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  • Crystallography, X-Ray  (123)
  • Mice, Inbred C57BL  (105)
  • Nature Publishing Group (NPG)  (228)
  • Essen : Verl. Glückauf
  • Krefeld : Geologischer Dienst Nordhein-Westfalen
  • Springer Nature
  • 2005-2009  (228)
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  • 1
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    Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-12-22
    Description: Broken chromosomes arising from DNA double-strand breaks result from endogenous events such as the production of reactive oxygen species during cellular metabolism, as well as from exogenous sources such as ionizing radiation. Left unrepaired or incorrectly repaired they can lead to genomic changes that may result in cell death or cancer. DNA-dependent protein kinase (DNA-PK), a holoenzyme that comprises the DNA-PK catalytic subunit (DNA-PKcs) and the heterodimer Ku70/Ku80, has a major role in non-homologous end joining-the main pathway in mammals used to repair double-strand breaks. DNA-PKcs is a serine/threonine protein kinase comprising a single polypeptide chain of 4,128 amino acids and belonging to the phosphatidylinositol-3-OH kinase (PI(3)K)-related protein family. DNA-PKcs is involved in the sensing and transmission of DNA damage signals to proteins such as p53, setting off events that lead to cell cycle arrest. It phosphorylates a wide range of substrates in vitro, including Ku70/Ku80, which is translocated along DNA. Here we present the crystal structure of human DNA-PKcs at 6.6 A resolution, in which the overall fold is clearly visible, to our knowledge, for the first time. The many alpha-helical HEAT repeats (helix-turn-helix motifs) facilitate bending and allow the polypeptide chain to fold into a hollow circular structure. The carboxy-terminal kinase domain is located on top of this structure, and a small HEAT repeat domain that probably binds DNA is inside. The structure provides a flexible cradle to promote DNA double-strand-break repair.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811870/" 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/PMC2811870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sibanda, Bancinyane L -- Chirgadze, Dimitri Y -- Blundell, Tom L -- 079281/Wellcome Trust/United Kingdom -- A3846/Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Jan 7;463(7277):118-21. doi: 10.1038/nature08648. Epub 2009 Dec 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Cambridge, Old Addenbrooke's site, 80 Tennis Court Road, Cambridge CB2 1GA, UK. lynn@cryst.bioc.cam.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20023628" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Nuclear/chemistry ; Catalytic Domain ; Crystallography, X-Ray ; DNA/metabolism ; DNA Breaks, Double-Stranded ; DNA-Activated Protein Kinase/*chemistry/metabolism ; DNA-Binding Proteins/chemistry ; HeLa Cells ; *Helix-Turn-Helix Motifs ; Humans ; Models, Molecular ; Nuclear Proteins/*chemistry/metabolism ; Protein Folding ; Protein Structure, Secondary
    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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    Linking the p53 tumour suppressor pathway to somatic cell reprogramming (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-08-12
    Description: Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. Here we show that reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing reprogramming-induced apoptosis in mouse fibroblasts increases reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735889/" 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/PMC2735889/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kawamura, Teruhisa -- Suzuki, Jotaro -- Wang, Yunyuan V -- Menendez, Sergio -- Morera, Laura Batlle -- Raya, Angel -- Wahl, Geoffrey M -- Izpisua Belmonte, Juan Carlos -- 5 R01 CA061449/CA/NCI NIH HHS/ -- 5 R01 CA100845/CA/NCI NIH HHS/ -- R01 CA061449/CA/NCI NIH HHS/ -- R01 CA061449-30/CA/NCI NIH HHS/ -- R01 CA100845/CA/NCI NIH HHS/ -- R01 CA100845-05/CA/NCI NIH HHS/ -- R33 HL088293/HL/NHLBI NIH HHS/ -- R33 HL088293-03/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Aug 27;460(7259):1140-4. doi: 10.1038/nature08311. Epub 2009 Aug 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19668186" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Cellular Reprogramming/*physiology ; Cyclin-Dependent Kinase Inhibitor p21/deficiency/genetics/metabolism ; Down-Regulation ; Embryo, Mammalian/cytology ; Female ; Fibroblasts/cytology/metabolism ; Humans ; Keratinocytes ; Male ; Mice ; Mice, Inbred C57BL ; Pluripotent Stem Cells/*cytology/*metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Adaptive immune features of natural killer cells (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-01-13
    Description: In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing 'memory' NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674434/" 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/PMC2674434/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Joseph C -- Beilke, Joshua N -- Lanier, Lewis L -- AI068129/AI/NIAID NIH HHS/ -- R01 AI068129/AI/NIAID NIH HHS/ -- R01 AI068129-09/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Jan 29;457(7229):557-61. doi: 10.1038/nature07665. Epub 2009 Jan 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology and the Cancer Research Institute, 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/19136945" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics ; Adoptive Transfer ; Animals ; Cell Proliferation ; Immunologic Memory/*immunology ; Killer Cells, Natural/*cytology/*immunology ; Lymphoid Tissue/immunology ; Mice ; Mice, Congenic ; Mice, Inbred C57BL ; *Models, Immunological ; Muromegalovirus/immunology/physiology ; Phenotype ; T-Lymphocytes, Cytotoxic/immunology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-06
    Description: The activation of innate immune responses by nucleic acids is crucial to protective and pathological immunities and is mediated by the transmembrane Toll-like receptors (TLRs) and cytosolic receptors. However, it remains unknown whether a mechanism exists that integrates these nucleic-acid-sensing systems. Here we show that high-mobility group box (HMGB) proteins 1, 2 and 3 function as universal sentinels for nucleic acids. HMGBs bind to all immunogenic nucleic acids examined with a correlation between affinity and immunogenic potential. Hmgb1(-/-) and Hmgb2(-/-) mouse cells are defective in type-I interferon and inflammatory cytokine induction by DNA or RNA targeted to activate the cytosolic nucleic-acid-sensing receptors; cells in which the expression of all three HMGBs is suppressed show a more profound defect, accompanied by impaired activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-kappaB. The absence of HMGBs also severely impairs the activation of TLR3, TLR7 and TLR9 by their cognate nucleic acids. Our results therefore indicate a hierarchy in the nucleic-acid-mediated activation of immune responses, wherein the selective activation of nucleic-acid-sensing receptors is contingent on the more promiscuous sensing of nucleic acids by HMGBs. These findings may have implications for understanding the evolution of the innate immune system and for the treatment of immunological disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yanai, Hideyuki -- Ban, Tatsuma -- Wang, ZhiChao -- Choi, Myoung Kwon -- Kawamura, Takeshi -- Negishi, Hideo -- Nakasato, Makoto -- Lu, Yan -- Hangai, Sho -- Koshiba, Ryuji -- Savitsky, David -- Ronfani, Lorenza -- Akira, Shizuo -- Bianchi, Marco E -- Honda, Kenya -- Tamura, Tomohiko -- Kodama, Tatsuhiko -- Taniguchi, Tadatsugu -- England -- Nature. 2009 Nov 5;462(7269):99-103. doi: 10.1038/nature08512.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19890330" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cytosol/immunology ; DNA/immunology ; HMGB Proteins/deficiency/genetics/*immunology/*metabolism ; HMGB1 Protein/deficiency/genetics/immunology/metabolism ; HMGB2 Protein/deficiency/genetics/immunology/metabolism ; Immunity, Innate/*immunology ; Interferon Regulatory Factor-3/metabolism ; Mice ; Mice, Inbred C57BL ; Models, Immunological ; NF-kappa B/metabolism ; Nucleic Acids/*immunology ; Nucleotides/chemistry/immunology/metabolism ; RNA/immunology ; Signal Transduction ; Toll-Like Receptors/immunology ; Virus Diseases/immunology/virology
    Print ISSN: 0028-0836
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  • 5
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    Cancer-associated IDH1 mutations produce 2-hydroxyglutarate (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-26
