain the protein ISWI, which uses its ATPase/DNA-translocase domain to pump DNA around the histone octamer to enable sliding. ISWI is positively regulated by two 'activating' nucleosomal epitopes: the 'basic patch' on the histone H4 tail, and extranucleosomal (linker) DNA. Previous work defined the HAND-SANT-SLIDE (HSS) domain at the ISWI carboxy terminus that binds linker DNA, needed for ISWI activity. Here we define two new, conserved and separate regulatory regions on Drosophila ISWI, termed AutoN and NegC, which negatively regulate ATP hydrolysis (AutoN) or the coupling of ATP hydrolysis to productive DNA translocation (NegC). The two aforementioned nucleosomal epitopes promote remodelling indirectly by preventing the negative regulation of AutoN and NegC. Notably, mutation or removal of AutoN and NegC enables marked nucleosome sliding without the H4 basic patch or extranucleosomal DNA, or the HSS domain, conferring on ISWI the biochemical attributes normally associated with SWI/SNF-family ATPases. Thus, the ISWI ATPase catalytic core is an intrinsically active DNA translocase that conducts nucleosome sliding, onto which selective 'inhibition-of-inhibition' modules are placed, to help ensure that remodelling occurs only in the presence of proper nucleosomal epitopes. This supports a general concept for the specialization of chromatin-remodelling ATPases, in which specific regulatory modules adapt an ancient active DNA translocase to conduct particular tasks only on the appropriate chromatin landscape.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631562/" 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/PMC3631562/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clapier, Cedric R -- Cairns, Bradley R -- CA042014/CA/NCI NIH HHS/ -- GM60415/GM/NIGMS NIH HHS/ -- R01 GM060415/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 13;492(7428):280-4. doi: 10.1038/nature11625. Epub 2012 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA. cedric.clapier@hci.utah.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23143334" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/*genetics/*metabolism ; Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Animals ; Chromatin Assembly and Disassembly ; Drosophila Proteins/chemistry/genetics/metabolism ; Drosophila melanogaster/enzymology/*genetics/*metabolism ; Epitopes/*metabolism ; *Gene Expression Regulation ; Hydrolysis ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Nucleosomes/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Regulatory Sequences, Nucleic Acid/genetics ; Sequence Alignment ; Transcription Factors/chemistry/*genetics/*metabolism
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    The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP (2012)
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    Publication Date: 2012-11-13
    Description: Mutations in the gene encoding NLRP3 cause a spectrum of autoinflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS). NLRP3 is a key component of one of several distinct cytoplasmic multiprotein complexes (inflammasomes) that mediate the maturation of the proinflammatory cytokine interleukin-1beta (IL-1beta) by activating caspase-1. Although several models for inflammasome activation, such as K(+) efflux, generation of reactive oxygen species and lysosomal destabilization, have been proposed, the precise molecular mechanism of NLRP3 inflammasome activation, as well as the mechanism by which CAPS-associated mutations activate NLRP3, remain to be elucidated. Here we show that the murine calcium-sensing receptor (CASR) activates the NLRP3 inflammasome, mediated by increased intracellular Ca(2+) and decreased cellular cyclic AMP (cAMP). Ca(2+) or other CASR agonists activate the NLRP3 inflammasome in the absence of exogenous ATP, whereas knockdown of CASR reduces inflammasome activation in response to known NLRP3 activators. CASR activates the NLRP3 inflammasome through phospholipase C, which catalyses inositol-1,4,5-trisphosphate production and thereby induces release of Ca(2+) from endoplasmic reticulum stores. The increased cytoplasmic Ca(2+) promotes the assembly of inflammasome components, and intracellular Ca(2+) is required for spontaneous inflammasome activity in cells from patients with CAPS. CASR stimulation also results in reduced intracellular cAMP, which independently activates the NLRP3 inflammasome. cAMP binds to NLRP3 directly to inhibit inflammasome assembly, and downregulation of cAMP relieves this inhibition. The binding affinity of cAMP for CAPS-associated mutant NLRP3 is substantially lower than for wild-type NLRP3, and the uncontrolled mature IL-1beta production from CAPS patients' peripheral blood mononuclear cells is attenuated by increasing cAMP. Taken together, these findings indicate that Ca(2+) and cAMP are two key molecular regulators of the NLRP3 inflammasome that have critical roles in the molecular pathogenesis of CAPS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175565/" 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/PMC4175565/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Geun-Shik -- Subramanian, Naeha -- Kim, Andrew I -- Aksentijevich, Ivona -- Goldbach-Mansky, Raphaela -- Sacks, David B -- Germain, Ronald N -- Kastner, Daniel L -- Chae, Jae Jin -- Z99 HG999999/Intramural NIH HHS/ -- England -- Nature. 2012 Dec 6;492(7427):123-7. doi: 10.1038/nature11588. Epub 2012 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23143333" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Calcium/*metabolism ; *Calcium Signaling ; Carrier Proteins/genetics/*metabolism ; Cryopyrin-Associated Periodic Syndromes/etiology/genetics/metabolism ; Cyclic AMP/*metabolism ; Endoplasmic Reticulum/metabolism ; Gene Knockdown Techniques ; Humans ; Inflammasomes/*metabolism ; Inositol 1,4,5-Trisphosphate/metabolism ; Interleukin-1beta/biosynthesis/metabolism ; Leukocytes, Mononuclear/metabolism ; Mice ; Protein Binding ; Receptors, Calcium-Sensing/*metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Type C Phospholipases/metabolism
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    The same pocket in menin binds both MLL and JUND but has opposite effects on transcription (2012)
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    Publication Date: 2012-02-14
    Description: Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs. Menin interacts with many proteins and is involved in a variety of cellular processes. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity. Several MEN1 missense mutations disrupt the menin-JUND interaction, suggesting a correlation between the tumour-suppressor function of menin and its suppression of JUND-activated transcription. Menin also interacts with mixed lineage leukaemia protein 1 (MLL1), a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription and promote MLL1-fusion-protein-induced leukaemogenesis. A recent report on the tethering of MLL1 to chromatin binding factor lens epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions of multiple proteins. Despite its importance, how menin interacts with many distinct partners and regulates their functions remains poorly understood. Here we present the crystal structures of human menin in its free form and in complexes with MLL1 or with JUND, or with an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983792/" 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/PMC3983792/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Jing -- Gurung, Buddha -- Wan, Bingbing -- Matkar, Smita -- Veniaminova, Natalia A -- Wan, Ke -- Merchant, Juanita L -- Hua, Xianxin -- Lei, Ming -- GM083015-01/GM/NIGMS NIH HHS/ -- R01 DK085121/DK/NIDDK NIH HHS/ -- R01-DK085121/DK/NIDDK NIH HHS/ -- R37 DK045729/DK/NIDDK NIH HHS/ -- R37-DK45729/DK/NIDDK NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 12;482(7386):542-6. doi: 10.1038/nature10806.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22327296" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Binding Sites ; Chromatin/metabolism ; Crystallography, X-Ray ; Fibroblasts ; HEK293 Cells ; Histone-Lysine N-Methyltransferase ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mice ; Models, Molecular ; Molecular Sequence Data ; Myeloid-Lymphoid Leukemia Protein/chemistry/*metabolism ; Phosphorylation ; Protein Binding ; Protein Multimerization ; Proto-Oncogene Proteins/*chemistry/*metabolism ; Proto-Oncogene Proteins c-jun/chemistry/*metabolism ; Structure-Activity Relationship ; *Transcription, Genetic
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    Broad and potent neutralization of HIV-1 by a gp41-specific human antibody (2012)
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    Publication Date: 2012-11-16
    Description: Characterization of human monoclonal antibodies is providing considerable insight into mechanisms of broad HIV-1 neutralization. Here we report an HIV-1 gp41 membrane-proximal external region (MPER)-specific antibody, named 10E8, which neutralizes approximately 98% of tested viruses. An analysis of sera from 78 healthy HIV-1-infected donors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-like specificities. In contrast to other neutralizing MPER antibodies, 10E8 did not bind phospholipids, was not autoreactive, and bound cell-surface envelope. The structure of 10E8 in complex with the complete MPER revealed a site of vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobic residues and a critical arginine or lysine just before the transmembrane region. Analysis of resistant HIV-1 variants confirmed the importance of these residues for neutralization. The highly conserved MPER is a target of potent, non-self-reactive neutralizing antibodies, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 envelope glycoprotein.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Jinghe -- Ofek, Gilad -- Laub, Leo -- Louder, Mark K -- Doria-Rose, Nicole A -- Longo, Nancy S -- Imamichi, Hiromi -- Bailer, Robert T -- Chakrabarti, Bimal -- Sharma, Shailendra K -- Alam, S Munir -- Wang, Tao -- Yang, Yongping -- Zhang, Baoshan -- Migueles, Stephen A -- Wyatt, Richard -- Haynes, Barton F -- Kwong, Peter D -- Mascola, John R -- Connors, Mark -- HSN261200800001E/PHS HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2012 Nov 15;491(7424):406-12. doi: 10.1038/nature11544. Epub 2012 Sep 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23151583" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution ; Antibodies, Neutralizing/chemistry/*metabolism ; Antibody Specificity ; Cells, Cultured ; HEK293 Cells ; HIV Antibodies/chemistry/isolation & purification/*metabolism ; HIV Envelope Protein gp41/chemistry/*immunology ; HIV-1/*physiology ; Humans ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Tertiary
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    A bimodular mechanism of calcium control in eukaryotes (2012)
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    Publication Date: 2012-10-23
    Description: Calcium ions (Ca(2+)) have an important role as secondary messengers in numerous signal transduction processes, and cells invest much energy in controlling and maintaining a steep gradient between intracellular ( approximately 0.1-micromolar) and extracellular ( approximately 2-millimolar) Ca(2+) concentrations. Calmodulin-stimulated calcium pumps, which include the plasma-membrane Ca(2+)-ATPases (PMCAs), are key regulators of intracellular Ca(2+) in eukaryotes. They contain a unique amino- or carboxy-terminal regulatory domain responsible for autoinhibition, and binding of calcium-loaded calmodulin to this domain releases autoinhibition and activates the pump. However, the structural basis for the activation mechanism is unknown and a key remaining question is how calmodulin-mediated PMCA regulation can cover both basal Ca(2+) levels in the nanomolar range as well as micromolar-range Ca(2+) transients generated by cell stimulation. Here we present an integrated study combining the determination of the high-resolution crystal structure of a PMCA regulatory-domain/calmodulin complex with in vivo characterization and biochemical, biophysical and bioinformatics data that provide mechanistic insights into a two-step PMCA activation mechanism mediated by calcium-loaded calmodulin. The structure shows the entire PMCA regulatory domain and reveals an unexpected 2:1 stoichiometry with two calcium-loaded calmodulin molecules binding to different sites on a long helix. A multifaceted characterization of the role of both sites leads to a general structural model for calmodulin-mediated regulation of PMCAs that allows stringent, highly responsive control of intracellular calcium in eukaryotes, making it possible to maintain a stable, basal level at a threshold Ca(2+) concentration, where steep activation occurs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tidow, Henning -- Poulsen, Lisbeth R -- Andreeva, Antonina -- Knudsen, Michael -- Hein, Kim L -- Wiuf, Carsten -- Palmgren, Michael G -- Nissen, Poul -- MC_U105192716/Medical Research Council/United Kingdom -- England -- Nature. 2012 Nov 15;491(7424):468-72. doi: 10.1038/nature11539. Epub 2012 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Membrane Pumps in Cells and Disease - PUMPKIN, Aarhus University, Gustav Wieds Vej 10c, DK-8000 Aarhus C, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23086147" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/chemistry/enzymology/*metabolism ; Arabidopsis Proteins/*chemistry/genetics/*metabolism ; Binding Sites ; Calcium/*metabolism ; Calcium-Transporting ATPases/*chemistry/genetics/*metabolism ; Calmodulin/*chemistry/metabolism ; Enzyme Activation ; Eukaryota/*metabolism ; Intracellular Space/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Tertiary ; Sequence Alignment
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    Tail-assisted pitch control in lizards, robots and dinosaurs (2012)
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    Publication Date: 2012-01-06
    Description: In 1969, a palaeontologist proposed that theropod dinosaurs used their tails as dynamic stabilizers during rapid or irregular movements, contributing to their depiction as active and agile predators. Since then the inertia of swinging appendages has been implicated in stabilizing human walking, aiding acrobatic manoeuvres by primates and rodents, and enabling cats to balance on branches. Recent studies on geckos suggest that active tail stabilization occurs during climbing, righting and gliding. By contrast, studies on the effect of lizard tail loss show evidence of a decrease, an increase or no change in performance. Application of a control-theoretic framework could advance our general understanding of inertial appendage use in locomotion. Here we report that lizards control the swing of their tails in a measured manner to redirect angular momentum from their bodies to their tails, stabilizing body attitude in the sagittal plane. We video-recorded Red-Headed Agama lizards (Agama agama) leaping towards a vertical surface by first vaulting onto an obstacle with variable traction to induce a range of perturbations in body angular momentum. To examine a known controlled tail response, we built a lizard-sized robot with an active tail that used sensory feedback to stabilize pitch as it drove off a ramp. Our dynamics model revealed that a body swinging its tail experienced less rotation than a body with a rigid tail, a passively compliant tail or no tail. To compare a range of tails, we calculated tail effectiveness as the amount of tailless body rotation a tail could stabilize. A model Velociraptor mongoliensis supported the initial tail stabilization hypothesis, showing as it did a greater tail effectiveness than the Agama lizards. Leaping lizards show that inertial control of body attitude can advance our understanding of appendage evolution and provide biological inspiration for the next generation of manoeuvrable search-and-rescue robots.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Libby, Thomas -- Moore, Talia Y -- Chang-Siu, Evan -- Li, Deborah -- Cohen, Daniel J -- Jusufi, Ardian -- Full, Robert J -- England -- Nature. 2012 Jan 4;481(7380):181-4. doi: 10.1038/nature10710.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Interdisciplinary Bio-Inspiration in Education and Research, University of California, Berkeley, California 94720-3140, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22217942" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Evolution ; Biomechanical Phenomena ; Computer Simulation ; Dinosaurs/*anatomy & histology/*physiology ; Feedback, Sensory/physiology ; Lizards/*anatomy & histology/*physiology ; Models, Biological ; Posture/physiology ; *Robotics/instrumentation ; Rotation ; Tail/*physiology
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    Lrp4 is a retrograde signal for presynaptic differentiation at neuromuscular synapses (2012)
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    Publication Date: 2012-08-03
    Description: Motor axons receive retrograde signals from skeletal muscle that are essential for the differentiation and stabilization of motor nerve terminals. Identification of these retrograde signals has proved elusive, but their production by muscle depends on the receptor tyrosine kinase, MuSK (muscle, skeletal receptor tyrosine-protein kinase), and Lrp4 (low-density lipoprotein receptor (LDLR)-related protein 4), an LDLR family member that forms a complex with MuSK, binds neural agrin and stimulates MuSK kinase activity. Here we show that Lrp4 also functions as a direct muscle-derived retrograde signal for early steps in presynaptic differentiation. We demonstrate that Lrp4 is necessary, independent of MuSK activation, for presynaptic differentiation in vivo, and we show that Lrp4 binds to motor axons and induces clustering of synaptic-vesicle and active-zone proteins. Thus, Lrp4 acts bidirectionally and coordinates synapse formation by binding agrin, activating MuSK and stimulating postsynaptic differentiation, and functioning in turn as a muscle-derived retrograde signal that is necessary and sufficient for presynaptic differentiation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448831/" 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/PMC3448831/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yumoto, Norihiro -- Kim, Natalie -- Burden, Steven J -- 5 P30CA16087-31/CA/NCI NIH HHS/ -- NS36193/NS/NINDS NIH HHS/ -- R01 NS036193/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Sep 20;489(7416):438-42. doi: 10.1038/nature11348. Epub 2012 Aug 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22854782" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis ; Animals ; *Cell Differentiation ; Cells, Cultured ; Coculture Techniques ; Diaphragm ; Mice ; Motor Neurons/metabolism ; Muscle, Skeletal/cytology/*innervation/metabolism ; Neural Tube/cytology/metabolism ; Neuromuscular Junction/*cytology/*metabolism ; Presynaptic Terminals/*metabolism ; Protein Binding ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptors, LDL/*metabolism ; Sarcopenia ; *Signal Transduction ; Synapsins/metabolism ; Tissue Culture Techniques
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    Genome-wide protein-DNA binding dynamics suggest a molecular clutch for transcription factor function (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-04-14
    Description: Dynamic access to genetic information is central to organismal development and environmental response. Consequently, genomic processes must be regulated by mechanisms that alter genome function relatively rapidly. Conventional chromatin immunoprecipitation (ChIP) experiments measure transcription factor occupancy, but give no indication of kinetics and are poor predictors of transcription factor function at a given locus. To measure transcription-factor-binding dynamics across the genome, we performed competition ChIP (refs 6, 7) with a sequence-specific Saccharomyces cerevisiae transcription factor, Rap1 (ref. 8). Rap1-binding dynamics and Rap1 occupancy were only weakly correlated (R(2) = 0.14), but binding dynamics were more strongly linked to function than occupancy. Long Rap1 residence was coupled to transcriptional activation, whereas fast binding turnover, which we refer to as 'treadmilling', was linked to low transcriptional output. Thus, DNA-binding events that seem identical by conventional ChIP may have different underlying modes of interaction that lead to opposing functional outcomes. We propose that transcription factor binding turnover is a major point of regulation in determining the functional consequences of transcription factor binding, and is mediated mainly by control of competition between transcription factors and nucleosomes. Our model predicts a clutch-like mechanism that rapidly engages a treadmilling transcription factor into a stable binding state, or vice versa, to modulate transcription factor function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341663/" 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/PMC3341663/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lickwar, Colin R -- Mueller, Florian -- Hanlon, Sean E -- McNally, James G -- Lieb, Jason D -- R01 GM072518/GM/NIGMS NIH HHS/ -- R01 GM072518-05/GM/NIGMS NIH HHS/ -- R01-GM072518/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2012 Apr 11;484(7393):251-5. doi: 10.1038/nature10985.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3280, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22498630" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Binding Sites ; Binding, Competitive ; Chromatin Immunoprecipitation ; DNA, Fungal/genetics/*metabolism ; Gene Expression Regulation, Fungal ; *Genome, Fungal ; Histone Acetyltransferases/metabolism ; *Models, Biological ; Nucleosomes/genetics/metabolism ; Protein Binding ; RNA Polymerase II/metabolism ; RNA, Messenger/biosynthesis/genetics ; Saccharomyces cerevisiae/classification/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; Telomere-Binding Proteins/*metabolism ; Time Factors ; Transcription Factors/*metabolism