    Description: Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818760/" 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/PMC2818760/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dang, Lenny -- White, David W -- Gross, Stefan -- Bennett, Bryson D -- Bittinger, Mark A -- Driggers, Edward M -- Fantin, Valeria R -- Jang, Hyun Gyung -- Jin, Shengfang -- Keenan, Marie C -- Marks, Kevin M -- Prins, Robert M -- Ward, Patrick S -- Yen, Katharine E -- Liau, Linda M -- Rabinowitz, Joshua D -- Cantley, Lewis C -- Thompson, Craig B -- Vander Heiden, Matthew G -- Su, Shinsan M -- P01 CA104838/CA/NCI NIH HHS/ -- P01 CA104838-05/CA/NCI NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- R01 CA105463-06/CA/NCI NIH HHS/ -- R21 CA128620/CA/NCI NIH HHS/ -- England -- Nature. 2009 Dec 10;462(7274):739-44. doi: 10.1038/nature08617. Epub .〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19935646" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/genetics ; Brain Neoplasms/*genetics/*metabolism/pathology ; Catalytic Domain ; Cell Line ; Crystallography, X-Ray ; Disease Progression ; Enzyme Assays ; Glioma/genetics/metabolism/pathology ; Glutarates/*metabolism ; Histidine/genetics/metabolism ; Humans ; Isocitrate Dehydrogenase/*genetics/*metabolism ; Ketoglutaric Acids/metabolism ; Models, Molecular ; Mutant Proteins/*genetics/*metabolism ; Mutation/genetics ; Protein Conformation
    Print ISSN: 0028-0836
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  • 6
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    Crystal structure of the ATP-gated P2X(4) ion channel in the closed state (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-07-31
    Description: P2X receptors are cation-selective ion channels gated by extracellular ATP, and are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. Because P2X receptors are not related to other ion channel proteins of known structure, there is at present no molecular foundation for mechanisms of ligand-gating, allosteric modulation and ion permeation. Here we present crystal structures of the zebrafish P2X(4) receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit-subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in beta-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the 'gate' is defined by an approximately 8 A slab of protein. We define the location of three non-canonical, intersubunit ATP-binding sites, and suggest that ATP binding promotes subunit rearrangement and ion channel opening.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720809/" 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/PMC2720809/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kawate, Toshimitsu -- Michel, Jennifer Carlisle -- Birdsong, William T -- Gouaux, Eric -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM075026-04/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jul 30;460(7255):592-8. doi: 10.1038/nature08198.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641588" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Gadolinium/metabolism ; Humans ; Ion Channels/antagonists & inhibitors/*chemistry ; Membrane Proteins/chemistry ; *Models, Molecular ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Purinergic P2 Receptor Antagonists ; Receptors, Purinergic P2/*chemistry ; Receptors, Purinergic P2X4 ; Zebrafish/*physiology ; Zebrafish Proteins/antagonists & inhibitors/*chemistry
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  • 7
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    Bidirectional plasticity in fast-spiking GABA circuits by visual experience (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-13
    Description: Experience-dependent plasticity in the brain requires balanced excitation-inhibition. How individual circuit elements contribute to plasticity outcome in complex neocortical networks remains unknown. Here we report an intracellular analysis of ocular dominance plasticity-the loss of acuity and cortical responsiveness for an eye deprived of vision in early life. Unlike the typical progressive loss of pyramidal-cell bias, direct recording from fast-spiking cells in vivo reveals a counterintuitive initial shift towards the occluded eye followed by a late preference for the open eye, consistent with a spike-timing-dependent plasticity rule for these inhibitory neurons. Intracellular pharmacology confirms a dynamic switch of GABA (gamma-aminobutyric acid) impact to pyramidal cells following deprivation in juvenile mice only. Together these results suggest that the bidirectional recruitment of an initially binocular GABA circuit may contribute to experience-dependent plasticity in the developing visual cortex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yazaki-Sugiyama, Yoko -- Kang, Siu -- Cateau, Hideyuki -- Fukai, Tomoki -- Hensch, Takao K -- England -- Nature. 2009 Nov 12;462(7270):218-21. doi: 10.1038/nature08485.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CREST, JST, Toyonaka, Osaka 560-0082, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907494" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/*physiology ; Aging/physiology ; Animals ; Dominance, Ocular/*physiology ; Interneurons/metabolism ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neuronal Plasticity/*physiology ; Neurons/*metabolism ; Photic Stimulation ; Pyramidal Cells/metabolism ; Receptors, GABA/metabolism ; Visual Cortex/cytology/physiology ; Visual Pathways/physiology ; Visual Perception/*physiology ; gamma-Aminobutyric Acid/*metabolism
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  • 8
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    Molecular basis of transport and regulation in the Na(+)/betaine symporter BetP (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-03-06
    Description: Osmoregulated transporters sense intracellular osmotic pressure and respond to hyperosmotic stress by accumulation of osmolytes to restore normal hydration levels. Here we report the determination of the X-ray structure of a member of the family of betaine/choline/carnitine transporters, the Na(+)-coupled symporter BetP from Corynebacterium glutamicum, which is a highly effective osmoregulated uptake system for glycine betaine. Glycine betaine is bound in a tryptophan box occluded from both sides of the membrane with aromatic side chains lining the transport pathway. BetP has the same overall fold as three unrelated Na(+)-coupled symporters. Whereas these are crystallized in either the outward-facing or the inward-facing conformation, the BetP structure reveals a unique intermediate conformation in the Na(+)-coupled transport cycle. The trimeric architecture of BetP and the break in three-fold symmetry by the osmosensing C-terminal helices suggest a regulatory mechanism of Na(+)-coupled osmolyte transport to counteract osmotic stress.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ressl, Susanne -- Terwisscha van Scheltinga, Anke C -- Vonrhein, Clemens -- Ott, Vera -- Ziegler, Christine -- England -- Nature. 2009 Mar 5;458(7234):47-52. doi: 10.1038/nature07819.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Biophysics, Department of Structural Biology, 60438 Frankfurt am Main, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19262666" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics/*metabolism ; Betaine/*metabolism ; Binding Sites ; Carrier Proteins/*chemistry/genetics/*metabolism ; Corynebacterium glutamicum/*chemistry/genetics ; Crystallography, X-Ray ; Ion Transport ; Models, Molecular ; Protein Binding ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Sodium/*metabolism ; Structure-Activity Relationship
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  • 9
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    CCR3 is a target for age-related macular degeneration diagnosis and therapy (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-06-16