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    A global synthesis reveals biodiversity loss as a major driver of ecosystem change (2012)
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    Publication Date: 2012-06-09
    Description: Evidence is mounting that extinctions are altering key processes important to the productivity and sustainability of Earth's ecosystems. Further species loss will accelerate change in ecosystem processes, but it is unclear how these effects compare to the direct effects of other forms of environmental change that are both driving diversity loss and altering ecosystem function. Here we use a suite of meta-analyses of published data to show that the effects of species loss on productivity and decomposition--two processes important in all ecosystems--are of comparable magnitude to the effects of many other global environmental changes. In experiments, intermediate levels of species loss (21-40%) reduced plant production by 5-10%, comparable to previously documented effects of ultraviolet radiation and climate warming. Higher levels of extinction (41-60%) had effects rivalling those of ozone, acidification, elevated CO(2) and nutrient pollution. At intermediate levels, species loss generally had equal or greater effects on decomposition than did elevated CO(2) and nitrogen addition. The identity of species lost also had a large effect on changes in productivity and decomposition, generating a wide range of plausible outcomes for extinction. Despite the need for more studies on interactive effects of diversity loss and environmental changes, our analyses clearly show that the ecosystem consequences of local species loss are as quantitatively significant as the direct effects of several global change stressors that have mobilized major international concern and remediation efforts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hooper, David U -- Adair, E Carol -- Cardinale, Bradley J -- Byrnes, Jarrett E K -- Hungate, Bruce A -- Matulich, Kristin L -- Gonzalez, Andrew -- Duffy, J Emmett -- Gamfeldt, Lars -- O'Connor, Mary I -- England -- Nature. 2012 May 2;486(7401):105-8. doi: 10.1038/nature11118.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Western Washington University, Bellingham, Washington 98225-9160, USA. hooper@biol.wwu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22678289" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biodiversity ; Ecology ; *Ecosystem ; *Extinction, Biological ; Models, Biological
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    Nonlinear material behaviour of spider silk yields robust webs (2012)
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    Publication Date: 2012-02-03
    Description: Natural materials are renowned for exquisite designs that optimize function, as illustrated by the elasticity of blood vessels, the toughness of bone and the protection offered by nacre. Particularly intriguing are spider silks, with studies having explored properties ranging from their protein sequence to the geometry of a web. This material system, highly adapted to meet a spider's many needs, has superior mechanical properties. In spite of much research into the molecular design underpinning the outstanding performance of silk fibres, and into the mechanical characteristics of web-like structures, it remains unknown how the mechanical characteristics of spider silk contribute to the integrity and performance of a spider web. Here we report web deformation experiments and simulations that identify the nonlinear response of silk threads to stress--involving softening at a yield point and substantial stiffening at large strain until failure--as being crucial to localize load-induced deformation and resulting in mechanically robust spider webs. Control simulations confirmed that a nonlinear stress response results in superior resistance to structural defects in the web compared to linear elastic or elastic-plastic (softening) material behaviour. We also show that under distributed loads, such as those exerted by wind, the stiff behaviour of silk under small deformation, before the yield point, is essential in maintaining the web's structural integrity. The superior performance of silk in webs is therefore not due merely to its exceptional ultimate strength and strain, but arises from the nonlinear response of silk threads to strain and their geometrical arrangement in a web.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cranford, Steven W -- Tarakanova, Anna -- Pugno, Nicola M -- Buehler, Markus J -- England -- Nature. 2012 Feb 1;482(7383):72-6. doi: 10.1038/nature10739.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22297972" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomechanical Phenomena ; Elasticity ; Hardness ; Models, Biological ; Silk/*chemistry ; *Spiders/physiology ; *Tensile Strength ; Wind
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    Direct imaging of RecA nucleation and growth on single molecules of SSB-coated ssDNA (2012)
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    Publication Date: 2012-10-30
    Description: Escherichia coli RecA is the defining member of a ubiquitous class of DNA strand-exchange proteins that are essential for homologous recombination, a pathway that maintains genomic integrity by repairing broken DNA. To function, filaments of RecA must nucleate and grow on single-stranded DNA (ssDNA) in direct competition with ssDNA-binding protein (SSB), which rapidly binds and continuously sequesters ssDNA, kinetically blocking RecA assembly. This dynamic self-assembly on a DNA lattice, in competition with another protein, is unique for the RecA family compared to other filament-forming proteins such as actin and tubulin. The complexity of this process has hindered our understanding of RecA filament assembly because ensemble measurements cannot reliably distinguish between the nucleation and growth phases, despite extensive and diverse attempts. Previous single-molecule assays have measured the nucleation and growth of RecA--and its eukaryotic homologue RAD51--on naked double-stranded DNA and ssDNA; however, the template for RecA self-assembly in vivo is SSB-coated ssDNA. Using single-molecule microscopy, here we directly visualize RecA filament assembly on single molecules of SSB-coated ssDNA, simultaneously measuring nucleation and growth. We establish that a dimer of RecA is required for nucleation, followed by growth of the filament through monomer addition, consistent with the finding that nucleation, but not growth, is modulated by nucleotide and magnesium ion cofactors. Filament growth is bidirectional, albeit faster in the 5'--〉3' direction. Both nucleation and growth are repressed at physiological conditions, highlighting the essential role of recombination mediators in potentiating assembly in vivo. We define a two-step kinetic mechanism in which RecA nucleates on transiently exposed ssDNA during SSB sliding and/or partial dissociation (DNA unwrapping) and then the RecA filament grows. We further demonstrate that the recombination mediator protein pair, RecOR (RecO and RecR), accelerates both RecA nucleation and filament growth, and that the introduction of RecF further stimulates RecA nucleation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112059/" 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/PMC4112059/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bell, Jason C -- Plank, Jody L -- Dombrowski, Christopher C -- Kowalczykowski, Stephen C -- CA136103/CA/NCI NIH HHS/ -- F32 CA136103/CA/NCI NIH HHS/ -- GM62653/GM/NIGMS NIH HHS/ -- GM64745/GM/NIGMS NIH HHS/ -- R01 GM062653/GM/NIGMS NIH HHS/ -- R01 GM064745/GM/NIGMS NIH HHS/ -- T32 CA10052159/CA/NCI NIH HHS/ -- T32 CA108459/CA/NCI NIH HHS/ -- T32 GM007377/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 8;491(7423):274-8. doi: 10.1038/nature11598. Epub 2012 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, University of California, Davis, California 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103864" target="_blank"〉PubMed〈/a〉
    Keywords: DNA, Single-Stranded/chemistry/*metabolism ; DNA-Binding Proteins/*metabolism ; Escherichia coli/*chemistry/enzymology ; Escherichia coli Proteins/*metabolism ; Hydrogen-Ion Concentration ; Ligands ; Microscopy, Fluorescence/*methods ; Models, Biological ; Models, Molecular ; Molecular Conformation ; Protein Multimerization ; Rec A Recombinases/*chemistry/*metabolism
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    Molecular machines governing exocytosis of synaptic vesicles (2012)
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    Publication Date: 2012-10-13
    Description: Calcium-dependent exocytosis of synaptic vesicles mediates the release of neurotransmitters. Important proteins in this process have been identified such as the SNAREs, synaptotagmins, complexins, Munc18 and Munc13. Structural and functional studies have yielded a wealth of information about the physiological role of these proteins. However, it has been surprisingly difficult to arrive at a unified picture of the molecular sequence of events from vesicle docking to calcium-triggered membrane fusion. Using mainly a biochemical and biophysical perspective, we briefly survey the molecular mechanisms in an attempt to functionally integrate the key proteins into the emerging picture of the neuronal fusion machine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461657/" 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/PMC4461657/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jahn, Reinhard -- Fasshauer, Dirk -- 3P01GM072694-05S1/GM/NIGMS NIH HHS/ -- P01 GM072694/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Oct 11;490(7419):201-7. doi: 10.1038/nature11320.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Max-Planck-Institute for Biophysical Chemistry, 37077 Gottingen, Germany. rjahn@gwdg.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23060190" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/metabolism ; Exocytosis/*physiology ; Humans ; Lipid Metabolism ; Models, Biological ; SNARE Proteins/chemistry/metabolism ; Synaptic Vesicles/*physiology
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    Structure-based prediction of protein-protein interactions on a genome-wide scale (2012)
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    Publication Date: 2012-10-02
    Description: The genome-wide identification of pairs of interacting proteins is an important step in the elucidation of cell regulatory mechanisms. Much of our present knowledge derives from high-throughput techniques such as the yeast two-hybrid assay and affinity purification, as well as from manual curation of experiments on individual systems. A variety of computational approaches based, for example, on sequence homology, gene co-expression and phylogenetic profiles, have also been developed for the genome-wide inference of protein-protein interactions (PPIs). Yet comparative studies suggest that the development of accurate and complete repertoires of PPIs is still in its early stages. Here we show that three-dimensional structural information can be used to predict PPIs with an accuracy and coverage that are superior to predictions based on non-structural evidence. Moreover, an algorithm, termed PrePPI, which combines structural information with other functional clues, is comparable in accuracy to high-throughput experiments, yielding over 30,000 high-confidence interactions for yeast and over 300,000 for human. Experimental tests of a number of predictions demonstrate the ability of the PrePPI algorithm to identify unexpected PPIs of considerable biological interest. The surprising effectiveness of three-dimensional structural information can be attributed to the use of homology models combined with the exploitation of both close and remote geometric relationships between proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482288/" 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/PMC3482288/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Qiangfeng Cliff -- Petrey, Donald -- Deng, Lei -- Qiang, Li -- Shi, Yu -- Thu, Chan Aye -- Bisikirska, Brygida -- Lefebvre, Celine -- Accili, Domenico -- Hunter, Tony -- Maniatis, Tom -- Califano, Andrea -- Honig, Barry -- CA082683/CA/NCI NIH HHS/ -- CA121852/CA/NCI NIH HHS/ -- DK057539/DK/NIDDK NIH HHS/ -- GM030518/GM/NIGMS NIH HHS/ -- GM094597/GM/NIGMS NIH HHS/ -- R01 CA082683/CA/NCI NIH HHS/ -- R01 DK057539/DK/NIDDK NIH HHS/ -- R01 GM030518/GM/NIGMS NIH HHS/ -- R01 NS043915/NS/NINDS NIH HHS/ -- R01NS043915/NS/NINDS NIH HHS/ -- U54 CA121852/CA/NCI NIH HHS/ -- U54 GM094597/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):556-60. doi: 10.1038/nature11503. Epub 2012 Sep 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, 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/23023127" target="_blank"〉PubMed〈/a〉
    Keywords: *Algorithms ; Animals ; Bayes Theorem ; Brain/metabolism ; Cadherins/metabolism ; High-Throughput Screening Assays ; Humans ; Matrix Attachment Region Binding Proteins/metabolism ; Mice ; Models, Molecular ; PPAR gamma/metabolism ; Phylogeny ; Protein Binding ; Protein Conformation ; Protein Interaction Mapping/*methods ; *Protein Interaction Maps ; Protein Kinases/chemistry/metabolism ; Proteins/*chemistry/*metabolism ; Proteome/chemistry/metabolism ; Proteomics/*methods ; ROC Curve ; Reproducibility of Results ; Saccharomyces cerevisiae/chemistry/metabolism ; Suppressor of Cytokine Signaling Proteins/metabolism ; Transcription Factors/metabolism
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    Identification and characterization of a bacterial hydrosulphide ion channel (2012)
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    Publication Date: 2012-03-13
    Description: The hydrosulphide ion (HS(-)) and its undissociated form, hydrogen sulphide (H(2)S), which are believed to have been critical to the origin of life on Earth, remain important in physiology and cellular signalling. As a major metabolite in anaerobic bacterial growth, hydrogen sulphide is a product of both assimilatory and dissimilatory sulphate reduction. These pathways can reduce various oxidized sulphur compounds including sulphate, sulphite and thiosulphate. The dissimilatory sulphate reduction pathway uses this molecule as the terminal electron acceptor for anaerobic respiration, in which process it produces excess amounts of H(2)S (ref. 4). The reduction of sulphite is a key intermediate step in all sulphate reduction pathways. In Clostridium and Salmonella, an inducible sulphite reductase is directly linked to the regeneration of NAD(+), which has been suggested to have a role in energy production and growth, as well as in the detoxification of sulphite. Above a certain concentration threshold, both H(2)S and HS(-) inhibit cell growth by binding the metal centres of enzymes and cytochrome oxidase, necessitating a release mechanism for the export of this toxic metabolite from the cell. Here we report the identification of a hydrosulphide ion channel in the pathogen Clostridium difficile through a combination of genetic, biochemical and functional approaches. The HS(-) channel is a member of the formate/nitrite transport family, in which about 50 hydrosulphide ion channels form a third subfamily alongside those for formate (FocA) and for nitrite (NirC). The hydrosulphide ion channel is permeable to formate and nitrite as well as to HS(-) ions. Such polyspecificity can be explained by the conserved ion selectivity filter observed in the channel's crystal structure. The channel has a low open probability and is tightly regulated, to avoid decoupling of the membrane proton gradient.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711795/" 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/PMC3711795/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Czyzewski, Bryan K -- Wang, Da-Neng -- F31 AI086072/AI/NIAID NIH HHS/ -- F31-AI086072/AI/NIAID NIH HHS/ -- R01 DK053973/DK/NIDDK NIH HHS/ -- R01 GM093825/GM/NIGMS NIH HHS/ -- R01 MH083840/MH/NIMH NIH HHS/ -- R01-DK053973-08A1S1/DK/NIDDK NIH HHS/ -- R01-DK073973/DK/NIDDK NIH HHS/ -- R01-GM093825/GM/NIGMS NIH HHS/ -- R01-MH083840/MH/NIMH NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54-GM075026/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 11;483(7390):494-7. doi: 10.1038/nature10881.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22407320" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/chemistry/genetics/isolation & purification/metabolism ; *Clostridium difficile/chemistry/drug effects/genetics ; Crystallography, X-Ray ; Formates/metabolism ; Ion Channel Gating ; Ion Channels/chemistry/genetics/*isolation & purification/*metabolism ; Ion Transport ; Models, Biological ; Models, Molecular ; Nitrites/metabolism ; Operon/genetics ; Proteolipids/metabolism ; Proton-Motive Force ; Structure-Activity Relationship ; Substrate Specificity ; Sulfides/*metabolism/toxicity
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    Eutrophication causes speciation reversal in whitefish adaptive radiations (2012)
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    Publication Date: 2012-02-18
    Description: Species diversity can be lost through two different but potentially interacting extinction processes: demographic decline and speciation reversal through introgressive hybridization. To investigate the relative contribution of these processes, we analysed historical and contemporary data of replicate whitefish radiations from 17 pre-alpine European lakes and reconstructed changes in genetic species differentiation through time using historical samples. Here we provide evidence that species diversity evolved in response to ecological opportunity, and that eutrophication, by diminishing this opportunity, has driven extinctions through speciation reversal and demographic decline. Across the radiations, the magnitude of eutrophication explains the pattern of species loss and levels of genetic and functional distinctiveness among remaining species. We argue that extinction by speciation reversal may be more widespread than currently appreciated. Preventing such extinctions will require that conservation efforts not only target existing species but identify and protect the ecological and evolutionary processes that generate and maintain species.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vonlanthen, P -- Bittner, D -- Hudson, A G -- Young, K A -- Muller, R -- Lundsgaard-Hansen, B -- Roy, D -- Di Piazza, S -- Largiader, C R -- Seehausen, O -- England -- Nature. 2012 Feb 15;482(7385):357-62. doi: 10.1038/nature10824.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Aquatic Ecology and Evolution, Institute of Ecology and Evolution, University of Bern, Baltzerstrasse 6, CH-3012 Bern, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22337055" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biodiversity ; *Biological Evolution ; Europe ; Eutrophication/*physiology ; *Extinction, Biological ; *Genetic Speciation ; Lakes ; Models, Biological ; Phenotype ; Salmonidae/genetics/*physiology
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    Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding (2012)
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    Publication Date: 2012-04-17
    Description: The development and maintenance of an epithelium requires finely balanced rates of growth and cell death. However, the mechanical and biochemical mechanisms that ensure proper feedback control of tissue growth, which when deregulated contribute to tumorigenesis, are poorly understood. Here we use the fly notum as a model system to identify a novel process of crowding-induced cell delamination that balances growth to ensure the development of well-ordered cell packing. In crowded regions of the tissue, a proportion of cells undergo a serial loss of cell-cell junctions and a progressive loss of apical area, before being squeezed out by their neighbours. This path of delamination is recapitulated by a simple computational model of epithelial mechanics, in which stochastic cell loss relieves overcrowding as the system tends towards equilibrium. We show that this process of delamination is mechanistically distinct from apoptosis-mediated cell extrusion and precedes the first signs of cell death. Overall, this analysis reveals a simple mechanism that buffers epithelia against variations in growth. Because live-cell delamination constitutes a mechanistic link between epithelial hyperplasia and cell invasion, this is likely to have important implications for our understanding of the early stages of cancer development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marinari, Eliana -- Mehonic, Aida -- Curran, Scott -- Gale, Jonathan -- Duke, Thomas -- Baum, Buzz -- 9786/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Apr 15;484(7395):542-5. doi: 10.1038/nature10984.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22504180" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Cell Communication ; Cell Count ; Cell Death ; Cell Growth Processes ; Cell Survival ; Drosophila melanogaster/*cytology ; Epithelial Cells/*cytology ; Female ; Male ; Models, Biological ; Neoplasms/pathology ; Stochastic Processes
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    Cell biology: High-tech yeast ageing (2012)
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    Publication Date: 2012-06-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Polymenis, Michael -- Kennedy, Brian K -- England -- Nature. 2012 Jun 6;486(7401):37-8. doi: 10.1038/486037a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22678274" target="_blank"〉PubMed〈/a〉
    Keywords: Automation ; *Cell Aging ; Cell Biology/instrumentation ; Cell Culture Techniques/*instrumentation ; Microfluidic Analytical Techniques/*instrumentation ; Miniaturization ; Models, Biological ; Saccharomyces cerevisiae/*cytology ; Single-Cell Analysis/*instrumentation/*methods
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    BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs (2012)
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    Publication Date: 2012-10-23
    Description: The differentiation of several T- and B-cell effector programs in the immune system is directed by signature transcription factors that induce rapid epigenetic remodelling. Here we report that promyelocytic leukaemia zinc finger (PLZF), the BTB-zinc finger (BTB-ZF) transcription factor directing the innate-like effector program of natural killer T-cell thymocytes, is prominently associated with cullin 3 (CUL3), an E3 ubiquitin ligase previously shown to use BTB domain-containing proteins as adaptors for substrate binding. PLZF transports CUL3 to the nucleus, where the two proteins are associated within a chromatin-modifying complex. Furthermore, PLZF expression results in selective ubiquitination changes of several components of this complex. CUL3 was also found associated with the BTB-ZF transcription factor BCL6, which directs the germinal-centre B cell and follicular T-helper cell programs. Conditional CUL3 deletion in mice demonstrated an essential role for CUL3 in the development of PLZF- and BCL6-dependent lineages. We conclude that distinct lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the ubiquitination pattern of their associated chromatin-modifying complex. We propose that this new function is essential to direct the differentiation of several T- and B-cell effector programs, and may also be involved in the oncogenic role of PLZF and BCL6 in leukaemias and lymphomas.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504649/" 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/PMC3504649/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mathew, Rebecca -- Seiler, Michael P -- Scanlon, Seth T -- Mao, Ai-ping -- Constantinides, Michael G -- Bertozzi-Villa, Clara -- Singer, Jeffrey D -- Bendelac, Albert -- 5R01GM082940/GM/NIGMS NIH HHS/ -- P30 DK042086/DK/NIDDK NIH HHS/ -- R01 AI038339/AI/NIAID NIH HHS/ -- R01 GM082940/GM/NIGMS NIH HHS/ -- R01AI038339/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Nov 22;491(7425):618-21. doi: 10.1038/nature11548. Epub 2012 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Committee on Immunology, Department of Pathology, The Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23086144" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/cytology/*metabolism ; Cell Differentiation ; Cell Line ; Cullin Proteins/chemistry/genetics/*metabolism ; DNA-Binding Proteins/metabolism ; Kruppel-Like Transcription Factors/*metabolism ; Mice ; Protein Binding ; Protein Transport ; T-Lymphocytes/cytology/*metabolism ; Ubiquitination ; *Zinc Fingers
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    Suppression of the antiviral response by an influenza histone mimic (2012)
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    Publication Date: 2012-03-16
    Description: Viral infection is commonly associated with virus-driven hijacking of host proteins. Here we describe a novel mechanism by which influenza virus affects host cells through the interaction of influenza non-structural protein 1 (NS1) with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 subtype possesses a histone-like sequence (histone mimic) that is used by the virus to target the human PAF1 transcription elongation complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C depends on the NS1 histone mimic and results in suppression of hPAF1C-mediated transcriptional elongation. Furthermore, human PAF1 has a crucial role in the antiviral response. Loss of hPAF1C binding by NS1 attenuates influenza infection, whereas hPAF1C deficiency reduces antiviral gene expression and renders cells more susceptible to viruses. We propose that the histone mimic in NS1 enables the influenza virus to affect inducible gene expression selectively, thus contributing to suppression of the antiviral response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598589/" 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/PMC3598589/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marazzi, Ivan -- Ho, Jessica S Y -- Kim, Jaehoon -- Manicassamy, Balaji -- Dewell, Scott -- Albrecht, Randy A -- Seibert, Chris W -- Schaefer, Uwe -- Jeffrey, Kate L -- Prinjha, Rab K -- Lee, Kevin -- Garcia-Sastre, Adolfo -- Roeder, Robert G -- Tarakhovsky, Alexander -- 1K99AI095320-01/AI/NIAID NIH HHS/ -- CA129325/CA/NCI NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- R01 CA129325/CA/NCI NIH HHS/ -- R01AI046954/AI/NIAID NIH HHS/ -- R01AI068058/AI/NIAID NIH HHS/ -- U19AI083025/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Mar 14;483(7390):428-33. doi: 10.1038/nature10892.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. imarazzi@rockefeller.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22419161" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; *Gene Expression Regulation/immunology ; Histones/chemistry/*metabolism ; Humans ; Influenza A Virus, H3N2 Subtype/genetics/*metabolism/pathogenicity ; Influenza, Human/*genetics/*immunology/pathology/virology ; *Molecular Mimicry ; Molecular Sequence Data ; Nuclear Proteins/antagonists & inhibitors/metabolism ; Protein Binding ; Transcription, Genetic/immunology ; Viral Nonstructural Proteins/chemistry/*metabolism
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    The hidden threat of West Nile virus (2012)
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    Publication Date: 2012-09-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maxmen, Amy -- England -- Nature. 2012 Sep 20;489(7416):349-50. doi: 10.1038/489349a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22996526" target="_blank"〉PubMed〈/a〉
    Keywords: Humans ; Kidney/pathology/virology ; Kidney Diseases/*etiology/pathology/prevention & control/*virology ; Models, Biological ; RNA, Viral/urine ; Reproducibility of Results ; United States/epidemiology ; West Nile Fever/*complications/epidemiology/therapy ; West Nile virus/genetics/isolation & purification/*pathogenicity
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    Control of somatic tissue differentiation by the long non-coding RNA TINCR (2012)
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    Publication Date: 2012-12-04
    Description: Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3. TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR-mRNA interaction occurs through a 25-nucleotide 'TINCR box' motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2, both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR-STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80. These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674581/" 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/PMC3674581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kretz, Markus -- Siprashvili, Zurab -- Chu, Ci -- Webster, Dan E -- Zehnder, Ashley -- Qu, Kun -- Lee, Carolyn S -- Flockhart, Ross J -- Groff, Abigail F -- Chow, Jennifer -- Johnston, Danielle -- Kim, Grace E -- Spitale, Robert C -- Flynn, Ryan A -- Zheng, Grace X Y -- Aiyer, Subhadra -- Raj, Arjun -- Rinn, John L -- Chang, Howard Y -- Khavari, Paul A -- AR49737/AR/NIAMS NIH HHS/ -- DP2 OD008514/OD/NIH HHS/ -- P30 CA124435/CA/NCI NIH HHS/ -- R01 AR049737/AR/NIAMS NIH HHS/ -- R01 HG004361/HG/NHGRI NIH HHS/ -- R01-HG004361/HG/NHGRI NIH HHS/ -- T32 AR007422/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jan 10;493(7431):231-5. doi: 10.1038/nature11661. Epub 2012 Dec 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201690" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Differentiation/*genetics ; Cells, Cultured ; Cytoskeletal Proteins/metabolism ; Epidermis/*cytology/*metabolism ; Gene Expression Regulation ; High-Throughput Screening Assays ; Humans ; Keratinocytes ; Mutation ; Nucleotide Motifs/genetics ; Protein Binding ; RNA Stability/genetics ; RNA, Long Noncoding/*genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; RNA-Binding Proteins/metabolism ; Skin Diseases/genetics
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    Defining the mode of tumour growth by clonal analysis (2012)
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    Publication Date: 2012-08-03
    Description: Recent studies using the isolation of a subpopulation of tumour cells followed by their transplantation into immunodeficient mice provide evidence that certain tumours, including squamous skin tumours, contain cells with high clonogenic potential that have been referred to as cancer stem cells (CSCs). Until now, CSC properties have only been investigated by transplantation assays, and their existence in unperturbed tumour growth is unproven. Here we make use of clonal analysis of squamous skin tumours using genetic lineage tracing to unravel the mode of tumour growth in vivo in its native environment. To this end, we used a genetic labelling strategy that allows individual tumour cells to be marked and traced over time at different stages of tumour progression. Surprisingly, we found that the majority of labelled tumour cells in benign papilloma have only limited proliferative potential, whereas a fraction has the capacity to persist long term, giving rise to progeny that occupy a significant part of the tumour. As well as confirming the presence of two distinct proliferative cell compartments within the papilloma, mirroring the composition, hierarchy and fate behaviour of normal tissue, quantitative analysis of clonal fate data indicates that the more persistent population has stem-cell-like characteristics and cycles twice per day, whereas the second represents a slower cycling transient population that gives rise to terminally differentiated tumour cells. Such behaviour is shown to be consistent with double-labelling experiments and detailed clonal fate characteristics. By contrast, measurements of clone size and proliferative potential in invasive squamous cell carcinoma show a different pattern of behaviour, consistent with geometric expansion of a single CSC population with limited potential for terminal differentiation. This study presents the first experimental evidence for the existence of CSCs during unperturbed solid tumour growth.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Driessens, Gregory -- Beck, Benjamin -- Caauwe, Amelie -- Simons, Benjamin D -- Blanpain, Cedric -- 079249/Wellcome Trust/United Kingdom -- 092096/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Aug 23;488(7412):527-30. doi: 10.1038/nature11344.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22854777" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carcinoma, Squamous Cell/genetics/pathology ; Cell Count ; Cell Differentiation ; *Cell Lineage ; Cell Proliferation ; *Cell Tracking ; Clone Cells/metabolism/pathology ; Disease Models, Animal ; Humans ; Mice ; Models, Biological ; Neoplastic Stem Cells/metabolism/pathology ; Skin Neoplasms/genetics/*pathology ; Stochastic Processes ; Tumor Microenvironment
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    The complex of tmRNA-SmpB and EF-G on translocating ribosomes (2012)
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    Publication Date: 2012-05-25
    Description: Bacterial ribosomes stalled at the 3' end of malfunctioning messenger RNAs can be rescued by transfer-messenger RNA (tmRNA)-mediated trans-translation. The SmpB protein forms a complex with the tmRNA, and the transfer-RNA-like domain (TLD) of the tmRNA then enters the A site of the ribosome. Subsequently, the TLD-SmpB module is translocated to the P site, a process that is facilitated by the elongation factor EF-G, and translation is switched to the mRNA-like domain (MLD) of the tmRNA. Accurate loading of the MLD into the mRNA path is an unusual initiation mechanism. Despite various snapshots of different ribosome-tmRNA complexes at low to intermediate resolution, it is unclear how the large, highly structured tmRNA is translocated and how the MLD is loaded. Here we present a cryo-electron microscopy reconstruction of a fusidic-acid-stalled ribosomal 70S-tmRNA-SmpB-EF-G complex (carrying both of the large ligands, that is, EF-G and tmRNA) at 8.3 A resolution. This post-translocational intermediate (TI(POST)) presents the TLD-SmpB module in an intrasubunit ap/P hybrid site and a tRNA(fMet) in an intrasubunit pe/E hybrid site. Conformational changes in the ribosome and tmRNA occur in the intersubunit space and on the solvent side. The key underlying event is a unique extra-large swivel movement of the 30S head, which is crucial for both tmRNA-SmpB translocation and MLD loading, thereby coupling translocation to MLD loading. This mechanism exemplifies the versatile, dynamic nature of the ribosome, and it shows that the conformational modes of the ribosome that normally drive canonical translation can also be used in a modified form to facilitate more complex tasks in specialized non-canonical pathways.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ramrath, David J F -- Yamamoto, Hiroshi -- Rother, Kristian -- Wittek, Daniela -- Pech, Markus -- Mielke, Thorsten -- Loerke, Justus -- Scheerer, Patrick -- Ivanov, Pavel -- Teraoka, Yoshika -- Shpanchenko, Olga -- Nierhaus, Knud H -- Spahn, Christian M T -- England -- Nature. 2012 May 6;485(7399):526-9. doi: 10.1038/nature11006.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut fur Medizinische Physik und Biophysik, Charite - Universitatsmedizin Berlin, Ziegelstrasse 5-9, 10117 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622583" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cryoelectron Microscopy ; Escherichia coli/*chemistry ; Fusidic Acid/metabolism ; Ligands ; Models, Molecular ; Nucleic Acid Conformation ; Peptide Elongation Factor G/chemistry/*metabolism/ultrastructure ; Protein Binding ; *Protein Biosynthesis ; Protein Conformation ; RNA, Bacterial/*chemistry/genetics/*metabolism/ultrastructure ; RNA-Binding Proteins/chemistry/*metabolism/ultrastructure ; Ribosome Subunits/chemistry/genetics/metabolism/ultrastructure ; Ribosomes/chemistry/genetics/*metabolism/ultrastructure
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    Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia (2012)
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    Publication Date: 2012-04-17
    Description: For an epithelium to provide a protective barrier, it must maintain homeostatic cell numbers by matching the number of dividing cells with the number of dying cells. Although compensatory cell division can be triggered by dying cells, it is unknown how cell death might relieve overcrowding due to proliferation. When we trigger apoptosis in epithelia, dying cells are extruded to preserve a functional barrier. Extrusion occurs by cells destined to die signalling to surrounding epithelial cells to contract an actomyosin ring that squeezes the dying cell out. However, it is not clear what drives cell death during normal homeostasis. Here we show in human, canine and zebrafish cells that overcrowding due to proliferation and migration induces extrusion of live cells to control epithelial cell numbers. Extrusion of live cells occurs at sites where the highest crowding occurs in vivo and can be induced by experimentally overcrowding monolayers in vitro. Like apoptotic cell extrusion, live cell extrusion resulting from overcrowding also requires sphingosine 1-phosphate signalling and Rho-kinase-dependent myosin contraction, but is distinguished by signalling through stretch-activated channels. Moreover, disruption of a stretch-activated channel, Piezo1, in zebrafish prevents extrusion and leads to the formation of epithelial cell masses. Our findings reveal that during homeostatic turnover, growth and division of epithelial cells on a confined substratum cause overcrowding that leads to their extrusion and consequent death owing to the loss of survival factors. These results suggest that live cell extrusion could be a tumour-suppressive mechanism that prevents the accumulation of excess epithelial cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593481/" 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/PMC4593481/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Eisenhoffer, George T -- Loftus, Patrick D -- Yoshigi, Masaaki -- Otsuna, Hideo -- Chien, Chi-Bin -- Morcos, Paul A -- Rosenblatt, Jody -- 1DP2OD002056-01/OD/NIH HHS/ -- 5T32 CA03247-8/CA/NCI NIH HHS/ -- DP2 OD002056/OD/NIH HHS/ -- EB-4443/EB/NIBIB NIH HHS/ -- P30 CA042014/CA/NCI NIH HHS/ -- R01 MH092256/MH/NIMH NIH HHS/ -- England -- Nature. 2012 Apr 15;484(7395):546-9. doi: 10.1038/nature10999.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, Utah 84112, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22504183" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Fins/anatomy & histology/cytology/embryology ; Animals ; Apoptosis ; Cell Count ; Cell Death ; Cell Line ; Cell Movement ; Cell Proliferation ; Cell Survival ; Colon/cytology ; Dogs ; Embryo, Nonmammalian/cytology/embryology ; Epidermis/cytology/embryology ; Epithelial Cells/*cytology ; *Homeostasis ; Humans ; Ion Channels/deficiency/genetics/metabolism ; Lysophospholipids/metabolism ; Models, Biological ; Neoplasms/pathology ; Sphingosine/analogs & derivatives/metabolism ; Zebrafish/anatomy & histology/embryology ; Zebrafish Proteins/deficiency/genetics/metabolism
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    The 2.8 A crystal structure of the dynein motor domain (2012)
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    Publication Date: 2012-03-09
    Description: Dyneins are microtubule-based AAA(+) motor complexes that power ciliary beating, cell division, cell migration and intracellular transport. Here we report the most complete structure obtained so far, to our knowledge, of the 380-kDa motor domain of Dictyostelium discoideum cytoplasmic dynein at 2.8 A resolution; the data are reliable enough to discuss the structure and mechanism at the level of individual amino acid residues. Features that can be clearly visualized at this resolution include the coordination of ADP in each of four distinct nucleotide-binding sites in the ring-shaped AAA(+) ATPase unit, a newly identified interaction interface between the ring and mechanical linker, and junctional structures between the ring and microtubule-binding stalk, all of which should be critical for the mechanism of dynein motility. We also identify a long-range allosteric communication pathway between the primary ATPase and the microtubule-binding sites. Our work provides a framework for understanding the mechanism of dynein-based motility.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kon, Takahide -- Oyama, Takuji -- Shimo-Kon, Rieko -- Imamula, Kenji -- Shima, Tomohiro -- Sutoh, Kazuo -- Kurisu, Genji -- England -- Nature. 2012 Mar 7;484(7394):345-50. doi: 10.1038/nature10955.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan. takahide.kon@protein.osaka-u.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22398446" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Allosteric Regulation ; Binding Sites ; Crystallography, X-Ray ; Cytoplasmic Dyneins/*chemistry/metabolism ; Dictyostelium/*chemistry ; Hydrolysis ; Microtubules/metabolism ; Models, Biological ; Models, Molecular ; Movement ; Protein Structure, Tertiary ; Structure-Activity Relationship
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    Recognition of SUMO-modified PCNA requires tandem receptor motifs in Srs2 (2012)
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    Publication Date: 2012-03-03
    Description: Ubiquitin (Ub) and ubiquitin-like (Ubl) modifiers such as SUMO (also known as Smt3 in Saccharomyces cerevisiae) mediate signal transduction through post-translational modification of substrate proteins in pathways that control differentiation, apoptosis and the cell cycle, and responses to stress such as the DNA damage response. In yeast, the proliferating cell nuclear antigen PCNA (also known as Pol30) is modified by ubiquitin in response to DNA damage and by SUMO during S phase. Whereas Ub-PCNA can signal for recruitment of translesion DNA polymerases, SUMO-PCNA signals for recruitment of the anti-recombinogenic DNA helicase Srs2. It remains unclear how receptors such as Srs2 specifically recognize substrates after conjugation to Ub and Ubls. Here we show, through structural, biochemical and functional studies, that the Srs2 carboxy-terminal domain harbours tandem receptor motifs that interact independently with PCNA and SUMO and that both motifs are required to recognize SUMO-PCNA specifically. The mechanism presented is pertinent to understanding how other receptors specifically recognize Ub- and Ubl-modified substrates to facilitate signal transduction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306252/" 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/PMC3306252/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Armstrong, Anthony A -- Mohideen, Firaz -- Lima, Christopher D -- F32 GM086066/GM/NIGMS NIH HHS/ -- F32 GM086066-01/GM/NIGMS NIH HHS/ -- F32 GM086066-02/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- P41RR012408/RR/NCRR NIH HHS/ -- R01 GM065872/GM/NIGMS NIH HHS/ -- R01 GM065872-08/GM/NIGMS NIH HHS/ -- R01 GM065872-09/GM/NIGMS NIH HHS/ -- R01 GM065872-10/GM/NIGMS NIH HHS/ -- R01 GM065872-11/GM/NIGMS NIH HHS/ -- R01 GM065872-12/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- England -- Nature. 2012 Feb 29;483(7387):59-63. doi: 10.1038/nature10883.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, 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/22382979" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Antigens, Nuclear/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; DNA Helicases/*chemistry/*metabolism ; Methylation ; Models, Molecular ; Proliferating Cell Nuclear Antigen/chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*chemistry/genetics/growth & development ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism ; Small Ubiquitin-Related Modifier Proteins/chemistry/*metabolism ; Structure-Activity Relationship ; *Sumoylation