    Description: Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization, which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712122/" 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/PMC2712122/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Takeda, Atsunobu -- Baffi, Judit Z -- Kleinman, Mark E -- Cho, Won Gil -- Nozaki, Miho -- Yamada, Kiyoshi -- Kaneko, Hiroki -- Albuquerque, Romulo J C -- Dridi, Sami -- Saito, Kuniharu -- Raisler, Brian J -- Budd, Steven J -- Geisen, Pete -- Munitz, Ariel -- Ambati, Balamurali K -- Green, Martha G -- Ishibashi, Tatsuro -- Wright, John D -- Humbles, Alison A -- Gerard, Craig J -- Ogura, Yuichiro -- Pan, Yuzhen -- Smith, Justine R -- Grisanti, Salvatore -- Hartnett, M Elizabeth -- Rothenberg, Marc E -- Ambati, Jayakrishna -- AI039759/AI/NIAID NIH HHS/ -- AI45898/AI/NIAID NIH HHS/ -- DK076893/DK/NIDDK NIH HHS/ -- EY010572/EY/NEI NIH HHS/ -- EY015130/EY/NEI NIH HHS/ -- EY015422/EY/NEI NIH HHS/ -- EY017011/EY/NEI NIH HHS/ -- EY017182/EY/NEI NIH HHS/ -- EY017950/EY/NEI NIH HHS/ -- EY018350/EY/NEI NIH HHS/ -- EY018836/EY/NEI NIH HHS/ -- R01 DK076893/DK/NIDDK NIH HHS/ -- R01 EY015422/EY/NEI NIH HHS/ -- R01 EY015422-04/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018350-02/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY018836-02/EY/NEI NIH HHS/ -- England -- Nature. 2009 Jul 9;460(7252):225-30. doi: 10.1038/nature08151. Epub 2009 Jun 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology & Visual Science, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19525930" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Chemokine CCL11/antagonists & inhibitors/metabolism ; Chemokine CCL24/antagonists & inhibitors/metabolism ; Chemokines, CC/antagonists & inhibitors/metabolism ; Choroid/blood supply/cytology/metabolism ; Choroidal Neovascularization/diagnosis/metabolism ; Disease Models, Animal ; Endothelial Cells/cytology/metabolism ; Humans ; Inflammation ; Leukocytes ; Ligands ; Macular Degeneration/*diagnosis/metabolism/*therapy ; Mice ; Mice, Inbred C57BL ; Quantum Dots ; Receptors, CCR3/analysis/*antagonists & ; inhibitors/genetics/immunology/*metabolism ; Retina/drug effects/pathology ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/immunology
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  • 10
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    Transport mechanism of a bacterial homologue of glutamate transporters (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-20
    Description: Glutamate transporters are integral membrane proteins that catalyse a thermodynamically uphill uptake of the neurotransmitter glutamate from the synaptic cleft into the cytoplasm of glia and neuronal cells by harnessing the energy of pre-existing electrochemical gradients of ions. Crucial to the reaction is the conformational transition of the transporters between outward and inward facing states, in which the substrate binding sites are accessible from the extracellular space and the cytoplasm, respectively. Here we describe the crystal structure of a double cysteine mutant of a glutamate transporter homologue from Pyrococcus horikoshii, Glt(Ph), which is trapped in the inward facing state by cysteine crosslinking. Together with the previously determined crystal structures of Glt(Ph) in the outward facing state, the structure of the crosslinked mutant allows us to propose a molecular mechanism by which Glt(Ph) and, by analogy, mammalian glutamate transporters mediate sodium-coupled substrate uptake.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934767/" 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/PMC2934767/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reyes, Nicolas -- Ginter, Christopher -- Boudker, Olga -- R01 NS064357/NS/NINDS NIH HHS/ -- R01 NS064357-01A1/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Dec 17;462(7275):880-5. doi: 10.1038/nature08616. Epub 2009 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, Box 75, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19924125" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Transport System X-AG/*chemistry/genetics/*metabolism ; Binding Sites ; Biological Transport ; Cross-Linking Reagents ; Crystallography, X-Ray ; Cysteine/genetics/metabolism ; Models, Molecular ; Movement ; Mutant Proteins/chemistry/genetics/metabolism ; Protein Structure, Tertiary ; Pyrococcus horikoshii/*chemistry ; Sodium/metabolism ; Structure-Activity Relationship
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  • 11
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    Role of Jhdm2a in regulating metabolic gene expression and obesity resistance (2009)
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    Publication Date: 2009-02-06
    Description: Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases. The H3K9-specific demethylase Jhdm2a (also known as Jmjd1a and Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development. Through disruption of the Jhdm2a gene in mice, here we demonstrate that Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. We provide evidence that the loss of Jhdm2a function disrupts beta-adrenergic-stimulated glycerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. Furthermore, we demonstrate that beta-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Ppargamma and Rxralpha and their co-activators Pgc1alpha (also known as Ppargc1a), CBP/p300 (Crebbp) and Src1 (Ncoa1) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085783/" 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/PMC4085783/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tateishi, Keisuke -- Okada, Yuki -- Kallin, Eric M -- Zhang, Yi -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Apr 9;458(7239):757-61. doi: 10.1038/nature07777. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194461" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/metabolism ; Animals ; Cells, Cultured ; Energy Metabolism/*physiology ; Gene Expression Profiling ; *Gene Expression Regulation ; Glycerol/metabolism ; Ion Channels/metabolism ; Jumonji Domain-Containing Histone Demethylases ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondrial Proteins/metabolism ; Muscle, Skeletal/metabolism ; Obesity/*metabolism ; Oxidation-Reduction ; Oxidoreductases, N-Demethylating/*genetics/*metabolism ; Phenotype ; Receptors, Adrenergic, beta/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 12
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    VEGFR1-activity-independent metastasis formation (2009)
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    Publication Date: 2009-09-18
    Description: Molecules such as vascular endothelial growth factor (VEGF) or placental growth factor-critical regulators of tumour angiogenesis-are also thought to mobilize into blood circulation bone marrow-derived cells (BMDCs), which may subsequently be recruited to tumours and facilitate tumour growth and metastasis. A study has suggested that BMDCs form 'metastatic niches' in lungs before arrival of cancer cells, and showed that pharmacological inhibition of VEGF receptor 1 (VEGFR1, also known as Flt1)-cognate receptor for VEGF and placental growth factor-prevented BMDC infiltration in lungs and 'metastatic niche' formation. Here we report that blockade of VEGFR1 activity does not affect the rate of spontaneous metastasis formation in a clinically relevant and widely used preclinical model. Therefore, alternative pathways probably mediate the priming of tissues for metastasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065241/" 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/PMC3065241/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dawson, Michelle R -- Duda, Dan G -- Fukumura, Dai -- Jain, Rakesh K -- P01 CA080124/CA/NCI NIH HHS/ -- P01 CA080124-05/CA/NCI NIH HHS/ -- P01 CA080124-06A2/CA/NCI NIH HHS/ -- P01 CA080124-07/CA/NCI NIH HHS/ -- P01 CA080124-08/CA/NCI NIH HHS/ -- P01 CA080124-09/CA/NCI NIH HHS/ -- R01 CA085140/CA/NCI NIH HHS/ -- R01 CA085140-06/CA/NCI NIH HHS/ -- R01 CA085140-07/CA/NCI NIH HHS/ -- R01 CA085140-08/CA/NCI NIH HHS/ -- R01 CA085140-09/CA/NCI NIH HHS/ -- R01 CA096915/CA/NCI NIH HHS/ -- R01 CA096915-04/CA/NCI NIH HHS/ -- R01 CA096915-05/CA/NCI NIH HHS/ -- R01 CA096915-06A1/CA/NCI NIH HHS/ -- R01 CA096915-07/CA/NCI NIH HHS/ -- R01 CA096915-08/CA/NCI NIH HHS/ -- R01 CA115767/CA/NCI NIH HHS/ -- R01 CA115767-01A1/CA/NCI NIH HHS/ -- R01 CA115767-02/CA/NCI NIH HHS/ -- R01 CA115767-03/CA/NCI NIH HHS/ -- R01 CA115767-04/CA/NCI NIH HHS/ -- R01 CA126642/CA/NCI NIH HHS/ -- R01 CA126642-01A1/CA/NCI NIH HHS/ -- R01 CA126642-02/CA/NCI NIH HHS/ -- R24 CA085140/CA/NCI NIH HHS/ -- R24 CA085140-05/CA/NCI NIH HHS/ -- T32 CA073479/CA/NCI NIH HHS/ -- T32 CA073479-08/CA/NCI NIH HHS/ -- T32 CA073479-09/CA/NCI NIH HHS/ -- T32 CA073479-10/CA/NCI NIH HHS/ -- T32 CA073479-11/CA/NCI NIH HHS/ -- T32 CA073479-12/CA/NCI NIH HHS/ -- England -- Nature. 2009 Sep 17;461(7262):E4; discussion E5. doi: 10.1038/nature08254.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19759568" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Cells/cytology ; Cell Movement ; Lung/pathology ; Lung Neoplasms/*secondary ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Neoplasms/*pathology ; Vascular Endothelial Growth Factor Receptor-1/*antagonists & ; inhibitors/deficiency/*metabolism
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    Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-06
    Description: The heterotrimeric influenza virus polymerase, containing the PA, PB1 and PB2 proteins, catalyses viral RNA replication and transcription in the nucleus of infected cells. PB1 holds the polymerase active site and reportedly harbours endonuclease activity, whereas PB2 is responsible for cap binding. The PA amino terminus is understood to be the major functional part of the PA protein and has been implicated in several roles, including endonuclease and protease activities as well as viral RNA/complementary RNA promoter binding. Here we report the 2.2 angstrom (A) crystal structure of the N-terminal 197 residues of PA, termed PA(N), from an avian influenza H5N1 virus. The PA(N) structure has an alpha/beta architecture and reveals a bound magnesium ion coordinated by a motif similar to the (P)DX(N)(D/E)XK motif characteristic of many endonucleases. Structural comparisons and mutagenesis analysis of the motif identified in PA(N) provide further evidence that PA(N) holds an endonuclease active site. Furthermore, functional analysis with in vivo ribonucleoprotein reconstitution and direct in vitro endonuclease assays strongly suggest that PA(N) holds the endonuclease active site and has critical roles in endonuclease activity of the influenza virus polymerase, rather than PB1. The high conservation of this endonuclease active site among influenza strains indicates that PA(N) is an important target for the design of new anti-influenza therapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yuan, Puwei -- Bartlam, Mark -- Lou, Zhiyong -- Chen, Shoudeng -- Zhou, Jie -- He, Xiaojing -- Lv, Zongyang -- Ge, Ruowen -- Li, Xuemei -- Deng, Tao -- Fodor, Ervin -- Rao, Zihe -- Liu, Yingfang -- G0700848/Medical Research Council/United Kingdom -- England -- Nature. 2009 Apr 16;458(7240):909-13. doi: 10.1038/nature07720. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194458" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Birds/virology ; Catalytic Domain ; Crystallography, X-Ray ; Endonucleases/*chemistry/genetics/*metabolism ; Influenza A Virus, H5N1 Subtype/*enzymology ; Influenza in Birds/*virology ; Models, Molecular ; Protein Subunits/chemistry/genetics/metabolism ; RNA Replicase/*chemistry/genetics/*metabolism ; Viral Proteins/*chemistry/genetics/*metabolism
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    Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis (2009)
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    Publication Date: 2009-01-06
    Description: Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours. To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. Here we show that, among the cell lines screened, Lewis lung carcinoma (LLC) were the most potent macrophage activators leading to production of interleukin-6 (IL-6) and tumour-necrosis factor-alpha (TNF-alpha) through activation of the Toll-like receptor (TLR) family members TLR2 and TLR6. Both TNF-alpha and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours including lung cancer, as a macrophage activator that acts through TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-alpha secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone-marrow-derived myeloid progenitors, to generate an inflammatory microenvironment hospitable for metastatic growth.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746432/" 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/PMC2746432/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Sunhwa -- Takahashi, Hiroyuki -- Lin, Wan-Wan -- Descargues, Pascal -- Grivennikov, Sergei -- Kim, Youngjun -- Luo, Jun-Li -- Karin, Michael -- R01 CA118165/CA/NCI NIH HHS/ -- R01 CA118165-02/CA/NCI NIH HHS/ -- R01 CA132586/CA/NCI NIH HHS/ -- R01 ES006376/ES/NIEHS NIH HHS/ -- R01 ES006376-14/ES/NIEHS NIH HHS/ -- T32 CA121938/CA/NCI NIH HHS/ -- England -- Nature. 2009 Jan 1;457(7225):102-6. doi: 10.1038/nature07623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19122641" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD14/metabolism ; Carcinoma, Lewis Lung/*metabolism/pathology/secretion ; Culture Media, Conditioned/metabolism/pharmacology ; Culture Media, Serum-Free/metabolism ; Interleukin-6/metabolism/secretion ; Liver Neoplasms/secondary ; Lung Neoplasms/metabolism/pathology/secondary ; *Macrophage Activation ; Macrophages/*metabolism/secretion ; Mice ; Mice, Inbred C57BL ; *Neoplasm Metastasis/pathology ; Neoplasm Transplantation ; Toll-Like Receptor 2/agonists/*metabolism ; Toll-Like Receptor 6/metabolism ; Tumor Necrosis Factor-alpha/metabolism/secretion ; Versicans/metabolism/pharmacology
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    CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia (2009)
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    Publication Date: 2009-06-19
    Description: T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents. T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse. For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy. Such complications include secondary tumours, neurocognitive deficits, endocrine disorders and growth impairment. Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance. Here we show, using T-ALL animal modelling and gene-expression profiling, that the chemokine receptor CCR7 (ref. 5) is the essential adhesion signal required for the targeting of leukaemic T-cells into the CNS. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 and is expressed in human tumours carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 (ref. 6) in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, murine CNS-targeting by human T-ALL cells depends on their ability to express CCR7. These studies identify a single chemokine-receptor interaction as a CNS 'entry' signal, and open the way for future pharmacological targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750496/" 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/PMC3750496/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buonamici, Silvia -- Trimarchi, Thomas -- Ruocco, Maria Grazia -- Reavie, Linsey -- Cathelin, Severine -- Mar, Brenton G -- Klinakis, Apostolos -- Lukyanov, Yevgeniy -- Tseng, Jen-Chieh -- Sen, Filiz -- Gehrie, Eric -- Li, Mengling -- Newcomb, Elizabeth -- Zavadil, Jiri -- Meruelo, Daniel -- Lipp, Martin -- Ibrahim, Sherif -- Efstratiadis, Argiris -- Zagzag, David -- Bromberg, Jonathan S -- Dustin, Michael L -- Aifantis, Iannis -- 1 P01 CA97403/CA/NCI NIH HHS/ -- P30CA016087/CA/NCI NIH HHS/ -- R01 AI041428/AI/NIAID NIH HHS/ -- R01 AI062765/AI/NIAID NIH HHS/ -- R01 AI072039/AI/NIAID NIH HHS/ -- R01 CA105129/CA/NCI NIH HHS/ -- R01 CA149655/CA/NCI NIH HHS/ -- R01AI072039/AI/NIAID NIH HHS/ -- R01AI41428/AI/NIAID NIH HHS/ -- R01CA105129/CA/NCI NIH HHS/ -- R01CA133379/CA/NCI NIH HHS/ -- R21 CA141399/CA/NCI NIH HHS/ -- R56AI070310/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Jun 18;459(7249):1000-4. doi: 10.1038/nature08020.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and New York University Cancer Institute, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536265" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Adhesion ; Cell Line, Tumor ; Central Nervous System/*metabolism/*pathology ; Chemokine CCL19/deficiency/metabolism ; Chemokine CCL21/metabolism ; Humans ; Leukemia, T-Cell/*metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology ; Receptor, Notch1/genetics/metabolism ; Receptors, CCR7/deficiency/*metabolism ; *Signal Transduction
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    CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation (2009)
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    Publication Date: 2009-06-16
    Description: Toll-like receptors (TLRs) are the best characterized pattern recognition receptors. Individual TLRs recruit diverse combinations of adaptor proteins, triggering signal transduction pathways and leading to the activation of various transcription factors, including nuclear factor kappaB, activation protein 1 and interferon regulatory factors. Interleukin-2 is one of the molecules produced by mouse dendritic cells after stimulation by different pattern recognition receptor agonists. By analogy with the events after T-cell receptor engagement leading to interleukin-2 production, it is therefore plausible that the stimulation of TLRs on dendritic cells may lead to activation of the Ca(2+)/calcineurin and NFAT (nuclear factor of activated T cells) pathway. Here we show that mouse dendritic cell stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase Cgamma2 activation, influx of extracellular Ca(2+) and calcineurin-dependent nuclear NFAT translocation. The initiation of this pathway is independent of TLR4 engagement, and dependent exclusively on CD14. We also show that LPS-induced NFAT activation via CD14 is necessary to cause the apoptotic death of terminally differentiated dendritic cells, an event that is essential for maintaining self-tolerance and preventing autoimmunity. Consequently, blocking this pathway in vivo causes prolonged dendritic cell survival and an increase in T-cell priming capability. Our findings reveal novel aspects of molecular signalling triggered by LPS in dendritic cells, and identify a new role for CD14: the regulation of the dendritic cell life cycle through NFAT activation. Given the involvement of CD14 in disease, including sepsis and chronic heart failure, the discovery of signal transduction pathways activated exclusively via CD14 is an important step towards the development of potential treatments involving interference with CD14 functions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zanoni, Ivan -- Ostuni, Renato -- Capuano, Giusy -- Collini, Maddalena -- Caccia, Michele -- Ronchi, Antonella Ellena -- Rocchetti, Marcella -- Mingozzi, Francesca -- Foti, Maria -- Chirico, Giuseppe -- Costa, Barbara -- Zaza, Antonio -- Ricciardi-Castagnoli, Paola -- Granucci, Francesca -- England -- Nature. 