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    MAP and kinesin-dependent nuclear positioning is required for skeletal muscle function (2012)
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    Publication Date: 2012-03-20
    Description: The basic unit of skeletal muscle in all metazoans is the multinucleate myofibre, within which individual nuclei are regularly positioned. The molecular machinery responsible for myonuclear positioning is not known. Improperly positioned nuclei are a hallmark of numerous diseases of muscle, including centronuclear myopathies, but it is unclear whether correct nuclear positioning is necessary for muscle function. Here we identify the microtubule-associated protein ensconsin (Ens)/microtubule-associated protein 7 (MAP7) and kinesin heavy chain (Khc)/Kif5b as essential, evolutionarily conserved regulators of myonuclear positioning in Drosophila and cultured mammalian myotubes. We find that these proteins interact physically and that expression of the Kif5b motor domain fused to the MAP7 microtubule-binding domain rescues nuclear positioning defects in MAP7-depleted cells. This suggests that MAP7 links Kif5b to the microtubule cytoskeleton to promote nuclear positioning. Finally, we show that myonuclear positioning is physiologically important. Drosophila ens mutant larvae have decreased locomotion and incorrect myonuclear positioning, and these phenotypes are rescued by muscle-specific expression of Ens. We conclude that improper nuclear positioning contributes to muscle dysfunction in a cell-autonomous fashion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321085/" 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/PMC3321085/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metzger, Thomas -- Gache, Vincent -- Xu, Mu -- Cadot, Bruno -- Folker, Eric S -- Richardson, Brian E -- Gomes, Edgar R -- Baylies, Mary K -- GM056989/GM/NIGMS NIH HHS/ -- GM0781318/GM/NIGMS NIH HHS/ -- R01 GM056989/GM/NIGMS NIH HHS/ -- R01 GM056989-09/GM/NIGMS NIH HHS/ -- R01 GM078318/GM/NIGMS NIH HHS/ -- R01 GM078318-04/GM/NIGMS NIH HHS/ -- T32 BM008539/BM/FDA HHS/ -- England -- Nature. 2012 Mar 18;484(7392):120-4. doi: 10.1038/nature10914.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Developmental 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/22425998" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Compartmentation/genetics ; Cell Line ; Cell Nucleus/*metabolism ; Cell Polarity/genetics ; Cells, Cultured ; Drosophila melanogaster/cytology/genetics/growth & development ; Kinesin/chemistry/deficiency/genetics/*metabolism ; Larva/cytology/genetics/metabolism ; Locomotion/genetics/physiology ; Mice ; Microtubule-Associated Proteins/chemistry/genetics/*metabolism ; Microtubules/metabolism ; Muscle Fibers, Skeletal/cytology/metabolism ; Muscle, Skeletal/*cytology/*physiology ; Organ Specificity ; Phenotype ; Protein Binding ; Protein Structure, Tertiary
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Sexual selection enables long-term coexistence despite ecological equivalence (2012)
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    Publication Date: 2012-04-03
    Description: Empirical data indicate that sexual preferences are critical for maintaining species boundaries, yet theoretical work has suggested that, on their own, they can have only a minimal role in maintaining biodiversity. This is because long-term coexistence within overlapping ranges is thought to be unlikely in the absence of ecological differentiation. Here we challenge this widely held view by generalizing a standard model of sexual selection to include two ubiquitous features of populations with sexual selection: spatial variation in local carrying capacity, and mate-search costs in females. We show that, when these two features are combined, sexual preferences can single-handedly maintain coexistence, even when spatial variation in local carrying capacity is so slight that it might go unnoticed empirically. This theoretical study demonstrates that sexual selection alone can promote the long-term coexistence of ecologically equivalent species with overlapping ranges, and it thus provides a novel explanation for the maintenance of species diversity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉M'Gonigle, Leithen K -- Mazzucco, Rupert -- Otto, Sarah P -- Dieckmann, Ulf -- England -- Nature. 2012 Apr 26;484(7395):506-9. doi: 10.1038/nature10971.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Zoology, University of British Columbia, 6270 University Boulevard, Vancouver, British Columbia, Canada. mgonigle@zoology.ubc.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22466286" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; *Biodiversity ; Cichlids/genetics/*physiology ; Female ; *Lakes ; Male ; Mating Preference, Animal/*physiology ; Models, Biological ; Species Specificity ; Time Factors
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    ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation (2012)
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    Publication Date: 2012-07-28
    Description: Malnutrition affects up to one billion people in the world and is a major cause of mortality. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure, cardiovascular functions and SARS infections. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hashimoto, Tatsuo -- Perlot, Thomas -- Rehman, Ateequr -- Trichereau, Jean -- Ishiguro, Hiroaki -- Paolino, Magdalena -- Sigl, Verena -- Hanada, Toshikatsu -- Hanada, Reiko -- Lipinski, Simone -- Wild, Birgit -- Camargo, Simone M R -- Singer, Dustin -- Richter, Andreas -- Kuba, Keiji -- Fukamizu, Akiyoshi -- Schreiber, Stefan -- Clevers, Hans -- Verrey, Francois -- Rosenstiel, Philip -- Penninger, Josef M -- England -- Nature. 2012 Jul 25;487(7408):477-81. doi: 10.1038/nature11228.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22837003" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Colitis/drug therapy/*etiology/*microbiology/pathology ; Dextran Sulfate ; Diarrhea/complications ; Dietary Proteins/metabolism/pharmacology ; Female ; Gene Deletion ; Genetic Predisposition to Disease ; Germ-Free Life ; Homeostasis ; Immunity, Innate ; Intestines/*microbiology/pathology ; Male ; Malnutrition/*complications/metabolism ; *Metagenome ; Mice ; Models, Biological ; Niacinamide/metabolism/pharmacology/therapeutic use ; Peptidyl-Dipeptidase A/deficiency/genetics/*metabolism ; Renin-Angiotensin System/physiology ; TOR Serine-Threonine Kinases/metabolism ; Trinitrobenzenesulfonic Acid ; Tryptophan/*metabolism/pharmacology/therapeutic use
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    Complete subunit architecture of the proteasome regulatory particle (2012)
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    Publication Date: 2012-01-13
    Description: The proteasome is the major ATP-dependent protease in eukaryotic cells, but limited structural information restricts a mechanistic understanding of its activities. The proteasome regulatory particle, consisting of the lid and base subcomplexes, recognizes and processes polyubiquitinated substrates. Here we used electron microscopy and a new heterologous expression system for the lid to delineate the complete subunit architecture of the regulatory particle from yeast. Our studies reveal the spatial arrangement of ubiquitin receptors, deubiquitinating enzymes and the protein unfolding machinery at subnanometre resolution, outlining the substrate's path to degradation. Unexpectedly, the ATPase subunits within the base unfoldase are arranged in a spiral staircase, providing insight into potential mechanisms for substrate translocation through the central pore. Large conformational rearrangements of the lid upon holoenzyme formation suggest allosteric regulation of deubiquitination. We provide a structural basis for the ability of the proteasome to degrade a diverse set of substrates and thus regulate vital cellular processes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285539/" 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/PMC3285539/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lander, Gabriel C -- Estrin, Eric -- Matyskiela, Mary E -- Bashore, Charlene -- Nogales, Eva -- Martin, Andreas -- R01 GM094497/GM/NIGMS NIH HHS/ -- R01 GM094497-01A1/GM/NIGMS NIH HHS/ -- R01-GM094497-01A1/GM/NIGMS NIH HHS/ -- RR017573/RR/NCRR NIH HHS/ -- T32 GM007232/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 11;482(7384):186-91. doi: 10.1038/nature10774.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22237024" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Binding Sites ; Endopeptidases/metabolism ; Escherichia coli/metabolism ; Holoenzymes/chemistry/genetics/metabolism ; Models, Molecular ; Proteasome Endopeptidase Complex/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Conformation ; Protein Subunits/*chemistry/genetics/*metabolism ; Recombinant Proteins/chemistry/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Ubiquitin/metabolism
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    The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity (2012)
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    Publication Date: 2012-10-30
    Description: Human chromosome ends are capped by shelterin, a protein complex that protects the natural ends from being recognized as sites of DNA damage and also regulates the telomere-replicating enzyme, telomerase. Shelterin includes the heterodimeric POT1-TPP1 protein, which binds the telomeric single-stranded DNA tail. TPP1 has been implicated both in recruiting telomerase to telomeres and in stimulating telomerase processivity (the addition of multiple DNA repeats after a single primer-binding event). Determining the mechanisms of these activities has been difficult, especially because genetic perturbations also tend to affect the essential chromosome end-protection function of TPP1 (refs 15-17). Here we identify separation-of-function mutants of human TPP1 that retain full telomere-capping function in vitro and in vivo, yet are defective in binding human telomerase. The seven separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these two activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a new target for anticancer drug development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521872/" 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/PMC3521872/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nandakumar, Jayakrishnan -- Bell, Caitlin F -- Weidenfeld, Ina -- Zaug, Arthur J -- Leinwand, Leslie A -- Cech, Thomas R -- K99 CA167644/CA/NCI NIH HHS/ -- K99CA167644/CA/NCI NIH HHS/ -- R01 GM029090/GM/NIGMS NIH HHS/ -- R01 GM099705/GM/NIGMS NIH HHS/ -- R01GM099705/GM/NIGMS NIH HHS/ -- R01GM29090/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 13;492(7428):285-9. doi: 10.1038/nature11648. Epub 2012 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Colorado BioFrontiers Institute, Boulder, Colorado 80309, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103865" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; HEK293 Cells ; HeLa Cells ; Humans ; Models, Molecular ; Mutation ; Protein Binding ; Protein Structure, Tertiary ; Telomerase/*metabolism ; Telomere/genetics/*metabolism ; Telomere-Binding Proteins/chemistry/genetics/*metabolism
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    Social science: Human reproductive assistance (2012)
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    Publication Date: 2012-03-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hill, Kim -- Hurtado, A Magdalena -- England -- Nature. 2012 Mar 7;483(7388):160-1. doi: 10.1038/483160a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22398548" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/physiology ; *Biological Evolution ; Competitive Behavior/physiology ; *Cooperative Behavior ; Emigration and Immigration ; *Family Characteristics ; Female ; Fertility/physiology ; Gambia ; Humans ; Male ; Menopause/*physiology ; Models, Biological ; Reproduction/*physiology ; *Reproductive Behavior
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    The NAD-dependent deacetylase SIRT2 is required for programmed necrosis (2012)
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    Publication Date: 2012-12-04
    Description: Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-alpha activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1-RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-alpha. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1-RIP3 complex formation and TNF-alpha-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2(-/-) mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Narayan, Nisha -- Lee, In Hye -- Borenstein, Ronen -- Sun, Junhui -- Wong, Renee -- Tong, Guang -- Fergusson, Maria M -- Liu, Jie -- Rovira, Ilsa I -- Cheng, Hwei-Ling -- Wang, Guanghui -- Gucek, Marjan -- Lombard, David -- Alt, Fredrick W -- Sack, Michael N -- Murphy, Elizabeth -- Cao, Liu -- Finkel, Toren -- Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 13;492(7428):199-204. doi: 10.1038/nature11700. Epub 2012 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201684" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Cell Line ; Female ; HEK293 Cells ; HeLa Cells ; Humans ; Jurkat Cells ; Male ; Mice ; Necrosis/*enzymology ; Nuclear Pore Complex Proteins/metabolism ; Protein Binding ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Sirtuin 2/*genetics/*metabolism
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    NPR3 and NPR4 are receptors for the immune signal salicylic acid in plants (2012)
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    Publication Date: 2012-06-16
    Description: Salicylic acid (SA) is a plant immune signal produced after pathogen challenge to induce systemic acquired resistance. It is the only major plant hormone for which the receptor has not been firmly identified. Systemic acquired resistance in Arabidopsis requires the transcription cofactor nonexpresser of PR genes 1 (NPR1), the degradation of which acts as a molecular switch. Here we show that the NPR1 paralogues NPR3 and NPR4 are SA receptors that bind SA with different affinities. NPR3 and NPR4 function as adaptors of the Cullin 3 ubiquitin E3 ligase to mediate NPR1 degradation in an SA-regulated manner. Accordingly, the Arabidopsis npr3 npr4 double mutant accumulates higher levels of NPR1, and is insensitive to induction of systemic acquired resistance. Moreover, this mutant is defective in pathogen effector-triggered programmed cell death and immunity. Our study reveals the mechanism of SA perception in determining cell death and survival in response to pathogen challenge.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376392/" 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/PMC3376392/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fu, Zheng Qing -- Yan, Shunping -- Saleh, Abdelaty -- Wang, Wei -- Ruble, James -- Oka, Nodoka -- Mohan, Rajinikanth -- Spoel, Steven H -- Tada, Yasuomi -- Zheng, Ning -- Dong, Xinnian -- CA107134/CA/NCI NIH HHS/ -- GM069594-05/GM/NIGMS NIH HHS/ -- R01 CA107134/CA/NCI NIH HHS/ -- R01 GM069594/GM/NIGMS NIH HHS/ -- T32 GM008268/GM/NIGMS NIH HHS/ -- T32GM008268-23/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 16;486(7402):228-32. doi: 10.1038/nature11162.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute-Gordon and Betty Moore Foundation, Department of Biology, PO Box 90338, Duke University, Durham, North Carolina 27708, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699612" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*genetics/immunology/*metabolism ; Arabidopsis Proteins/genetics/metabolism ; Mutation ; Protein Binding ; Salicylic Acid/*metabolism ; *Signal Transduction ; Two-Hybrid System Techniques ; Ubiquitin-Protein Ligases/metabolism
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    Teneurins instruct synaptic partner matching in an olfactory map (2012)
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    Publication Date: 2012-03-20
    Description: Neurons are interconnected with extraordinary precision to assemble a functional nervous system. Compared to axon guidance, far less is understood about how individual pre- and postsynaptic partners are matched. To ensure the proper relay of olfactory information in the fruitfly Drosophila, axons of approximately 50 classes of olfactory receptor neurons (ORNs) form one-to-one connections with dendrites of approximately 50 classes of projection neurons (PNs). Here, using genetic screens, we identified two evolutionarily conserved, epidermal growth factor (EGF)-repeat containing transmembrane Teneurin proteins, Ten-m and Ten-a, as synaptic-partner-matching molecules between PN dendrites and ORN axons. Ten-m and Ten-a are highly expressed in select PN-ORN matching pairs. Teneurin loss- and gain-of-function cause specific mismatching of select ORNs and PNs. Finally, Teneurins promote homophilic interactions in vitro, and Ten-m co-expression in non-partner PNs and ORNs promotes their ectopic connections in vivo. We propose that Teneurins instruct matching specificity between synaptic partners through homophilic attraction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345284/" 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/PMC3345284/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hong, Weizhe -- Mosca, Timothy J -- Luo, Liqun -- 5T32 NS007280/NS/NINDS NIH HHS/ -- HD007249/HD/NICHD NIH HHS/ -- R01 DC-005982/DC/NIDCD NIH HHS/ -- R01 DC005982/DC/NIDCD NIH HHS/ -- R01 DC005982-10/DC/NIDCD NIH HHS/ -- T32 HD007249/HD/NICHD NIH HHS/ -- T32 HD007249-28/HD/NICHD NIH HHS/ -- T32 NS007280/NS/NINDS NIH HHS/ -- T32 NS007280-25/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 18;484(7393):201-7. doi: 10.1038/nature10926.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425994" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/metabolism ; Drosophila Proteins/*metabolism ; Drosophila melanogaster/*cytology/*metabolism ; Olfactory Pathways/*physiology ; Olfactory Receptor Neurons/metabolism ; Protein Binding ; RNA Interference ; Receptors, Cell Surface/*metabolism ; Smell/physiology ; Synapses/*metabolism ; Tenascin/*metabolism
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    Prions and chaperones: Outside the fold (2012)
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    Publication Date: 2012-02-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trivedi, Bijal P -- England -- Nature. 2012 Feb 15;482(7385):294-6. doi: 10.1038/482294a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22337030" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/drug therapy/metabolism/prevention & control ; Amyloid beta-Peptides/metabolism ; Animals ; *Biological Evolution ; Clinical Trials as Topic ; Drosophila Proteins/deficiency/genetics/metabolism ; Drosophila melanogaster/genetics/metabolism ; Genetic Variation/genetics ; HSP90 Heat-Shock Proteins/antagonists & inhibitors/*metabolism ; Heat-Shock Proteins/deficiency/genetics/metabolism ; Heat-Shock Response/physiology ; History, 20th Century ; History, 21st Century ; Humans ; Models, Biological ; Neoplasms/drug therapy/metabolism ; Peptide Termination Factors/metabolism ; Prions/chemistry/*metabolism ; Protein Folding ; Saccharomyces cerevisiae/genetics/growth & development/metabolism ; Saccharomyces cerevisiae Proteins/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Molecular biology: Choose your protein partners (2012)
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    Publication Date: 2012-10-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Samant, Rahul S -- Workman, Paul -- England -- Nature. 2012 Oct 18;490(7420):351-2. doi: 10.1038/490351a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23075983" target="_blank"〉PubMed〈/a〉
    Keywords: Enzyme Stability ; HSP90 Heat-Shock Proteins/antagonists & inhibitors/*metabolism ; Luminescent Measurements ; Protein Binding ; Protein Interaction Mapping ; *Protein Interaction Maps ; Substrate Specificity
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    Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells (2012)
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    Publication Date: 2012-01-27
    Description: Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-beta precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-beta(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3beta (aGSK-3beta). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with beta-secretase inhibitors, but not gamma-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3beta levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-beta, in GSK-3beta activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338985/" 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/PMC3338985/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Israel, Mason A -- Yuan, Shauna H -- Bardy, Cedric -- Reyna, Sol M -- Mu, Yangling -- Herrera, Cheryl -- Hefferan, Michael P -- Van Gorp, Sebastiaan -- Nazor, Kristopher L -- Boscolo, Francesca S -- Carson, Christian T -- Laurent, Louise C -- Marsala, Martin -- Gage, Fred H -- Remes, Anne M -- Koo, Edward H -- Goldstein, Lawrence S B -- K12 HD001259/HD/NICHD NIH HHS/ -- P30 NS047101/NS/NINDS NIH HHS/ -- P50 AG005131/AG/NIA NIH HHS/ -- RC1 NS068705/NS/NINDS NIH HHS/ -- RC1 NS068705-01/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 25;482(7384):216-20. doi: 10.1038/nature10821.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22278060" target="_blank"〉PubMed〈/a〉