2009 Jul 9;460(7252):264-8. doi: 10.1038/nature08118. Epub 2009 Jun 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19525933" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD14/*metabolism ; Apoptosis/drug effects ; Bone Marrow Cells/drug effects ; CD4-Positive T-Lymphocytes/drug effects/immunology ; Calcium/metabolism ; Calcium Signaling/drug effects ; Cell Differentiation ; Cell Survival/drug effects ; Dendritic Cells/*cytology/drug effects/*immunology/metabolism ; Lipopolysaccharides/*immunology/pharmacology ; Macrophages/cytology/drug effects/immunology ; Mice ; Mice, Inbred C57BL ; NFATC Transcription Factors/*metabolism ; Phospholipase C gamma/metabolism ; src-Family Kinases/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-27
    Description: Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype. To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-kappaB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease-a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841516/" 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/PMC2841516/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gu, YuanYuan -- Harley, Isaac T W -- Henderson, Lindsay B -- Aronow, Bruce J -- Vietor, Ilja -- Huber, Lukas A -- Harley, John B -- Kilpatrick, Jeffrey R -- Langefeld, Carl D -- Williams, Adrienne H -- Jegga, Anil G -- Chen, Jing -- Wills-Karp, Marsha -- Arshad, S Hasan -- Ewart, Susan L -- Thio, Chloe L -- Flick, Leah M -- Filippi, Marie-Dominique -- Grimes, H Leighton -- Drumm, Mitchell L -- Cutting, Garry R -- Knowles, Michael R -- Karp, Christopher L -- R01 AI024717/AI/NIAID NIH HHS/ -- R01 HL068890/HL/NHLBI NIH HHS/ -- R01 HL068890-01/HL/NHLBI NIH HHS/ -- R01 HL068927/HL/NHLBI NIH HHS/ -- R01 HL068927-01/HL/NHLBI NIH HHS/ -- R01 HL079312/HL/NHLBI NIH HHS/ -- R01 HL079312-01A1/HL/NHLBI NIH HHS/ -- R37 AI024717/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Apr 23;458(7241):1039-42. doi: 10.1038/nature07811. Epub 2009 Feb 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242412" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Cohort Studies ; Cystic Fibrosis/*genetics/*pathology ; Disease Models, Animal ; Genotype ; Humans ; Immediate-Early Proteins/deficiency/*genetics ; Inflammation/genetics/pathology ; Mice ; Mice, Inbred C57BL ; Neutrophils/immunology/metabolism ; Polymorphism, Single Nucleotide/genetics ; Pseudomonas aeruginosa/immunology/pathogenicity ; Transcription Factor RelA/metabolism
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    Complete but curtailed T-cell response to very low-affinity antigen (2009)
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    Publication Date: 2009-02-03
    Description: After an infection, T cells that carry the CD8 marker are activated and undergo a characteristic kinetic sequence of rapid expansion, subsequent contraction and formation of memory cells. The pool of naive T-cell clones is diverse and contains cells bearing T-cell antigen receptors (TCRs) that differ in their affinity for the same antigen. How these differences in affinity affect the function and the response kinetics of individual T-cell clones was previously unknown. Here we show that during the in vivo response to microbial infection, even very weak TCR-ligand interactions are sufficient to activate naive T cells, induce rapid initial proliferation and generate effector and memory cells. The strength of the TCR-ligand interaction critically affects when expansion stops, when the cells exit lymphoid organs and when contraction begins; that is, strongly stimulated T cells contract and exit lymphoid organs later than weakly stimulated cells. Our data challenge the prevailing view that strong TCR ligation is a prerequisite for CD8(+) T-cell activation. Instead, very weak interactions are sufficient for activation, but strong TCR ligation is required to sustain T-cell expansion. We propose that in response to microbial challenge, T-cell clones with a broad range of avidities for foreign ligands are initially recruited, and that the pool of T cells subsequently matures in affinity owing to the more prolonged expansion of high-affinity T-cell clones.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735344/" 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/PMC2735344/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zehn, Dietmar -- Lee, Sarah Y -- Bevan, Michael J -- R01 AI019335/AI/NIAID NIH HHS/ -- R01 AI019335-27/AI/NIAID NIH HHS/ -- R01 AI019335-28/AI/NIAID NIH HHS/ -- R01 AI019335-29/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Mar 12;458(7235):211-4. doi: 10.1038/nature07657. Epub 2009 Jan 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Howard Hughes Medical Institute, University of Washington, Box 357370, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19182777" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody Affinity/*immunology ; Antigens, Bacterial/*immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Movement/immunology ; Immunologic Memory/immunology ; Ligands ; Listeria monocytogenes/immunology ; Listeriosis/immunology ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes/*immunology
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  • 19
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    HDAC2 negatively regulates memory formation and synaptic plasticity (2009)
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    Publication Date: 2009-05-09
    Description: Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498958/" 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/PMC3498958/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guan, Ji-Song -- Haggarty, Stephen J -- Giacometti, Emanuela -- Dannenberg, Jan-Hermen -- Joseph, Nadine -- Gao, Jun -- Nieland, Thomas J F -- Zhou, Ying -- Wang, Xinyu -- Mazitschek, Ralph -- Bradner, James E -- DePinho, Ronald A -- Jaenisch, Rudolf -- Tsai, Li-Huei -- R01 DA028301/DA/NIDA NIH HHS/ -- R01 DA028301-02/DA/NIDA NIH HHS/ -- R01 NS051874/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 May 7;459(7243):55-60. doi: 10.1038/nature07925.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19424149" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Butyrates/pharmacology ; Dendritic Spines/physiology ; Electrical Synapses/*physiology ; Female ; Gene Expression Regulation ; Hippocampus/metabolism ; Histone Deacetylase 1 ; Histone Deacetylase 2 ; Histone Deacetylase Inhibitors ; Histone Deacetylases/deficiency/genetics/*metabolism ; Hydroxamic Acids/pharmacology ; Learning/drug effects ; Male ; Memory/drug effects/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/metabolism ; Promoter Regions, Genetic/genetics ; Repressor Proteins/antagonists & inhibitors/genetics/*metabolism ; Sodium/pharmacology
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    T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-06-06
    Description: Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process. The inflammatory response must be actively terminated, however, because failure to do so can result in 'bystander' damage to tissues and diseases such as arthritis or type-2 diabetes. Yet the mechanisms controlling excessive inflammatory responses are still poorly understood. Here we show that mouse effector and memory CD4(+) T cells abolish macrophage inflammasome-mediated caspase-1 activation and subsequent interleukin 1beta release in a cognate manner. Inflammasome inhibition is observed for all tested NLRP1 (commonly called NALP1) and NLRP3 (NALP3 or cryopyrin) activators, whereas NLRC4 (IPAF) inflammasome function and release of other inflammatory mediators such as CXCL2, interleukin 6 and tumour necrosis factor are not affected. Suppression of the NLRP3 inflammasome requires cell-to-cell contact and can be mimicked by macrophage stimulation with selected ligands of the tumour necrosis factor family, such as CD40L (also known as CD40LG). In a NLRP3-dependent peritonitis model, effector CD4(+) T cells are responsible for decreasing neutrophil recruitment in an antigen-dependent manner. Our findings reveal an unexpected mechanism of inflammasome inhibition, whereby effector and memory T cells suppress potentially damaging inflammation, yet leave the primary inflammatory response, crucial for the onset of immunity, intact.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guarda, Greta -- Dostert, Catherine -- Staehli, Francesco -- Cabalzar, Katrin -- Castillo, Rosa -- Tardivel, Aubry -- Schneider, Pascal -- Tschopp, Jurg -- England -- Nature. 2009 Jul 9;460(7252):269-73. doi: 10.1038/nature08100. Epub 2009 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19494813" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/*antagonists & inhibitors/metabolism ; Animals ; Antigens/immunology ; Apoptosis Regulatory Proteins/*antagonists & inhibitors/metabolism ; Bone Marrow Cells/cytology ; CD4-Positive T-Lymphocytes/*immunology ; Carrier Proteins/*antagonists & inhibitors/metabolism ; Caspase 1/metabolism ; Cells, Cultured ; Immunity, Innate/*immunology ; Immunologic Memory ; Inflammation/immunology/*metabolism/pathology ; Interleukin-1beta/immunology ; Ligands ; Macrophages/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neutrophils/immunology ; Peritoneal Cavity/cytology ; Tumor Necrosis Factors/immunology/metabolism