    Keywords: Aged, 80 and over ; Alzheimer Disease/*metabolism/*pathology ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Amyloid beta-Peptides/metabolism/secretion ; Amyloid beta-Protein Precursor/genetics/metabolism/secretion ; Astrocytes/cytology ; Biomarkers/metabolism ; Cells, Cultured ; Cellular Reprogramming ; Coculture Techniques ; Endosomes/metabolism ; Enzyme Activation ; Female ; Fibroblasts/cytology/metabolism ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Induced Pluripotent Stem Cells/*metabolism/*pathology ; Male ; Middle Aged ; Models, Biological ; Neurons/drug effects/*metabolism/pathology ; Peptide Fragments/metabolism/secretion ; Phosphoproteins/metabolism ; Phosphorylation/drug effects ; Protease Inhibitors/pharmacology ; Proteolysis ; Synapsins/metabolism ; tau Proteins/metabolism
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    Large-scale prediction and testing of drug activity on side-effect targets (2012)
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    Publication Date: 2012-06-23
    Description: Discovering the unintended 'off-targets' that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity of 656 marketed drugs on 73 unintended 'side-effect' targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 muM. To explore relevance, we developed an association metric to prioritize those new off-targets that explained side effects better than any known target of a given drug, creating a drug-target-adverse drug reaction network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic oestrogen chlorotrianisene was mediated through its newly discovered inhibition of the enzyme cyclooxygenase-1. The clinical relevance of this inhibition was borne out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383642/" 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/PMC3383642/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lounkine, Eugen -- Keiser, Michael J -- Whitebread, Steven -- Mikhailov, Dmitri -- Hamon, Jacques -- Jenkins, Jeremy L -- Lavan, Paul -- Weber, Eckhard -- Doak, Allison K -- Cote, Serge -- Shoichet, Brian K -- Urban, Laszlo -- AG002132/AG/NIA NIH HHS/ -- GM71896/GM/NIGMS NIH HHS/ -- GM93456/GM/NIGMS NIH HHS/ -- P01 AG002132/AG/NIA NIH HHS/ -- R01 GM071896/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Jun 10;486(7403):361-7. doi: 10.1038/nature11159.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722194" target="_blank"〉PubMed〈/a〉
    Keywords: Blood Platelets/drug effects ; Chlorotrianisene/adverse effects/chemistry/pharmacology ; Cyclooxygenase 1/metabolism ; Cyclooxygenase Inhibitors/adverse effects/pharmacology ; Databases, Factual ; Drug Evaluation, Preclinical/*methods ; *Drug-Related Side Effects and Adverse Reactions ; Estrogens, Non-Steroidal/adverse effects/pharmacology ; Forecasting ; Humans ; Models, Biological ; Molecular Targeted Therapy/adverse effects ; Platelet Aggregation/drug effects ; Reproducibility of Results ; Substrate Specificity ; Toxicity Tests/*methods
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    Three-dimensional limb joint mobility in the early tetrapod Ichthyostega (2012)
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    Publication Date: 2012-06-23
    Description: The origin of tetrapods and the transition from swimming to walking was a pivotal step in the evolution and diversification of terrestrial vertebrates. During this time, modifications of the limbs-particularly the specialization of joints and the structures that guide their motions-fundamentally changed the ways in which early tetrapods could move. Nonetheless, little is known about the functional consequences of limb anatomy in early tetrapods and how that anatomy influenced locomotion capabilities at this very critical stage in vertebrate evolution. Here we present a three-dimensional reconstruction of the iconic Devonian tetrapod Ichthyostega and a quantitative and comparative analysis of limb mobility in this early tetrapod. We show that Ichthyostega could not have employed typical tetrapod locomotory behaviours, such as lateral sequence walking. In particular, it lacked the necessary rotary motions in its limbs to push the body off the ground and move the limbs in an alternating sequence. Given that long-axis rotation was present in the fins of tetrapodomorph fishes, it seems that either early tetrapods evolved through an initial stage of restricted shoulder and hip joint mobility or that Ichthyostega was unique in this respect. We conclude that early tetrapods with the skeletal morphology and limb mobility of Ichthyostega were unlikely to have made some of the recently described Middle Devonian trackways.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pierce, Stephanie E -- Clack, Jennifer A -- Hutchinson, John R -- England -- Nature. 2012 Jun 28;486(7404):523-6. doi: 10.1038/nature11124.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Veterinary Basic Sciences and Structure and Motion Laboratory, The Royal Veterinary College, Hawkshead Lane, Hatfield AL9 7TA, UK. spierce@rvc.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722854" target="_blank"〉PubMed〈/a〉
    Keywords: Alligators and Crocodiles/physiology ; Amphibians/*anatomy & histology/*physiology ; Animals ; Extremities/*anatomy & histology/*physiology ; Fossils ; History, Ancient ; Joints/*anatomy & histology/*physiology ; Models, Biological ; Movement/*physiology ; Otters/physiology ; Platypus/physiology ; Posture/physiology ; Seals, Earless/physiology ; Skeleton ; Swimming/physiology ; Urodela/physiology ; Walking/physiology
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    RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation (2012)
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    Publication Date: 2012-05-19
    Description: Evolution of the mammalian sex chromosomes has resulted in a heterologous X and Y pair, where the Y chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random inactivation of one X chromosome in all female somatic cells. Upregulation of Xist transcription on the future inactive X chromosome acts against Tsix antisense transcription, and spreading of Xist RNA in cis triggers epigenetic changes leading to X-chromosome inactivation. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is upregulated in differentiating mouse embryonic stem cells and activates Xist transcription and X-chromosome inactivation. Here we identify the pluripotency factor REX1 as a key target of RNF12 in the mechanism of X-chromosome inactivation. RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout embryonic stem cells show an increased level of REX1. Using chromatin immunoprecipitation sequencing, REX1 binding sites were detected in Xist and Tsix regulatory regions. Overexpression of REX1 in female embryonic stem cells was found to inhibit Xist transcription and X-chromosome inactivation, whereas male Rex1(+/-) embryonic stem cells showed ectopic X-chromosome inactivation. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate X-chromosome inactivation. Rex1 and Xist are present only in placental mammals, which points to co-evolution of these two genes and X-chromosome inactivation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gontan, Cristina -- Achame, Eskeatnaf Mulugeta -- Demmers, Jeroen -- Barakat, Tahsin Stefan -- Rentmeester, Eveline -- van IJcken, Wilfred -- Grootegoed, J Anton -- Gribnau, Joost -- England -- Nature. 2012 Apr 29;485(7398):386-90. doi: 10.1038/nature11070.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Reproduction and Development, Erasmus MC, University Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22596162" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; Embryonic Stem Cells/metabolism ; Female ; Gene Expression Regulation ; Male ; Mice ; Molecular Sequence Data ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; RNA, Long Noncoding ; RNA, Untranslated/genetics ; Transcription Factors/deficiency/genetics/*metabolism ; Transcription, Genetic ; Ubiquitin-Protein Ligases/genetics/*metabolism ; Ubiquitination ; X Chromosome/*genetics ; *X Chromosome Inactivation
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    Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia (2012)
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    Publication Date: 2012-04-17
    Description: Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390926/" 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/PMC3390926/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smith, Catherine C -- Wang, Qi -- Chin, Chen-Shan -- Salerno, Sara -- Damon, Lauren E -- Levis, Mark J -- Perl, Alexander E -- Travers, Kevin J -- Wang, Susana -- Hunt, Jeremy P -- Zarrinkar, Patrick P -- Schadt, Eric E -- Kasarskis, Andrew -- Kuriyan, John -- Shah, Neil P -- P50 CA100632/CA/NCI NIH HHS/ -- P50 CA100632-06/CA/NCI NIH HHS/ -- R01 CA12886/CA/NCI NIH HHS/ -- R01 CA128864/CA/NCI NIH HHS/ -- R01 CA166616/CA/NCI NIH HHS/ -- England -- Nature. 2012 Apr 15;485(7397):260-3. doi: 10.1038/nature11016.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology/Oncology, University of California, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22504184" target="_blank"〉PubMed〈/a〉
    Keywords: Benzothiazoles/pharmacology/*therapeutic use ; Cell Line, Tumor ; DNA Mutational Analysis ; Drug Resistance, Neoplasm/genetics ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/*genetics/metabolism ; Models, Molecular ; Molecular Structure ; *Molecular Targeted Therapy ; Mutation/*genetics ; Phenylurea Compounds/pharmacology/*therapeutic use ; Protein Binding ; Protein Structure, Tertiary/genetics ; Recurrence ; Reproducibility of Results ; fms-Like Tyrosine Kinase 3/*antagonists & inhibitors/*genetics/metabolism
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    Molecular motors: A staggering giant (2012)
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    Publication Date: 2012-02-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Walter, Wilhelm J -- Diez, Stefan -- England -- Nature. 2012 Feb 1;482(7383):44-5. doi: 10.1038/482044a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22297968" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Dyneins/chemistry/*metabolism ; Microtubules/chemistry/metabolism ; Models, Biological ; *Movement ; Walking/physiology
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    Intrinsic coupling of lagging-strand synthesis to chromatin assembly (2012)
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    Publication Date: 2012-03-16
    Description: Fifty per cent of the genome is discontinuously replicated on the lagging strand as Okazaki fragments. Eukaryotic Okazaki fragments remain poorly characterized and, because nucleosomes are rapidly deposited on nascent DNA, Okazaki fragment processing and nucleosome assembly potentially affect one another. Here we show that ligation-competent Okazaki fragments in Saccharomyces cerevisiae are sized according to the nucleosome repeat. Using deep sequencing, we demonstrate that ligation junctions preferentially occur near nucleosome midpoints rather than in internucleosomal linker regions. Disrupting chromatin assembly or lagging-strand polymerase processivity affects both the size and the distribution of Okazaki fragments, suggesting a role for nascent chromatin, assembled immediately after the passage of the replication fork, in the termination of Okazaki fragment synthesis. Our studies represent the first high-resolution analysis--to our knowledge--of eukaryotic Okazaki fragments in vivo, and reveal the interconnection between lagging-strand synthesis and chromatin assembly.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490407/" 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/PMC3490407/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smith, Duncan J -- Whitehouse, Iestyn -- P30 CA008748/CA/NCI NIH HHS/ -- R01 GM102253/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 14;483(7390):434-8. doi: 10.1038/nature10895.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22419157" target="_blank"〉PubMed〈/a〉
    Keywords: Chromatin Assembly and Disassembly/*physiology ; DNA/*biosynthesis/genetics/metabolism ; DNA Ligases/deficiency/metabolism ; DNA Polymerase III/metabolism ; *DNA Replication ; DNA-Binding Proteins/metabolism ; High-Throughput Nucleotide Sequencing ; Nucleosomes/genetics/*metabolism ; Protein Binding ; Saccharomyces cerevisiae/enzymology/*genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Transcription Factors/metabolism
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    TET2 promotes histone O-GlcNAcylation during gene transcription (2012)
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    Details
    Publication Date: 2012-12-12
    Description: Ten eleven translocation (TET) enzymes, including TET1, TET2 and TET3, convert 5-methylcytosine to 5-hydroxymethylcytosine and regulate gene transcription. However, the molecular mechanism by which TET family enzymes regulate gene transcription remains elusive. Using protein affinity purification, here we search for functional partners of TET proteins, and find that TET2 and TET3 associate with O-linked beta-N-acetylglucosamine (O-GlcNAc) transferase (OGT), an enzyme that by itself catalyses the addition of O-GlcNAc onto serine and threonine residues (O-GlcNAcylation) in vivo. TET2 directly interacts with OGT, which is important for the chromatin association of OGT in vivo. Although this specific interaction does not regulate the enzymatic activity of TET2, it facilitates OGT-dependent histone O-GlcNAcylation. Moreover, OGT associates with TET2 at transcription start sites. Downregulation of TET2 reduces the amount of histone 2B Ser 112 GlcNAc marks in vivo, which are associated with gene transcription regulation. Taken together, these results reveal a TET2-dependent O-GlcNAcylation of chromatin. The double epigenetic modifications on both DNA and histones by TET2 and OGT coordinate together for the regulation of gene transcription.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684361/" 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/PMC3684361/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Qiang -- Chen, Yibin -- Bian, Chunjing -- Fujiki, Ryoji -- Yu, Xiaochun -- CA130899/CA/NCI NIH HHS/ -- CA132755/CA/NCI NIH HHS/ -- P30 DK034933/DK/NIDDK NIH HHS/ -- R01 CA130899/CA/NCI NIH HHS/ -- R01 CA132755/CA/NCI NIH HHS/ -- England -- Nature. 2013 Jan 24;493(7433):561-4. doi: 10.1038/nature11742. Epub 2012 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23222540" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Chromatin/chemistry/metabolism ; DNA-Binding Proteins/*metabolism ; Epigenesis, Genetic ; Glycosylation ; Histones/*chemistry/*metabolism ; Humans ; N-Acetylglucosaminyltransferases/*metabolism ; Protein Binding ; Proto-Oncogene Proteins/*metabolism ; Serine/metabolism ; Transcription Initiation Site ; *Transcription, Genetic
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    DNA-repair scaffolds dampen checkpoint signalling by counteracting the adaptor Rad9 (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-11-20
    Description: In response to genotoxic stress, a transient arrest in cell-cycle progression enforced by the DNA-damage checkpoint (DDC) signalling pathway positively contributes to genome maintenance. Because hyperactivated DDC signalling can lead to a persistent and detrimental cell-cycle arrest, cells must tightly regulate the activity of the kinases involved in this pathway. Despite their importance, the mechanisms for monitoring and modulating DDC signalling are not fully understood. Here we show that the DNA-repair scaffolding proteins Slx4 and Rtt107 prevent the aberrant hyperactivation of DDC signalling by lesions that are generated during DNA replication in Saccharomyces cerevisiae. On replication stress, cells lacking Slx4 or Rtt107 show hyperactivation of the downstream DDC kinase Rad53, whereas activation of the upstream DDC kinase Mec1 remains normal. An Slx4-Rtt107 complex counteracts the checkpoint adaptor Rad9 by physically interacting with Dpb11 and phosphorylated histone H2A, two positive regulators of Rad9-dependent Rad53 activation. A decrease in DDC signalling results from hypomorphic mutations in RAD53 and H2A and rescues the hypersensitivity to replication stress of cells lacking Slx4 or Rtt107. We propose that the Slx4-Rtt107 complex modulates Rad53 activation by a competition-based mechanism that balances the engagement of Rad9 at replication-induced lesions. Our findings show that DDC signalling is monitored and modulated through the direct action of DNA-repair factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536934/" 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/PMC3536934/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ohouo, Patrice Y -- Bastos de Oliveira, Francisco M -- Liu, Yi -- Ma, Chu Jian -- Smolka, Marcus B -- F31 GM093588/GM/NIGMS NIH HHS/ -- F31-GM093588/GM/NIGMS NIH HHS/ -- R01 GM097272/GM/NIGMS NIH HHS/ -- R01-GM097272/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jan 3;493(7430):120-4. doi: 10.1038/nature11658. Epub 2012 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23160493" target="_blank"〉PubMed〈/a〉
    Keywords: Binding, Competitive ; Cell Cycle Checkpoints/*physiology ; Cell Cycle Proteins/antagonists & inhibitors/deficiency/genetics/*metabolism ; Checkpoint Kinase 2 ; DNA Damage/drug effects ; DNA Repair/drug effects/*physiology ; DNA Replication/drug effects ; Endodeoxyribonucleases/deficiency/metabolism ; Enzyme Activation ; Histones/chemistry/genetics/metabolism ; Hydroxyurea/pharmacology ; Intracellular Signaling Peptides and Proteins/metabolism ; Mutation ; Nuclear Proteins/deficiency/metabolism ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases/genetics/metabolism ; Saccharomyces cerevisiae/*cytology/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; Signal Transduction ; Stress, Physiological/drug effects
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    Post-replicative repair involves separase-dependent removal of the kleisin subunit of cohesin (2012)
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    Publication Date: 2012-11-28
    Description: DNA double-strand break repair is critical for cell viability and involves highly coordinated pathways to restore DNA integrity at the lesion. An early event during homology-dependent repair is resection of the break to generate progressively longer 3' single-strand tails that are used to identify suitable templates for repair. Sister chromatids provide near-perfect sequence homology and are therefore the preferred templates during homologous recombination. To provide a bias for the use of sisters as donors, cohesin--the complex that tethers sister chromatids together--is recruited to the break to enforce physical proximity. Here we show that DNA breaks promote dissociation of cohesin loaded during the previous S phase in budding yeast, and that damage-induced dissociation of cohesin requires separase, the protease that dissolves cohesion in anaphase. Moreover, a separase-resistant allele of the gene coding for the alpha-kleisin subunit of cohesin, Mcd1 (also known as Scc1), reduces double-strand break resection and compromises the efficiency of repair even when loaded during DNA damage. We conclude that post-replicative DNA repair involves cohesin dissociation by separase to promote accessibility to repair factors during the coordinated cellular response to restore DNA integrity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McAleenan, Alexandra -- Clemente-Blanco, Andres -- Cordon-Preciado, Violeta -- Sen, Nicholas -- Esteras, Miguel -- Jarmuz, Adam -- Aragon, Luis -- MC_U120074328/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2013 Jan 10;493(7431):250-4. doi: 10.1038/nature11630. Epub 2012 Nov 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Cycle Group, MRC Clinical Sciences Centre, Imperial College, Du Cane Road, London W12 0NN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23178808" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Anaphase ; Cell Cycle Proteins/*chemistry/genetics/*metabolism ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/*chemistry/genetics/*metabolism ; DNA Breaks, Double-Stranded ; *DNA Repair ; *DNA Replication ; Endopeptidases/*metabolism ; G2 Phase ; Metaphase ; Protein Binding ; Protein Stability ; Protein Subunits/chemistry/metabolism ; S Phase ; Saccharomyces cerevisiae/cytology/enzymology/genetics/*physiology ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; Separase
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    Peroxiredoxins are conserved markers of circadian rhythms (2012)
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    Publication Date: 2012-05-25