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    Presenilins are essential for regulating neurotransmitter release (2009)
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    Publication Date: 2009-07-31
    Description: Mutations in the presenilin genes are the main cause of familial Alzheimer's disease. Loss of presenilin activity and/or accumulation of amyloid-beta peptides have been proposed to mediate the pathogenesis of Alzheimer's disease by impairing synaptic function. However, the precise site and nature of the synaptic dysfunction remain unknown. Here we use a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. We show that long-term potentiation induced by theta-burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, we found that presynaptic but not postsynaptic inactivation of presenilins alters short-term plasticity and synaptic facilitation. The probability of evoked glutamate release, measured with the open-channel NMDA (N-methyl-D-aspartate) receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Notably, depletion of endoplasmic reticulum Ca(2+) stores by thapsigargin, or blockade of Ca(2+) release from these stores by ryanodine receptor inhibitors, mimics and occludes the effects of presynaptic presenilin inactivation. Collectively, these results indicate a selective role for presenilins in the activity-dependent regulation of neurotransmitter release and long-term potentiation induction by modulation of intracellular Ca(2+) release in presynaptic terminals, and further suggest that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in Alzheimer's disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744588/" 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/PMC2744588/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Chen -- Wu, Bei -- Beglopoulos, Vassilios -- Wines-Samuelson, Mary -- Zhang, Dawei -- Dragatsis, Ioannis -- Sudhof, Thomas C -- Shen, Jie -- R01 NS041783/NS/NINDS NIH HHS/ -- R01 NS041783-04/NS/NINDS NIH HHS/ -- R01 NS041783-08/NS/NINDS NIH HHS/ -- R01NS041783/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Jul 30;460(7255):632-6. doi: 10.1038/nature08177.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neurologic Diseases, Brigham & Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641596" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/metabolism ; Cells, Cultured ; *Gene Expression Regulation ; Glutamic Acid/metabolism ; Hippocampus/cytology/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Neurons/*metabolism ; Neurotransmitter Agents/*metabolism ; Presenilins/*genetics/*metabolism ; Presynaptic Terminals/metabolism
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    Structural biology: Molecular coin slots for urea (2009)
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    Publication Date: 2009-12-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knepper, Mark A -- Mindell, Joseph A -- England -- Nature. 2009 Dec 10;462(7274):733-4. doi: 10.1038/462733a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010678" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Desulfovibrio vulgaris/*chemistry ; Humans ; Kidney/metabolism ; Membrane Transport Proteins/*chemistry/*metabolism ; Protein Structure, Quaternary ; Structure-Activity Relationship ; Urea/chemistry/*metabolism
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    From molecular to macroscopic via the rational design of a self-assembled 3D DNA crystal (2009)
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    Publication Date: 2009-09-04
    Description: We live in a macroscopic three-dimensional (3D) world, but our best description of the structure of matter is at the atomic and molecular scale. Understanding the relationship between the two scales requires a bridge from the molecular world to the macroscopic world. Connecting these two domains with atomic precision is a central goal of the natural sciences, but it requires high spatial control of the 3D structure of matter. The simplest practical route to producing precisely designed 3D macroscopic objects is to form a crystalline arrangement by self-assembly, because such a periodic array has only conceptually simple requirements: a motif that has a robust 3D structure, dominant affinity interactions between parts of the motif when it self-associates, and predictable structures for these affinity interactions. Fulfilling these three criteria to produce a 3D periodic system is not easy, but should readily be achieved with well-structured branched DNA motifs tailed by sticky ends. Complementary sticky ends associate with each other preferentially and assume the well-known B-DNA structure when they do so; the helically repeating nature of DNA facilitates the construction of a periodic array. It is essential that the directions of propagation associated with the sticky ends do not share the same plane, but extend to form a 3D arrangement of matter. Here we report the crystal structure at 4 A resolution of a designed, self-assembled, 3D crystal based on the DNA tensegrity triangle. The data demonstrate clearly that it is possible to design and self-assemble a well-ordered macromolecular 3D crystalline lattice with precise control.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764300/" 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/PMC2764300/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Jianping -- Birktoft, Jens J -- Chen, Yi -- Wang, Tong -- Sha, Ruojie -- Constantinou, Pamela E -- Ginell, Stephan L -- Mao, Chengde -- Seeman, Nadrian C -- 1R21EB007472/EB/NIBIB NIH HHS/ -- R21 EB007472/EB/NIBIB NIH HHS/ -- R21 EB007472-03/EB/NIBIB NIH HHS/ -- England -- Nature. 2009 Sep 3;461(7260):74-7. doi: 10.1038/nature08274.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, New York University, New York 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19727196" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Crystallization ; Crystallography, X-Ray ; DNA/*chemistry/genetics ; *Drug Design ; Molecular Sequence Data ; *Nucleic Acid Conformation
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    An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene (2009)
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    Publication Date: 2009-04-17
    Description: Biosynthesis of the DNA base thymine depends on activity of the enzyme thymidylate synthase to catalyse the methylation of the uracil moiety of 2'-deoxyuridine-5'-monophosphate. All known thymidylate synthases rely on an active site residue of the enzyme to activate 2'-deoxyuridine-5'-monophosphate. This functionality has been demonstrated for classical thymidylate synthases, including human thymidylate synthase, and is instrumental in mechanism-based inhibition of these enzymes. Here we report an example of thymidylate biosynthesis that occurs without an enzymatic nucleophile. This unusual biosynthetic pathway occurs in organisms containing the thyX gene, which codes for a flavin-dependent thymidylate synthase (FDTS), and is present in several human pathogens. Our findings indicate that the putative active site nucleophile is not required for FDTS catalysis, and no alternative nucleophilic residues capable of serving this function can be identified. Instead, our findings suggest that a hydride equivalent (that is, a proton and two electrons) is transferred from the reduced flavin cofactor directly to the uracil ring, followed by an isomerization of the intermediate to form the product, 2'-deoxythymidine-5'-monophosphate. These observations indicate a very different chemical cascade than that of classical thymidylate synthases or any other known biological methylation. The findings and chemical mechanism proposed here, together with available structural data, suggest that selective inhibition of FDTSs, with little effect on human thymine biosynthesis, should be feasible. Because several human pathogens depend on FDTS for DNA biosynthesis, its unique mechanism makes it an attractive target for antibiotic drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759699/" 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/PMC2759699/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koehn, Eric M -- Fleischmann, Todd -- Conrad, John A -- Palfey, Bruce A -- Lesley, Scott A -- Mathews, Irimpan I -- Kohen, Amnon -- GM08270/GM/NIGMS NIH HHS/ -- R01 GM065368/GM/NIGMS NIH HHS/ -- R01 GM065368-05/GM/NIGMS NIH HHS/ -- R01 GM61087/GM/NIGMS NIH HHS/ -- U54GM074898/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 16;458(7240):919-23. doi: 10.1038/nature07973.