    Description: Cellular life emerged approximately 3.7 billion years ago. With scant exception, terrestrial organisms have evolved under predictable daily cycles owing to the Earth's rotation. The advantage conferred on organisms that anticipate such environmental cycles has driven the evolution of endogenous circadian rhythms that tune internal physiology to external conditions. The molecular phylogeny of mechanisms driving these rhythms has been difficult to dissect because identified clock genes and proteins are not conserved across the domains of life: Bacteria, Archaea and Eukaryota. Here we show that oxidation-reduction cycles of peroxiredoxin proteins constitute a universal marker for circadian rhythms in all domains of life, by characterizing their oscillations in a variety of model organisms. Furthermore, we explore the interconnectivity between these metabolic cycles and transcription-translation feedback loops of the clockwork in each system. Our results suggest an intimate co-evolution of cellular timekeeping with redox homeostatic mechanisms after the Great Oxidation Event approximately 2.5 billion years ago.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398137/" 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/PMC3398137/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Edgar, Rachel S -- Green, Edward W -- Zhao, Yuwei -- van Ooijen, Gerben -- Olmedo, Maria -- Qin, Ximing -- Xu, Yao -- Pan, Min -- Valekunja, Utham K -- Feeney, Kevin A -- Maywood, Elizabeth S -- Hastings, Michael H -- Baliga, Nitin S -- Merrow, Martha -- Millar, Andrew J -- Johnson, Carl H -- Kyriacou, Charalambos P -- O'Neill, John S -- Reddy, Akhilesh B -- 083643/Wellcome Trust/United Kingdom -- 083643/Z/07/Z/Wellcome Trust/United Kingdom -- 093734/Wellcome Trust/United Kingdom -- 093734/Z/10/Z/Wellcome Trust/United Kingdom -- BB/C006941/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/D019621/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/D019621/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105170643/Medical Research Council/United Kingdom -- P50 GM076547/GM/NIGMS NIH HHS/ -- P50GM076547/GM/NIGMS NIH HHS/ -- R01 GM067152/GM/NIGMS NIH HHS/ -- R01 GM088595/GM/NIGMS NIH HHS/ -- R01GM067152/GM/NIGMS NIH HHS/ -- R01GM088595/GM/NIGMS NIH HHS/ -- R21 HL102492/HL/NHLBI NIH HHS/ -- R21HL102492/HL/NHLBI NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2012 May 16;485(7399):459-64. doi: 10.1038/nature11088.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622569" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Archaea/metabolism ; Bacteria/metabolism ; Biomarkers/metabolism ; Catalytic Domain ; Circadian Clocks/genetics/physiology ; Circadian Rhythm/genetics/*physiology ; *Conserved Sequence ; Eukaryotic Cells/metabolism ; *Evolution, Molecular ; Feedback, Physiological ; Homeostasis ; Humans ; Models, Biological ; Molecular Sequence Data ; Oxidation-Reduction ; Peroxiredoxins/chemistry/*metabolism ; Phylogeny ; Prokaryotic Cells/metabolism ; Protein Biosynthesis ; Transcription, Genetic
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    Zero-valent sulphur is a key intermediate in marine methane oxidation (2012)
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    Publication Date: 2012-11-09
    Description: Emissions of methane, a potent greenhouse gas, from marine sediments are controlled by anaerobic oxidation of methane coupled primarily to sulphate reduction (AOM). Sulphate-coupled AOM is believed to be mediated by a consortium of methanotrophic archaea (ANME) and sulphate-reducing Deltaproteobacteria but the underlying mechanism has not yet been resolved. Here we show that zero-valent sulphur compounds (S(0)) are formed during AOM through a new pathway for dissimilatory sulphate reduction performed by the methanotrophic archaea. Hence, AOM might not be an obligate syntrophic process but may be carried out by the ANME alone. Furthermore, we show that the produced S(0)--in the form of disulphide--is disproportionated by the Deltaproteobacteria associated with the ANME. Our observations expand the diversity of known microbially mediated sulphur transformations and have significant implications for our understanding of the biogeochemical carbon and sulphur cycles.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Milucka, Jana -- Ferdelman, Timothy G -- Polerecky, Lubos -- Franzke, Daniela -- Wegener, Gunter -- Schmid, Markus -- Lieberwirth, Ingo -- Wagner, Michael -- Widdel, Friedrich -- Kuypers, Marcel M M -- England -- Nature. 2012 Nov 22;491(7425):541-6. doi: 10.1038/nature11656. Epub 2012 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Marine Microbiology, Celsiusstrasse 1, 28359 Bremen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23135396" target="_blank"〉PubMed〈/a〉
    Keywords: Anaerobiosis ; Aquatic Organisms/*metabolism ; Archaea/*metabolism ; Carbon Cycle ; Carbon Dioxide/metabolism ; Deltaproteobacteria/*metabolism ; Disulfides/metabolism ; Geologic Sediments/chemistry ; Methane/*metabolism ; Models, Biological ; Oxidation-Reduction ; Sulfates/metabolism ; Sulfur/*chemistry/*metabolism
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    The mechanism of OTUB1-mediated inhibition of ubiquitination (2012)
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    Publication Date: 2012-03-01
    Description: Histones are ubiquitinated in response to DNA double-strand breaks (DSB), promoting recruitment of repair proteins to chromatin. UBC13 (also known as UBE2N) is a ubiquitin-conjugating enzyme (E2) that heterodimerizes with UEV1A (also known as UBE2V1) and synthesizes K63-linked polyubiquitin (K63Ub) chains at DSB sites in concert with the ubiquitin ligase (E3), RNF168 (ref. 3). K63Ub synthesis is regulated in a non-canonical manner by the deubiquitinating enzyme, OTUB1 (OTU domain-containing ubiquitin aldehyde-binding protein 1), which binds preferentially to the UBC13 approximately Ub thiolester. Residues amino-terminal to the OTU domain, which had been implicated in ubiquitin binding, are required for binding to UBC13 approximately Ub and inhibition of K63Ub synthesis. Here we describe structural and biochemical studies elucidating how OTUB1 inhibits UBC13 and other E2 enzymes. We unexpectedly find that OTUB1 binding to UBC13 approximately Ub is allosterically regulated by free ubiquitin, which binds to a second site in OTUB1 and increases its affinity for UBC13 approximately Ub, while at the same time disrupting interactions with UEV1A in a manner that depends on the OTUB1 N terminus. Crystal structures of an OTUB1-UBC13 complex and of OTUB1 bound to ubiquitin aldehyde and a chemical UBC13 approximately Ub conjugate show that binding of free ubiquitin to OTUB1 triggers conformational changes in the OTU domain and formation of a ubiquitin-binding helix in the N terminus, thus promoting binding of the conjugated donor ubiquitin in UBC13 approximately Ub to OTUB1. The donor ubiquitin thus cannot interact with the E2 enzyme, which has been shown to be important for ubiquitin transfer. The N-terminal helix of OTUB1 is positioned to interfere with UEV1A binding to UBC13, as well as with attack on the thiolester by an acceptor ubiquitin, thereby inhibiting K63Ub synthesis. OTUB1 binding also occludes the RING E3 binding site on UBC13, thus providing a further component of inhibition. The general features of the inhibition mechanism explain how OTUB1 inhibits other E2 enzymes in a non-catalytic manner.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319311/" 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/PMC3319311/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wiener, Reuven -- Zhang, Xiangbin -- Wang, Tao -- Wolberger, Cynthia -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 22;483(7391):618-22. doi: 10.1038/nature10911.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biophysical Chemistry and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22367539" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Sequence ; Animals ; Binding Sites ; Caenorhabditis elegans ; Caenorhabditis elegans Proteins/chemistry/genetics/*metabolism ; Cysteine Endopeptidases/chemistry/genetics/*metabolism ; DNA Damage ; Humans ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Tertiary ; Ubiquitin/*antagonists & inhibitors/metabolism ; Ubiquitin-Conjugating Enzymes/antagonists & ; inhibitors/chemistry/genetics/metabolism ; *Ubiquitination ; Ubiquitins/chemistry/metabolism
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    Interaction landscape of membrane-protein complexes in Saccharomyces cerevisiae (2012)
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    Publication Date: 2012-09-04
    Description: Macromolecular assemblies involving membrane proteins (MPs) serve vital biological roles and are prime drug targets in a variety of diseases. Large-scale affinity purification studies of soluble-protein complexes have been accomplished for diverse model organisms, but no global characterization of MP-complex membership has been described so far. Here we report a complete survey of 1,590 putative integral, peripheral and lipid-anchored MPs from Saccharomyces cerevisiae, which were affinity purified in the presence of non-denaturing detergents. The identities of the co-purifying proteins were determined by tandem mass spectrometry and subsequently used to derive a high-confidence physical interaction map encompassing 1,726 membrane protein-protein interactions and 501 putative heteromeric complexes associated with the various cellular membrane systems. Our analysis reveals unexpected physical associations underlying the membrane biology of eukaryotes and delineates the global topological landscape of the membrane interactome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Babu, Mohan -- Vlasblom, James -- Pu, Shuye -- Guo, Xinghua -- Graham, Chris -- Bean, Bjorn D M -- Burston, Helen E -- Vizeacoumar, Franco J -- Snider, Jamie -- Phanse, Sadhna -- Fong, Vincent -- Tam, Yuen Yi C -- Davey, Michael -- Hnatshak, Olha -- Bajaj, Navgeet -- Chandran, Shamanta -- Punna, Thanuja -- Christopolous, Constantine -- Wong, Victoria -- Yu, Analyn -- Zhong, Gouqing -- Li, Joyce -- Stagljar, Igor -- Conibear, Elizabeth -- Wodak, Shoshana J -- Emili, Andrew -- Greenblatt, Jack F -- MOP 81156/Canadian Institutes of Health Research/Canada -- MOP 64394/Canadian Institutes of Health Research/Canada -- MOP 82940/Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Sep 27;489(7417):585-9. doi: 10.1038/nature11354. Epub 2012 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Banting and Best Department of Medical Research, Donnelly Centre, 160 College Street, University of Toronto, Toronto, Ontario M5S 3E1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22940862" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Membrane/chemistry/metabolism ; Chitin Synthase/metabolism ; Detergents ; Endoplasmic Reticulum/metabolism ; Golgi Apparatus/metabolism ; Mass Spectrometry ; Membrane Proteins/analysis/chemistry/*metabolism ; Protein Binding ; Protein Interaction Mapping ; *Protein Interaction Maps ; Proteome/analysis/chemistry/metabolism ; Saccharomyces cerevisiae/chemistry/cytology/*metabolism ; Saccharomyces cerevisiae Proteins/analysis/chemistry/*metabolism
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    The mu transpososome structure sheds light on DDE recombinase evolution (2012)
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    Publication Date: 2012-11-09
    Description: Studies of bacteriophage Mu transposition paved the way for understanding retroviral integration and V(D)J recombination as well as many other DNA transposition reactions. Here we report the structure of the Mu transpososome--Mu transposase (MuA) in complex with bacteriophage DNA ends and target DNA--determined from data that extend anisotropically to 5.2 A, 5.2 A and 3.7 A resolution, in conjunction with previously determined structures of individual domains. The highly intertwined structure illustrates why chemical activity depends on formation of the synaptic complex, and reveals that individual domains have different roles when bound to different sites. The structure also provides explanations for the increased stability of the final product complex and for its preferential recognition by the ATP-dependent unfoldase ClpX. Although MuA and many other recombinases share a structurally conserved 'DDE' catalytic domain, comparisons among the limited set of available complex structures indicate that some conserved features, such as catalysis in trans and target DNA bending, arose through convergent evolution because they are important for function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536463/" 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/PMC3536463/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Montano, Sherwin P -- Pigli, Ying Z -- Rice, Phoebe A -- GM086826/GM/NIGMS NIH HHS/ -- R01 GM086826/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 15;491(7424):413-7. doi: 10.1038/nature11602. Epub 2012 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23135398" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophage mu/classification/*enzymology ; DNA, Viral/chemistry ; *Evolution, Molecular ; Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; Recombinases/*chemistry/*metabolism ; Transposases/*chemistry/metabolism
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    Structure of AMP-PNP-bound vitamin B12 transporter BtuCD-F (2012)
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    Publication Date: 2012-09-25
    Description: The ATP-binding cassette (ABC) transporter BtuCD mediates the uptake of vitamin B(12) across the inner membrane of Escherichia coli. Previous structures have shown the conformations of apo states, but the transport mechanism has remained unclear. Here we report the 3.5 A crystal structure of the transporter-binding protein complex BtuCD-BtuF (BtuCD-F) trapped in an beta-gamma-imidoadenosine 5'-phosphate (AMP-PNP)-bound intermediate state. Although the ABC domains (BtuD subunits) form the expected closed sandwich dimer, the membrane-spanning BtuC subunits adopt a new conformation, with the central translocation pathway sealed by a previously unrecognized cytoplasmic gate. A fully enclosed cavity is thus formed approximately halfway across the membrane. It is large enough to accommodate a vitamin B(12) molecule, and radioligand trapping showed that liposome-reconstituted BtuCD-F indeed contains bound B(12) in the presence of AMP-PNP. In combination with engineered disulphide crosslinking and functional assays, our data suggest an unexpected peristaltic transport mechanism that is distinct from those observed in other ABC transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Korkhov, Vladimir M -- Mireku, Samantha A -- Locher, Kaspar P -- England -- Nature. 2012 Oct 18;490(7420):367-72. doi: 10.1038/nature11442. Epub 2012 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, CH-8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23000901" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/genetics/metabolism ; Adenosine Triphosphatases/chemistry/metabolism ; Adenosine Triphosphate/metabolism ; Adenylyl Imidodiphosphate/chemistry/*metabolism ; Amino Acid Sequence ; Crystallography, X-Ray ; Cytoplasm/metabolism ; Disulfides/chemistry/metabolism ; Escherichia coli/*chemistry/genetics ; Escherichia coli Proteins/*chemistry/genetics/metabolism ; Magnesium/metabolism ; Models, Biological ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Mutation ; Periplasmic Binding Proteins/*chemistry/genetics/metabolism ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry/genetics/metabolism ; Structure-Activity Relationship ; Vitamin B 12/chemistry/*metabolism
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    Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism (2012)
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    Publication Date: 2012-01-17
    Description: Mass spectrometry with stable isotope labels has been seminal in discovering the dynamic state of living matter, but is limited to bulk tissues or cells. We developed multi-isotope imaging mass spectrometry (MIMS) that allowed us to view and measure stable isotope incorporation with submicrometre resolution. Here we apply MIMS to diverse organisms, including Drosophila, mice and humans. We test the 'immortal strand hypothesis', which predicts that during asymmetric stem cell division chromosomes containing older template DNA are segregated to the daughter destined to remain a stem cell, thus insuring lifetime genetic stability. After labelling mice with (15)N-thymidine from gestation until post-natal week 8, we find no (15)N label retention by dividing small intestinal crypt cells after a four-week chase. In adult mice administered (15)N-thymidine pulse-chase, we find that proliferating crypt cells dilute the (15)N label, consistent with random strand segregation. We demonstrate the broad utility of MIMS with proof-of-principle studies of lipid turnover in Drosophila and translation to the human haematopoietic system. These studies show that MIMS provides high-resolution quantification of stable isotope labels that cannot be obtained using other techniques and that is broadly applicable to biological and medical research.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267887/" 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/PMC3267887/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Steinhauser, Matthew L -- Bailey, Andrew P -- Senyo, Samuel E -- Guillermier, Christelle -- Perlstein, Todd S -- Gould, Alex P -- Lee, Richard T -- Lechene, Claude P -- AG032977/AG/NIA NIH HHS/ -- AG034641/AG/NIA NIH HHS/ -- EB001974/EB/NIBIB NIH HHS/ -- K08 DK090147/DK/NIDDK NIH HHS/ -- MC_U117584237/Medical Research Council/United Kingdom -- R01 AG032977/AG/NIA NIH HHS/ -- R01 AG032977-04/AG/NIA NIH HHS/ -- R01 AG040019/AG/NIA NIH HHS/ -- R01 AG040019-02/AG/NIA NIH HHS/ -- U117584237/Medical Research Council/United Kingdom -- England -- Nature. 2012 Jan 15;481(7382):516-9. doi: 10.1038/nature10734.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22246326" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; *Cell Division ; DNA/biosynthesis/genetics/metabolism ; Drosophila melanogaster/cytology ; Enterocytes/cytology ; Fibroblasts/cytology ; Humans ; Intestine, Small/cytology ; Isotope Labeling ; Isotopes ; Leukocytes/cytology ; Lipid Metabolism ; Lymphopoiesis ; Mass Spectrometry/*methods ; Mice ; Mice, Inbred C57BL ; Models, Biological ; Stem Cells/*cytology/*metabolism/pathology ; Templates, Genetic ; Thymidine/metabolism
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    Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106 (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-07
    Description: Dynamic variations in the structure of chromatin influence virtually all DNA-related processes in eukaryotes and are controlled in part by post-translational modifications of histones. One such modification, the acetylation of lysine 56 (H3K56ac) in the amino-terminal alpha-helix (alphaN) of histone H3, has been implicated in the regulation of nucleosome assembly during DNA replication and repair, and nucleosome disassembly during gene transcription. In Saccharomyces cerevisiae, the histone chaperone Rtt106 contributes to the deposition of newly synthesized H3K56ac-carrying H3-H4 complex on replicating DNA, but it is unclear how Rtt106 binds H3-H4 and specifically recognizes H3K56ac as there is no apparent acetylated lysine reader domain in Rtt106. Here, we show that two domains of Rtt106 are involved in a combinatorial recognition of H3-H4. An N-terminal domain homodimerizes and interacts with H3-H4 independently of acetylation while a double pleckstrin-homology (PH) domain binds the K56-containing region of H3. Affinity is markedly enhanced upon acetylation of K56, an effect that is probably due to increased conformational entropy of the alphaN helix of H3. Our data support a mode of interaction where the N-terminal homodimeric domain of Rtt106 intercalates between the two H3-H4 components of the (H3-H4)(2) tetramer while two double PH domains in the Rtt106 dimer interact with each of the two H3K56ac sites in (H3-H4)(2). We show that the Rtt106-(H3-H4)(2) interaction is important for gene silencing and the DNA damage response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439842/" 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/PMC3439842/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Dan -- Hu, Qi -- Li, Qing -- Thompson, James R -- Cui, Gaofeng -- Fazly, Ahmed -- Davies, Brian A -- Botuyan, Maria Victoria -- Zhang, Zhiguo -- Mer, Georges -- P50 CA108961/CA/NCI NIH HHS/ -- R01 CA132878/CA/NCI NIH HHS/ -- R01 CA132878-04/CA/NCI NIH HHS/ -- R01 GM072719/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Feb 5;483(7387):104-7. doi: 10.1038/nature10861.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22307274" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Binding Sites ; Crystallography, X-Ray ; DNA Damage ; Gene Silencing ; Genomic Instability ; Histones/*chemistry/*metabolism ; Lysine/analogs & derivatives/chemistry/metabolism ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Chaperones/*chemistry/genetics/*metabolism ; Mutation/genetics ; Pliability ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*chemistry ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Xenopus laevis
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    Differential oestrogen receptor binding is associated with clinical outcome in breast cancer (2012)
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    Publication Date: 2012-01-06
    Description: Oestrogen receptor-alpha (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems. Here we map genome-wide ER-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumours from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER-positive disease exclusively. We find that the differential ER-binding programme observed in tumours from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FOXA1-mediated reprogramming of ER binding on a rapid timescale. The parallel redistribution of ER and FOXA1 binding events in drug-resistant cellular contexts is supported by histological co-expression of ER and FOXA1 in metastatic samples. By establishing transcription-factor mapping in primary tumour material, we show that there is plasticity in ER-binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272464/" 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/PMC3272464/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ross-Innes, Caryn S -- Stark, Rory -- Teschendorff, Andrew E -- Holmes, Kelly A -- Ali, H Raza -- Dunning, Mark J -- Brown, Gordon D -- Gojis, Ondrej -- Ellis, Ian O -- Green, Andrew R -- Ali, Simak -- Chin, Suet-Feung -- Palmieri, Carlo -- Caldas, Carlos -- Carroll, Jason S -- A10178/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Jan 4;481(7381):389-93. doi: 10.1038/nature10730.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22217937" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Breast Neoplasms/*diagnosis/drug therapy/*genetics/pathology ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects/genetics ; Female ; *Gene Expression Regulation, Neoplastic/drug effects ; Hepatocyte Nuclear Factor 3-alpha/metabolism ; Humans ; Neoplasm Metastasis/genetics ; Prognosis ; Protein Binding ; Receptors, Estrogen/*metabolism ; Regulatory Sequences, Nucleic Acid/genetics ; Survival Analysis ; Tamoxifen/pharmacology/therapeutic use ; Treatment Outcome
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    Structure of the TatC core of the twin-arginine protein transport system (2012)
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    Publication Date: 2012-12-04
    Description: The twin-arginine translocation (Tat) pathway is one of two general protein transport systems found in the prokaryotic cytoplasmic membrane and is conserved in the thylakoid membrane of plant chloroplasts. The defining, and highly unusual, property of the Tat pathway is that it transports folded proteins, a task that must be achieved without allowing appreciable ion leakage across the membrane. The integral membrane TatC protein is the central component of the Tat pathway. TatC captures substrate proteins by binding their signal peptides. TatC then recruits TatA family proteins to form the active translocation complex. Here we report the crystal structure of TatC from the hyperthermophilic bacterium Aquifex aeolicus. This structure provides a molecular description of the core of the Tat translocation system and a framework for understanding the unique Tat transport mechanism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573685/" 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/PMC3573685/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rollauer, Sarah E -- Tarry, Michael J -- Graham, James E -- Jaaskelainen, Mari -- Jager, Franziska -- Johnson, Steven -- Krehenbrink, Martin -- Liu, Sai-Man -- Lukey, Michael J -- Marcoux, Julien -- McDowell, Melanie A -- Rodriguez, Fernanda -- Roversi, Pietro -- Stansfeld, Phillip J -- Robinson, Carol V -- Sansom, Mark S P -- Palmer, Tracy -- Hogbom, Martin -- Berks, Ben C -- Lea, Susan M -- 083599/Wellcome Trust/United Kingdom -- 088150/Wellcome Trust/United Kingdom -- 092970/Wellcome Trust/United Kingdom -- 092970MA/Wellcome Trust/United Kingdom -- BB/1019855/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/E023347/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/F02150X/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/I019855/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- G0900888/Medical Research Council/United Kingdom -- G0900888(92020)/Medical Research Council/United Kingdom -- G100164/Medical Research Council/United Kingdom -- G1001640/Medical Research Council/United Kingdom -- G1001640/1/Medical Research Council/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):210-4. doi: 10.1038/nature11683. Epub 2012 Dec 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201679" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Escherichia coli/genetics ; Gram-Negative Bacteria/*chemistry/genetics/*metabolism ; Membrane Transport Proteins/*chemistry/metabolism ; *Models, Molecular ; Protein Binding ; Protein Sorting Signals ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/genetics
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    Structural basis of highly conserved ribosome recycling in eukaryotes and archaea (2012)
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    Publication Date: 2012-02-24
    Description: Ribosome-driven protein biosynthesis is comprised of four phases: initiation, elongation, termination and recycling. In bacteria, ribosome recycling requires ribosome recycling factor and elongation factor G, and several structures of bacterial recycling complexes have been determined. In the eukaryotic and archaeal kingdoms, however, recycling involves the ABC-type ATPase ABCE1 and little is known about its structural basis. Here we present cryo-electron microscopy reconstructions of eukaryotic and archaeal ribosome recycling complexes containing ABCE1 and the termination factor paralogue Pelota. These structures reveal the overall binding mode of ABCE1 to be similar to canonical translation factors. Moreover, the iron-sulphur cluster domain of ABCE1 interacts with and stabilizes Pelota in a conformation that reaches towards the peptidyl transferase centre, thus explaining how ABCE1 may stimulate peptide-release activity of canonical termination factors. Using the mechanochemical properties of ABCE1, a conserved mechanism in archaea and eukaryotes is suggested that couples translation termination to recycling, and eventually to re-initiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Becker, Thomas -- Franckenberg, Sibylle -- Wickles, Stephan -- Shoemaker, Christopher J -- Anger, Andreas M -- Armache, Jean-Paul -- Sieber, Heidemarie -- Ungewickell, Charlotte -- Berninghausen, Otto -- Daberkow, Ingo -- Karcher, Annette -- Thomm, Michael -- Hopfner, Karl-Peter -- Green, Rachel -- Beckmann, Roland -- U19 AI083025/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 22;482(7386):501-6. doi: 10.1038/nature10829.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Center and Center for integrated Protein Science Munich, Department of Biochemistry, University of Munich, Feodor-Lynen-Strasse 25, 81377 Munich, Germany. becker@lmb.uni-muenchen.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22358840" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/chemistry/metabolism ; Cell Cycle Proteins/chemistry/metabolism ; Cryoelectron Microscopy ; Endoribonucleases/chemistry/metabolism ; *Evolution, Molecular ; Iron-Sulfur Proteins/chemistry/metabolism ; Models, Molecular ; Movement ; Multiprotein Complexes/chemistry/metabolism ; Nuclear Proteins/chemistry/metabolism ; Peptide Termination Factors/chemistry/metabolism ; Protein Binding ; Protein Stability ; Protein Structure, Tertiary ; Pyrococcus furiosus/*chemistry/metabolism ; Ribosomes/*chemistry/*metabolism/ultrastructure ; Saccharomyces cerevisiae/*chemistry/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/metabolism
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    Evolution of the chalcone-isomerase fold from fatty-acid binding to stereospecific catalysis (2012)
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    Publication Date: 2012-05-25
    Description: Specialized metabolic enzymes biosynthesize chemicals of ecological importance, often sharing a pedigree with primary metabolic enzymes. However, the lineage of the enzyme chalcone isomerase (CHI) remained unknown. In vascular plants, CHI-catalysed conversion of chalcones to chiral (S)-flavanones is a committed step in the production of plant flavonoids, compounds that contribute to attraction, defence and development. CHI operates near the diffusion limit with stereospecific control. Although associated primarily with plants, the CHI fold occurs in several other eukaryotic lineages and in some bacteria. Here we report crystal structures, ligand-binding properties and in vivo functional characterization of a non-catalytic CHI-fold family from plants. Arabidopsis thaliana contains five actively transcribed genes encoding CHI-fold proteins, three of which additionally encode amino-terminal chloroplast-transit sequences. These three CHI-fold proteins localize to plastids, the site of de novo fatty-acid biosynthesis in plant cells. Furthermore, their expression profiles correlate with those of core fatty-acid biosynthetic enzymes, with maximal expression occurring in seeds and coinciding with increased fatty-acid storage in the developing embryo. In vitro, these proteins are fatty-acid-binding proteins (FAPs). FAP knockout A. thaliana plants show elevated alpha-linolenic acid levels and marked reproductive defects, including aberrant seed formation. Notably, the FAP discovery defines the adaptive evolution of a stereospecific and catalytically 'perfected' enzyme from a non-enzymatic ancestor over a defined period of plant evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880581/" 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/PMC3880581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ngaki, Micheline N -- Louie, Gordon V -- Philippe, Ryan N -- Manning, Gerard -- Pojer, Florence -- Bowman, Marianne E -- Li, Ling -- Larsen, Elise -- Wurtele, Eve Syrkin -- Noel, Joseph P -- CA14195/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 13;485(7399):530-3. doi: 10.1038/nature11009.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, Iowa 50011, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622584" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*chemistry/enzymology/genetics/growth & development ; Arabidopsis Proteins/chemistry/genetics/metabolism ; *Biocatalysis ; Crystallography, X-Ray ; *Evolution, Molecular ; Fatty Acid-Binding Proteins/chemistry/deficiency/genetics/metabolism ; Fatty Acids/*metabolism ; Intramolecular Lyases/*chemistry/deficiency/genetics/*metabolism ; Ligands ; Models, Molecular ; Phenotype ; Protein Binding ; *Protein Folding ; Stereoisomerism ; alpha-Linolenic Acid/metabolism
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    Autoregulation of microRNA biogenesis by let-7 and Argonaute (2012)
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    Publication Date: 2012-06-23
    Description: MicroRNAs (miRNAs) comprise a large family of small RNA molecules that post-transcriptionally regulate gene expression in many biological pathways. Most miRNAs are derived from long primary transcripts that undergo processing by Drosha to produce ~65-nucleotide precursors that are then cleaved by Dicer, resulting in the mature 22-nucleotide forms. Serving as guides in Argonaute protein complexes, mature miRNAs use imperfect base pairing to recognize sequences in messenger RNA transcripts, leading to translational repression and destabilization of the target messenger RNAs. Here we show that the miRNA complex also targets and regulates non-coding RNAs that serve as substrates for the miRNA-processing pathway. We found that the Argonaute protein in Caenorhabditis elegans, ALG-1, binds to a specific site at the 3' end of let-7 miRNA primary transcripts and promotes downstream processing events. This interaction is mediated by mature let-7 miRNA through a conserved complementary site in its own primary transcript, thus creating a positive-feedback loop. We further show that ALG-1 associates with let-7 primary transcripts in nuclear fractions. Argonaute also binds let-7 primary transcripts in human cells, demonstrating that the miRNA pathway targets non-coding RNAs in addition to protein-coding messenger RNAs across species. Moreover, our studies in C. elegans reveal a novel role for Argonaute in promoting biogenesis of a targeted transcript, expanding the functions of the miRNA pathway in gene regulation. This discovery of autoregulation of let-7 biogenesis establishes a new mechanism for controlling miRNA expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387326/" 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/PMC3387326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zisoulis, Dimitrios G -- Kai, Zoya S -- Chang, Roger K -- Pasquinelli, Amy E -- GM071654/GM/NIGMS NIH HHS/ -- R01 GM071654/GM/NIGMS NIH HHS/ -- R01 GM071654-09/GM/NIGMS NIH HHS/ -- T32 CA009523/CA/NCI NIH HHS/ -- England -- Nature. 2012 Jun 28;486(7404):541-4. doi: 10.1038/nature11134.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biology, University of California, San Diego, La Jolla, California 92093-0349, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722835" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Pairing ; Base Sequence ; Binding Sites ; Caenorhabditis elegans/classification/cytology/*genetics/*metabolism ; Caenorhabditis elegans Proteins/*metabolism ; Cell Nucleus/genetics/metabolism ; Feedback, Physiological ; *Gene Expression Regulation ; MicroRNAs/*biosynthesis/*genetics/metabolism ; Protein Binding ; RNA Processing, Post-Transcriptional ; RNA, Messenger/biosynthesis/genetics/metabolism ; RNA-Binding Proteins/*metabolism ; Transcription, Genetic
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    Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK (2012)
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    Publication Date: 2012-02-10
    Description: First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme-substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277212/" 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/PMC3277212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Yu-yi -- Kiihl, Samara -- Suhail, Yasir -- Liu, Shang-Yun -- Chou, Yi-hsuan -- Kuang, Zheng -- Lu, Jin-ying -- Khor, Chin Ni -- Lin, Chi-Long -- Bader, Joel S -- Irizarry, Rafael -- Boeke, Jef D -- U54 RR 020839/RR/NCRR NIH HHS/ -- U54 RR020839/RR/NCRR NIH HHS/ -- U54 RR020839-09/RR/NCRR NIH HHS/ -- England -- Nature. 2012 Feb 8;482(7384):251-5. doi: 10.1038/nature10804.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. yuyilin@ntu.edu.tw〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22318606" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/chemistry/genetics/*metabolism ; Acetylation ; Biocatalysis ; Catalytic Domain ; Cell Cycle ; Cell Line ; Cell Line, Tumor ; Histone Deacetylase 1/genetics/*metabolism ; Humans ; Lysine/*metabolism ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases/metabolism ; RNA Interference ; Substrate Specificity ; p300-CBP Transcription Factors/genetics/*metabolism
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    Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling (2012)
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    Publication Date: 2012-03-20
    Description: Developing tissues and growing tumours produce vascular endothelial growth factors (VEGFs), leading to the activation of the corresponding receptors in endothelial cells. The resultant angiogenic expansion of the local vasculature can promote physiological and pathological growth processes. Previous work has uncovered that the VEGF and Notch pathways are tightly linked. Signalling triggered by VEGF-A (also known as VEGF) has been shown to induce expression of the Notch ligand DLL4 in angiogenic vessels and, most prominently, in the tip of endothelial sprouts. DLL4 activates Notch in adjacent cells, which suppresses the expression of VEGF receptors and thereby restrains endothelial sprouting and proliferation. Here we show, by using inducible loss-of-function genetics in combination with inhibitors in vivo, that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 signalling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGF-A receptor and is considered to be indispensable for these processes. By contrast, VEGFR3, the main receptor for VEGF-C, was strongly modulated by Notch. VEGFR3 kinase-activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signalling activity. Our results establish that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. We propose that successful anti-angiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Benedito, Rui -- Rocha, Susana F -- Woeste, Marina -- Zamykal, Martin -- Radtke, Freddy -- Casanovas, Oriol -- Duarte, Antonio -- Pytowski, Bronislaw -- Adams, Ralf H -- England -- Nature. 2012 Mar 18;484(7392):110-4. doi: 10.1038/nature10908.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, D-48149 Munster, Germany. rui.benedito@mpi-muenster.mpg.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22426001" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Endothelial Cells/cytology/drug effects/metabolism ; Female ; HEK293 Cells ; Human Umbilical Vein Endothelial Cells ; Humans ; Intracellular Signaling Peptides and Proteins/deficiency/genetics/metabolism ; Male ; Membrane Proteins/deficiency/genetics/metabolism ; Mice ; Models, Biological ; Neovascularization, Physiologic/drug effects/*physiology ; Protein Kinase Inhibitors/pharmacology ; Receptors, Notch/antagonists & inhibitors/*metabolism ; *Signal Transduction/drug effects ; Transcription, Genetic ; *Up-Regulation ; Vascular Endothelial Growth Factor A/*metabolism ; Vascular Endothelial Growth Factor Receptor-2/deficiency/genetics/*metabolism ; Vascular Endothelial Growth Factor Receptor-3/biosynthesis/genetics/*metabolism
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    Centralspindlin links the mitotic spindle to the plasma membrane during cytokinesis (2012)
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    Publication Date: 2012-12-14
    Description: At the end of cell division, cytokinesis splits the cytoplasm of nascent daughter cells and partitions segregated sister genomes. To coordinate cell division with chromosome segregation, the mitotic spindle controls cytokinetic events at the cell envelope. The spindle midzone stimulates the actomyosin-driven contraction of the cleavage furrow, which proceeds until the formation of a microtubule-rich intercellular bridge with the midbody at its centre. The midbody directs the final membrane abscission reaction and has been proposed to attach the cleavage furrow to the intercellular bridge. How the mitotic spindle is connected to the plasma membrane during cytokinesis is not understood. Here we identify a plasma membrane tethering activity in the centralspindlin protein complex, a conserved component of the spindle midzone and midbody. We demonstrate that the C1 domain of the centralspindlin subunit MgcRacGAP associates with the plasma membrane by interacting with polyanionic phosphoinositide lipids. Using X-ray crystallography we determine the structure of this atypical C1 domain. Mutations in the hydrophobic cap and in basic residues of the C1 domain of MgcRacGAP prevent association of the protein with the plasma membrane, and abrogate cytokinesis in human and chicken cells. Artificial membrane tethering of centralspindlin restores cell division in the absence of the C1 domain of MgcRacGAP. Although C1 domain function is dispensable for the formation of the midzone and midbody, it promotes contractility and is required for the attachment of the plasma membrane to the midbody, a long-postulated function of this organelle. Our analysis suggests that centralspindlin links the mitotic spindle to the plasma membrane to secure the final cut during cytokinesis in animal cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lekomtsev, Sergey -- Su, Kuan-Chung -- Pye, Valerie E -- Blight, Ken -- Sundaramoorthy, Sriramkumar -- Takaki, Tohru -- Collinson, Lucy M -- Cherepanov, Peter -- Divecha, Nullin -- Petronczki, Mark -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):276-9. doi: 10.1038/nature11773.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235882" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Membrane/*metabolism ; Cytokinesis/genetics/*radiation effects ; GTPase-Activating Proteins/chemistry/genetics/*metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Microtubule-Associated Proteins/chemistry/genetics/*metabolism ; Microtubules/chemistry/metabolism ; Models, Molecular ; Protein Binding ; Protein Kinase C-alpha/metabolism ; Protein Structure, Tertiary ; Protein Transport/drug effects ; Spindle Apparatus/*metabolism ; Tetradecanoylphorbol Acetate/analogs & derivatives/pharmacology
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    Compensatory dendritic cell development mediated by BATF-IRF interactions (2012)
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    Publication Date: 2012-09-21
    Description: The AP1 transcription factor Batf3 is required for homeostatic development of CD8alpha(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8alpha(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-gamma. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482832/" 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/PMC3482832/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tussiwand, Roxane -- Lee, Wan-Ling -- Murphy, Theresa L -- Mashayekhi, Mona -- KC, Wumesh -- Albring, Jorn C -- Satpathy, Ansuman T -- Rotondo, Jeffrey A -- Edelson, Brian T -- Kretzer, Nicole M -- Wu, Xiaodi -- Weiss, Leslie A -- Glasmacher, Elke -- Li, Peng -- Liao, Wei -- Behnke, Michael -- Lam, Samuel S K -- Aurthur, Cora T -- Leonard, Warren J -- Singh, Harinder -- Stallings, Christina L -- Sibley, L David -- Schreiber, Robert D -- Murphy, Kenneth M -- AI076427-02/AI/NIAID NIH HHS/ -- P30 CA91842/CA/NCI NIH HHS/ -- R01 AI036629/AI/NIAID NIH HHS/ -- R01 AI076427/AI/NIAID NIH HHS/ -- R01 CA043059/CA/NCI NIH HHS/ -- T32 AI007163/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):502-7. doi: 10.1038/nature11531. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigen Presentation ; Antigens, CD/metabolism ; Antigens, CD8/immunology/metabolism ; Basic-Leucine Zipper Transcription ; Factors/chemistry/deficiency/genetics/*metabolism ; CD4-Positive T-Lymphocytes/cytology/immunology ; CTLA-4 Antigen/metabolism ; Cell Differentiation ; Cell Line, Tumor ; Cell Lineage ; Dendritic Cells/*cytology/immunology/*metabolism ; Female ; Fibrosarcoma/immunology/metabolism/pathology ; Gene Expression Regulation ; Integrin alpha Chains/metabolism ; Interferon Regulatory Factors/deficiency/genetics/*metabolism ; Interleukin-10/metabolism ; Interleukin-12/immunology/metabolism ; Leucine Zippers ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Oncogene Protein p65(gag-jun)/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/deficiency/genetics ; T-Lymphocytes, Helper-Inducer/cytology/immunology/metabolism ; Toxoplasma/immunology