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19370033" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Deoxyuracil Nucleotides/chemistry/metabolism ; Deuterium/metabolism ; Electrons ; Flavin-Adenine Dinucleotide/chemistry/metabolism ; Flavins/chemistry/*metabolism ; Helicobacter pylori/enzymology ; Humans ; Magnetic Resonance Spectroscopy ; Methylation ; Models, Molecular ; Mycobacterium tuberculosis/enzymology ; Protons ; Thermotoga maritima/*enzymology/*metabolism ; Thymidine/analogs & derivatives/metabolism ; Thymidine Monophosphate/*biosynthesis ; Thymidylate Synthase/antagonists & inhibitors/*genetics/*metabolism ; Uracil/metabolism
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    Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses (2009)
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    Publication Date: 2009-02-03
    Description: In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of T(H)1, T(H)2 or T(H)17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (T(reg)). T(reg) cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented T(H)1 and T(H)2 cytokine production. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets. Here we show that in mouse T(reg) cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for T(H)2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows T(reg) cells with the ability to suppress T(H)2 responses. Indeed, ablation of a conditional Irf4 allele in T(reg) cells resulted in selective dysregulation of T(H)2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking T(reg) cells. Our results indicate that T(reg) cells use components of the transcriptional machinery, promoting a particular type of effector CD4(+) T cell differentiation, to efficiently restrain the corresponding type of the immune response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864791/" 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/PMC2864791/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Ye -- Chaudhry, Ashutosh -- Kas, Arnold -- deRoos, Paul -- Kim, Jeong M -- Chu, Tin-Tin -- Corcoran, Lynn -- Treuting, Piper -- Klein, Ulf -- Rudensky, Alexander Y -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Mar 19;458(7236):351-6. doi: 10.1038/nature07674. Epub 2009 Feb 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19182775" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmune Diseases/pathology ; CD4 Lymphocyte Count ; Cell Differentiation ; Forkhead Transcription Factors/deficiency/genetics/metabolism ; Immunoglobulin E/blood/immunology ; Immunoglobulin G/blood/immunology ; Interferon Regulatory Factors/deficiency/genetics/*metabolism ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes, Regulatory/*immunology ; Th2 Cells/cytology/*immunology/metabolism ; Thymus Gland/cytology
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    Association of reactive oxygen species levels and radioresistance in cancer stem cells (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-06
    Description: The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778612/" 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/PMC2778612/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diehn, Maximilian -- Cho, Robert W -- Lobo, Neethan A -- Kalisky, Tomer -- Dorie, Mary Jo -- Kulp, Angela N -- Qian, Dalong -- Lam, Jessica S -- Ailles, Laurie E -- Wong, Manzhi -- Joshua, Benzion -- Kaplan, Michael J -- Wapnir, Irene -- Dirbas, Frederick M -- Somlo, George -- Garberoglio, Carlos -- Paz, Benjamin -- Shen, Jeannie -- Lau, Sean K -- Quake, Stephen R -- Brown, J Martin -- Weissman, Irving L -- Clarke, Michael F -- R01 CA100225/CA/NCI NIH HHS/ -- R01 CA100225-05/CA/NCI NIH HHS/ -- U54 CA126524/CA/NCI NIH HHS/ -- U54 CA126524-04/CA/NCI NIH HHS/ -- England -- Nature. 2009 Apr 9;458(7239):780-3. doi: 10.1038/nature07733.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Radiation Oncology, 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/19194462" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/physiopathology ; Cells, Cultured ; DNA Damage/genetics/radiation effects ; Female ; Gene Expression ; Humans ; Mammary Glands, Human/cytology/metabolism ; Mice ; Mice, Inbred C57BL ; Neoplastic Stem Cells/*metabolism/*radiation effects ; Radiation Tolerance/*physiology ; Reactive Oxygen Species/*metabolism
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    Photon capture and signalling by melanopsin retinal ganglion cells (2009)
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    Publication Date: 2009-01-02
    Description: A subset of retinal ganglion cells has recently been discovered to be intrinsically photosensitive, with melanopsin as the pigment. These cells project primarily to brain centres for non-image-forming visual functions such as the pupillary light reflex and circadian photoentrainment. How well they signal intrinsic light absorption to drive behaviour remains unclear. Here we report fundamental parameters governing their intrinsic light responses and associated spike generation. The membrane density of melanopsin is 10(4)-fold lower than that of rod and cone pigments, resulting in a very low photon catch and a phototransducing role only in relatively bright light. Nonetheless, each captured photon elicits a large and extraordinarily prolonged response, with a unique shape among known photoreceptors. Notably, like rods, these cells are capable of signalling single-photon absorption. A flash causing a few hundred isomerized melanopsin molecules in a retina is sufficient for reaching threshold for the pupillary light reflex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794210/" 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/PMC2794210/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Do, Michael Tri H -- Kang, Shin H -- Xue, Tian -- Zhong, Haining -- Liao, Hsi-Wen -- Bergles, Dwight E -- Yau, King-Wai -- F32 EY016959/EY/NEI NIH HHS/ -- F32 EY016959-01/EY/NEI NIH HHS/ -- F32 EY016959-02/EY/NEI NIH HHS/ -- F32 EY016959-03/EY/NEI NIH HHS/ -- R01 DC006904/DC/NIDCD NIH HHS/ -- R01 DC006904-01/DC/NIDCD NIH HHS/ -- R01 DC006904-02/DC/NIDCD NIH HHS/ -- R01 DC006904-03/DC/NIDCD NIH HHS/ -- R01 DC006904-04/DC/NIDCD NIH HHS/ -- R01 DC006904-05/DC/NIDCD NIH HHS/ -- R01 EY006837/EY/NEI NIH HHS/ -- R01 EY006837-16A1/EY/NEI NIH HHS/ -- R01 EY006837-18/EY/NEI NIH HHS/ -- R01 EY006837-20A1/EY/NEI NIH HHS/ -- R01 EY006837-21/EY/NEI NIH HHS/ -- R01 EY006837-22/EY/NEI NIH HHS/ -- R01 EY014596/EY/NEI NIH HHS/ -- R01 EY014596-01/EY/NEI NIH HHS/ -- R01 EY014596-02/EY/NEI NIH HHS/ -- R01 EY014596-03/EY/NEI NIH HHS/ -- R01 EY014596-04/EY/NEI NIH HHS/ -- R01 EY014596-05/EY/NEI NIH HHS/ -- R01 EY014596-06/EY/NEI NIH HHS/ -- R01 EY014596-07/EY/NEI NIH HHS/ -- R01 EY014596-07S1/EY/NEI NIH HHS/ -- R01 NS051509/NS/NINDS NIH HHS/ -- R01 NS051509-01A1/NS/NINDS NIH HHS/ -- R01 NS051509-02/NS/NINDS NIH HHS/ -- R01 NS051509-03/NS/NINDS NIH HHS/ -- R01 NS051509-04/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Jan 15;457(7227):281-7. doi: 10.1038/nature07682. Epub 2008 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. mdo@jhmi.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19118382" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/radiation effects ; Animals ; Brain/metabolism ; Kinetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; *Photons ; Pupil/physiology/radiation effects ; Reflex, Pupillary/radiation effects ; Retinal Ganglion Cells/*metabolism/*radiation effects ; Rod Opsins/*metabolism
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    Cooperative binding of two acetylation marks on a histone tail by a single bromodomain (2009)
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    Publication Date: 2009-10-02