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    Protein activity regulation by conformational entropy (2012)
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    Publication Date: 2012-07-18
    Description: How the interplay between protein structure and internal dynamics regulates protein function is poorly understood. Often, ligand binding, post-translational modifications and mutations modify protein activity in a manner that is not possible to rationalize solely on the basis of structural data. It is likely that changes in the internal motions of proteins have a major role in regulating protein activity, but the nature of their contributions remains elusive, especially in quantitative terms. Here we show that changes in conformational entropy can determine whether protein-ligand interactions will occur, even among protein complexes with identical binding interfaces. We have used NMR spectroscopy to determine the changes in structure and internal dynamics that are elicited by the binding of DNA to several variants of the catabolite activator protein (CAP) that differentially populate the inactive and active DNA-binding domain states. We found that the CAP variants have markedly different affinities for DNA, despite the CAP-DNA-binding interfaces being essentially identical in the various complexes. Combined with thermodynamic data, the results show that conformational entropy changes can inhibit the binding of CAP variants that are structurally poised for optimal DNA binding or can stimulate the binding activity of CAP variants that only transiently populate the DNA-binding-domain active state. Collectively, the data show how changes in fast internal dynamics (conformational entropy) and slow internal dynamics (energetically excited conformational states) can regulate binding activity in a way that cannot be predicted on the basis of the protein's ground-state structure.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tzeng, Shiou-Ru -- Kalodimos, Charalampos G -- England -- Nature. 2012 Aug 9;488(7410):236-40. doi: 10.1038/nature11271.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry & Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801505" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cyclic AMP Receptor Protein/*chemistry/genetics/*metabolism ; DNA/chemistry/metabolism ; *Entropy ; Models, Molecular ; Motion ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Structure, Tertiary ; Time Factors
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    Molecular recognition of a single sphingolipid species by a protein's transmembrane domain (2012)
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    Publication Date: 2012-01-11
    Description: Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Contreras, F-Xabier -- Ernst, Andreas M -- Haberkant, Per -- Bjorkholm, Patrik -- Lindahl, Erik -- Gonen, Basak -- Tischer, Christian -- Elofsson, Arne -- von Heijne, Gunnar -- Thiele, Christoph -- Pepperkok, Rainer -- Wieland, Felix -- Brugger, Britta -- 232648/European Research Council/International -- England -- Nature. 2012 Jan 9;481(7382):525-9. doi: 10.1038/nature10742.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22230960" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Binding Sites ; CHO Cells ; COP-Coated Vesicles/metabolism ; Cell Membrane/*metabolism ; Computational Biology ; Conserved Sequence ; Cricetinae ; Membrane Proteins/*chemistry/*metabolism ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Transport ; Second Messenger Systems/physiology ; Sphingolipids/*metabolism ; Sphingomyelins/metabolism ; Substrate Specificity
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    Cancer metabolism: When more is less (2012)
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    Publication Date: 2012-09-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Lei -- Deberardinis, Ralph J -- England -- Nature. 2012 Sep 27;489(7417):511-2. doi: 10.1038/489511a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23018962" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Cell Division/drug effects ; Disease Progression ; Enzyme Activation/drug effects ; Glucose/*metabolism ; *Glycolysis/drug effects ; Isoenzymes/antagonists & inhibitors/metabolism ; Models, Biological ; Neoplasms/drug therapy/enzymology/*metabolism/*pathology ; Pyruvate Kinase/antagonists & inhibitors/classification/metabolism
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    A comparative analysis of the evolution of imperfect mimicry (2012)
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    Publication Date: 2012-03-23
    Description: Although exceptional examples of adaptation are frequently celebrated, some outcomes of natural selection seem far from perfect. For example, many hoverflies (Diptera: Syrphidae) are harmless (Batesian) mimics of stinging Hymenoptera. However, although some hoverfly species are considered excellent mimics, other species bear only a superficial resemblance to their models and it is unclear why this is so. To evaluate hypotheses that have been put forward to explain interspecific variation in the mimetic fidelity of Palearctic Syrphidae we use a comparative approach. We show that the most plausible explanation is that predators impose less selection for mimetic fidelity on smaller hoverfly species because they are less profitable prey items. In particular, our findings, in combination with previous results, allow us to reject several key hypotheses for imperfect mimicry: first, human ratings of mimetic fidelity are positively correlated with both morphometric measures and avian rankings, indicating that variation in mimetic fidelity is not simply an illusion based on human perception; second, no species of syrphid maps out in multidimensional space as being intermediate in appearance between several different hymenopteran model species, as the multimodel hypothesis requires; and third, we find no evidence for a negative relationship between mimetic fidelity and abundance, which calls into question the kin-selection hypothesis. By contrast, a strong positive relationship between mimetic fidelity and body size supports the relaxed-selection hypothesis, suggesting that reduced predation pressure on less profitable prey species limits the selection for mimetic perfection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Penney, Heather D -- Hassall, Christopher -- Skevington, Jeffrey H -- Abbott, Kevin R -- Sherratt, Thomas N -- England -- Nature. 2012 Mar 21;483(7390):461-4. doi: 10.1038/nature10961.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, K1S 5B6, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22437614" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Bites and Stings ; Body Size/physiology ; Diptera/*anatomy & histology/classification/*physiology ; Models, Biological ; Molecular Mimicry/*physiology ; Phylogeny ; Predatory Behavior/physiology ; Selection, Genetic
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    Popularity versus similarity in growing networks (2012)
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    Publication Date: 2012-09-14
    Description: The principle that 'popularity is attractive' underlies preferential attachment, which is a common explanation for the emergence of scaling in growing networks. If new connections are made preferentially to more popular nodes, then the resulting distribution of the number of connections possessed by nodes follows power laws, as observed in many real networks. Preferential attachment has been directly validated for some real networks (including the Internet), and can be a consequence of different underlying processes based on node fitness, ranking, optimization, random walks or duplication. Here we show that popularity is just one dimension of attractiveness; another dimension is similarity. We develop a framework in which new connections optimize certain trade-offs between popularity and similarity, instead of simply preferring popular nodes. The framework has a geometric interpretation in which popularity preference emerges from local optimization. As opposed to preferential attachment, our optimization framework accurately describes the large-scale evolution of technological (the Internet), social (trust relationships between people) and biological (Escherichia coli metabolic) networks, predicting the probability of new links with high precision. The framework that we have developed can thus be used for predicting new links in evolving networks, and provides a different perspective on preferential attachment as an emergent phenomenon.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Papadopoulos, Fragkiskos -- Kitsak, Maksim -- Serrano, M Angeles -- Boguna, Marian -- Krioukov, Dmitri -- England -- Nature. 2012 Sep 27;489(7417):537-40. doi: 10.1038/nature11459. Epub 2012 Sep 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Electrical Engineering, Computer Engineering and Informatics, Cyprus University of Technology, 33 Saripolou Street, 3036 Limassol, Cyprus. f.papadopoulos@cut.ac.cy〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22972194" target="_blank"〉PubMed〈/a〉
    Keywords: Escherichia coli/metabolism ; Humans ; Internet/*statistics & numerical data ; *Metabolic Networks and Pathways ; Models, Biological ; *Models, Theoretical ; Probability ; Reproducibility of Results ; *Social Networking ; Trust
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    Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans (2012)
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    Publication Date: 2012-09-25
    Description: P-glycoprotein (P-gp) is an ATP-binding cassette transporter that confers multidrug resistance in cancer cells. It also affects the absorption, distribution and clearance of cancer-unrelated drugs and xenobiotics. For these reasons, the structure and function of P-gp have been studied extensively for decades. Here we present biochemical characterization of P-gp from Caenorhabditis elegans and its crystal structure at a resolution of 3.4 angstroms. We find that the apparent affinities of P-gp for anticancer drugs actinomycin D and paclitaxel are approximately 4,000 and 100 times higher, respectively, in the membrane bilayer than in detergent. This affinity enhancement highlights the importance of membrane partitioning when a drug accesses the transporter in the membrane. Furthermore, the transporter in the crystal structure opens its drug pathway at the level of the membrane's inner leaflet. In the helices flanking the opening to the membrane, we observe extended loops that may mediate drug binding, function as hinges to gate the pathway or both. We also find that the interface between the transmembrane and nucleotide-binding domains, which couples ATP hydrolysis to transport, contains a ball-and-socket joint and salt bridges similar to the ATP-binding cassette importers, suggesting that ATP-binding cassette exporters and importers may use similar mechanisms to achieve alternating access for transport. Finally, a model of human P-gp derived from the structure of C. elegans P-gp not only is compatible with decades of biochemical analysis, but also helps to explain perplexing functional data regarding the Phe335Ala mutant. These results increase our understanding of the structure and function of this important molecule.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482266/" 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/PMC3482266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jin, Mi Sun -- Oldham, Michael L -- Zhang, Qiuju -- Chen, Jue -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):566-9. doi: 10.1038/nature11448. Epub 2012 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Purdue University, Indiana 47907, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23000902" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; Caenorhabditis elegans/*chemistry ; Crystallography, X-Ray ; Dactinomycin/metabolism ; Humans ; Hydrolysis ; Lipid Bilayers/metabolism ; Models, Biological ; Models, Molecular ; P-Glycoprotein/*chemistry/metabolism ; Paclitaxel/metabolism ; Protein Structure, Tertiary ; Structural Homology, Protein ; Structure-Activity Relationship
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-31
    Description: Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusive. Here we report the crystal structure of the dimeric RING domain of rat RNF4 in complex with E2 (UbcH5A) linked by an isopeptide bond to ubiquitin. While the E2 contacts a single protomer of the RING, ubiquitin is folded back onto the E2 by contacts from both RING protomers. The carboxy-terminal tail of ubiquitin is locked into an active site groove on the E2 by an intricate network of interactions, resulting in changes at the E2 active site. This arrangement is primed for catalysis as it can deprotonate the incoming substrate lysine residue and stabilize the consequent tetrahedral transition-state intermediate.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442243/" 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/PMC3442243/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Plechanovova, Anna -- Jaffray, Ellis G -- Tatham, Michael H -- Naismith, James H -- Hay, Ronald T -- 081862/Wellcome Trust/United Kingdom -- 098391/Wellcome Trust/United Kingdom -- 13067/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Sep 6;489(7414):115-20. doi: 10.1038/nature11376.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22842904" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Hydrolysis ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Mutation ; Nuclear Proteins/*chemistry/genetics/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Transcription Factors/*chemistry/genetics/metabolism ; Ubiquitin/chemistry/genetics/*metabolism ; Ubiquitin-Conjugating Enzymes/*chemistry/genetics/*metabolism ; Ubiquitin-Protein Ligases/*chemistry/metabolism ; Ubiquitination ; *Zinc Fingers
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Brain development: The neuron family tree remodelled (2012)
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    Publication Date: 2012-10-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marin, Oscar -- England -- Nature. 2012 Oct 11;490(7419):185-6. doi: 10.1038/490185a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23060186" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/*cytology/*embryology ; Humans ; Mice ; Models, Biological ; Neocortex/cytology/embryology ; Neurons/*cytology
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    Stereospecific binding of a disordered peptide segment mediates BK channel inactivation (2012)
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    Publication Date: 2012-04-24
    Description: A number of functionally important actions of proteins are mediated by short, intrinsically disordered peptide segments, but the molecular interactions that allow disordered domains to mediate their effects remain a topic of active investigation. Many K+ channel proteins, after initial channel opening, show a time-dependent reduction in current flux, termed 'inactivation', which involves movement of mobile cytosolic peptide segments (approximately 20-30 residues) into a position that physically occludes ion permeation. Peptide segments that produce inactivation show little amino-acid identity and tolerate appreciable mutational substitutions without disrupting the inactivation process. Solution nuclear magnetic resonance of several isolated inactivation domains reveals substantial conformational heterogeneity with only minimal tendency to ordered structures. Channel inactivation mechanisms may therefore help us to decipher how intrinsically disordered regions mediate functional effects. Whereas many aspects of inactivation of voltage-dependent K+ channels (Kv) can be described by a simple one-step occlusion mechanism, inactivation of the voltage-dependent large-conductance Ca2+-gated K+ (BK) channel mediated by peptide segments of auxiliary beta-subunits involves two distinguishable kinetic steps. Here we show that two-step inactivation mediated by an intrinsically disordered BK beta-subunit peptide involves a stereospecific binding interaction that precedes blockade. In contrast, blocking mediated by a Shaker Kv inactivation peptide is consistent with direct, simple occlusion by a hydrophobic segment without substantial steric requirement. The results indicate that two distinct types of molecular interaction between disordered peptide segments and their binding sites produce qualitatively similar functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348258/" 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/PMC3348258/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gonzalez-Perez, Vivian -- Zeng, Xu-Hui -- Henzler-Wildman, Katie -- Lingle, Christopher J -- GM-081748/GM/NIGMS NIH HHS/ -- R01 GM081748/GM/NIGMS NIH HHS/ -- R01 GM081748-16/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 May 3;485(7396):133-6. doi: 10.1038/nature10994.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Anesthesiology, 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/22522931" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acids/metabolism ; Animals ; Binding, Competitive ; Humans ; Ion Channel Gating/*drug effects ; Large-Conductance Calcium-Activated Potassium Channels/*antagonists & ; inhibitors/chemistry/*metabolism ; Mice ; Oocytes/metabolism ; Peptides/chemistry/*metabolism/*pharmacology ; Potassium/metabolism ; Protein Binding ; Protein Subunits/antagonists & inhibitors/metabolism ; Shaker Superfamily of Potassium Channels/antagonists & ; inhibitors/chemistry/metabolism ; Xenopus laevis
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Public health: India's diabetes time bomb (2012)
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    Publication Date: 2012-05-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shetty, Priya -- England -- Nature. 2012 May 17;485(7398):S14-6.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22616100" target="_blank"〉PubMed〈/a〉
    Keywords: Body Mass Index ; Diabetes Mellitus, Type 2/diagnosis/*epidemiology/genetics/prevention & control ; Diabetes, Gestational/diagnosis/epidemiology ; Disease Susceptibility ; Epigenesis, Genetic ; Female ; Humans ; India/epidemiology ; Infant, Low Birth Weight/metabolism ; Infant, Newborn ; Life Style/ethnology ; *Maternal Nutritional Physiological Phenomena ; Models, Biological ; Pregnancy ; Prenatal Exposure Delayed Effects/*metabolism ; Public Health/*statistics & numerical data ; Rural Health/statistics & numerical data ; Urban Health/statistics & numerical data
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    Convergent acoustic field of view in echolocating bats (2012)
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    Publication Date: 2012-11-23
    Description: Most echolocating bats exhibit a strong correlation between body size and the frequency of maximum energy in their echolocation calls (peak frequency), with smaller species using signals of higher frequency than larger ones. Size-signal allometry or acoustic detection constraints imposed on wavelength by preferred prey size have been used to explain this relationship. Here we propose the hypothesis that smaller bats emit higher frequencies to achieve directional sonar beams, and that variable beam width is critical for bats. Shorter wavelengths relative to the size of the emitter translate into more directional sound beams. Therefore, bats that emit their calls through their mouths should show a relationship between mouth size and wavelength, driving smaller bats to signals of higher frequency. We found that in a flight room mimicking a closed habitat, six aerial hawking vespertilionid species (ranging in size from 4 to 21 g, ref. 5) produced sonar beams of extraordinarily similar shape and volume. Each species had a directivity index of 11 +/- 1 dB (a half-amplitude angle of approximately 37 degrees ) and an on-axis sound level of 108 +/- 4 dB sound pressure level referenced to 20 muPa root mean square at 10 cm. Thus all bats adapted their calls to achieve similar acoustic fields of view. We propose that the necessity for high directionality has been a key constraint on the evolution of echolocation, which explains the relationship between bat size and echolocation call frequency. Our results suggest that echolocation is a dynamic system that allows different species, regardless of their body size, to converge on optimal fields of view in response to habitat and task.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jakobsen, Lasse -- Ratcliffe, John M -- Surlykke, Annemarie -- England -- Nature. 2013 Jan 3;493(7430):93-6. doi: 10.1038/nature11664. Epub 2012 Nov 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sound Communication Group, Institute of Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23172147" target="_blank"〉PubMed〈/a〉
    Keywords: *Acoustics ; Animals ; Body Size/physiology ; Chiroptera/anatomy & histology/classification/*physiology ; Echolocation/*physiology ; Ecosystem ; Flight, Animal ; Models, Biological ; Mouth/anatomy & histology/physiology ; Nose/anatomy & histology/physiology ; Predatory Behavior ; Skull/anatomy & histology/physiology ; Vocalization, Animal/physiology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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