    Description: A key step in many chromatin-related processes is the recognition of histone post-translational modifications by effector modules such as bromodomains and chromo-like domains of the Royal family. Whereas effector-mediated recognition of single post-translational modifications is well characterized, how the cell achieves combinatorial readout of histones bearing multiple modifications is poorly understood. One mechanism involves multivalent binding by linked effector modules. For example, the tandem bromodomains of human TATA-binding protein-associated factor-1 (TAF1) bind better to a diacetylated histone H4 tail than to monoacetylated tails, a cooperative effect attributed to each bromodomain engaging one acetyl-lysine mark. Here we report a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family. Brdt associates with hyperacetylated histone H4 (ref. 7) and is implicated in the marked chromatin remodelling that follows histone hyperacetylation during spermiogenesis, the stage of spermatogenesis in which post-meiotic germ cells mature into fully differentiated sperm. Notably, we find that a single bromodomain (BD1) of Brdt is responsible for selectively recognizing histone H4 tails bearing two or more acetylation marks. The crystal structure of BD1 bound to a diacetylated H4 tail shows how two acetyl-lysine residues cooperate to interact with one binding pocket. Structure-based mutagenesis that reduces the selectivity of BD1 towards diacetylated tails destabilizes the association of Brdt with acetylated chromatin in vivo. Structural analysis suggests that other chromatin-associated proteins may be capable of a similar mode of ligand recognition, including yeast Bdf1, human TAF1 and human CBP/p300 (also known as CREBBP and EP300, respectively). Our findings describe a new mechanism for the combinatorial readout of histone modifications in which a single effector module engages two marks on a histone tail as a composite binding epitope.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moriniere, Jeanne -- Rousseaux, Sophie -- Steuerwald, Ulrich -- Soler-Lopez, Montserrat -- Curtet, Sandrine -- Vitte, Anne-Laure -- Govin, Jerome -- Gaucher, Jonathan -- Sadoul, Karin -- Hart, Darren J -- Krijgsveld, Jeroen -- Khochbin, Saadi -- Muller, Christoph W -- Petosa, Carlo -- England -- Nature. 2009 Oct 1;461(7264):664-8. doi: 10.1038/nature08397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, BP 181, 38042 Grenoble Cedex 9, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794495" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Allosteric Regulation ; Animals ; Binding Sites ; COS Cells ; Cercopithecus aethiops ; Chromatin/chemistry/metabolism ; Crystallography, X-Ray ; Histones/*chemistry/*metabolism ; Lysine/metabolism ; Mice ; Models, Molecular ; Nuclear Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Substrate Specificity
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    The structure of a cytolytic alpha-helical toxin pore reveals its assembly mechanism (2009)
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    Publication Date: 2009-05-08
    Description: Pore-forming toxins (PFTs) are a class of potent virulence factors that convert from a soluble form to a membrane-integrated pore. They exhibit their toxic effect either by destruction of the membrane permeability barrier or by delivery of toxic components through the pores. Among the group of bacterial PFTs are some of the most dangerous toxins, such as diphtheria and anthrax toxin. Examples of eukaryotic PFTs are perforin and the membrane-attack complex, proteins of the immune system. PFTs can be subdivided into two classes, alpha-PFTs and beta-PFTs, depending on the suspected mode of membrane integration, either by alpha-helical or beta-sheet elements. The only high-resolution structure of a transmembrane PFT pore is available for a beta-PFT--alpha-haemolysin from Staphylococcus aureus. Cytolysin A (ClyA, also known as HlyE), an alpha-PFT, is a cytolytic -helical toxin responsible for the haemolytic phenotype of several Escherichia coli and Salmonella enterica strains. ClyA is cytotoxic towards cultured mammalian cells, induces apoptosis of macrophages and promotes tissue pervasion. Electron microscopic reconstructions demonstrated that the soluble monomer of ClyA must undergo large conformational changes to form the transmembrane pore. Here we report the 3.3 A crystal structure of the 400 kDa dodecameric transmembrane pore formed by ClyA. The tertiary structure of ClyA protomers in the pore is substantially different from that in the soluble monomer. The conversion involves more than half of all residues. It results in large rearrangements, up to 140 A, of parts of the monomer, reorganization of the hydrophobic core, and transitions of -sheets and loop regions to -helices. The large extent of interdependent conformational changes indicates a sequential mechanism for membrane insertion and pore formation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mueller, Marcus -- Grauschopf, Ulla -- Maier, Timm -- Glockshuber, Rudi -- Ban, Nenad -- England -- Nature. 2009 Jun 4;459(7247):726-30. doi: 10.1038/nature08026.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19421192" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Membrane/chemistry ; Crystallography, X-Ray ; Escherichia coli K12/*chemistry ; Escherichia coli Proteins/*chemistry ; Hemolysin Proteins/*chemistry ; Membrane Proteins/*chemistry ; *Models, Molecular ; *Protein Folding ; Protein Structure, Tertiary
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    Structural basis for leucine-rich nuclear export signal recognition by CRM1 (2009)
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    Publication Date: 2009-04-03
    Description: CRM1 (also known as XPO1 and exportin 1) mediates nuclear export of hundreds of proteins through the recognition of the leucine-rich nuclear export signal (LR-NES). Here we present the 2.9 A structure of CRM1 bound to snurportin 1 (SNUPN). Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal LR-NES and its nucleotide-binding domain. The LR-NES is a combined alpha-helical-extended structure that occupies a hydrophobic groove between two CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin 1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437623/" 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/PMC3437623/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Xiuhua -- Biswas, Anindita -- Suel, Katherine E -- Jackson, Laurie K -- Martinez, Rita -- Gu, Hongmei -- Chook, Yuh Min -- 5-T32-GM008297/GM/NIGMS NIH HHS/ -- R01 GM069909/GM/NIGMS NIH HHS/ -- R01GM069909/GM/NIGMS NIH HHS/ -- R01GM069909-03S1/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 30;458(7242):1136-41. doi: 10.1038/nature07975. Epub 2009 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park, Dallas, Texas 75390-9041, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19339969" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Crystallography, X-Ray ; Epitopes ; Fatty Acids, Unsaturated/pharmacology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Karyopherins/*chemistry/*metabolism ; Leucine/*metabolism ; Models, Molecular ; Nuclear Export Signals/*physiology ; Protein Binding/drug effects ; Protein Conformation ; Receptors, Cytoplasmic and Nuclear/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; snRNP Core Proteins/chemistry/metabolism
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    Central control of fever and female body temperature by RANKL/RANK (2009)
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    Publication Date: 2009-11-27
    Description: Receptor-activator of NF-kappaB ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland. RANKL and RANK are also expressed in the central nervous system. However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1beta and TNFalpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanada, Reiko -- Leibbrandt, Andreas -- Hanada, Toshikatsu -- Kitaoka, Shiho -- Furuyashiki, Tomoyuki -- Fujihara, Hiroaki -- Trichereau, Jean -- Paolino, Magdalena -- Qadri, Fatimunnisa -- Plehm, Ralph -- Klaere, Steffen -- Komnenovic, Vukoslav -- Mimata, Hiromitsu -- Yoshimatsu, Hironobu -- Takahashi, Naoyuki -- von Haeseler, Arndt -- Bader, Michael -- Kilic, Sara Sebnem -- Ueta, Yoichi -- Pifl, Christian -- Narumiya, Shuh -- Penninger, Josef M -- England -- Nature. 2009 Nov 26;462(7272):505-9. doi: 10.1038/nature08596.〈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/19940926" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytes/drug effects/metabolism ; Body Temperature Regulation/*drug effects/*physiology ; Child ; Dinoprostone/metabolism ; Female ; Fever/*chemically induced/complications/*metabolism ; Gene Expression Profiling ; Humans ; Injections, Intraventricular ; Male ; Mice ; Mice, Inbred C57BL ; Pneumonia/complications/metabolism ; RANK Ligand/administration & dosage/antagonists & ; inhibitors/metabolism/*pharmacology ; Rats ; Rats, Wistar ; Receptor Activator of Nuclear Factor-kappa B/genetics/*metabolism ; Receptors, Prostaglandin E/metabolism ; Receptors, Prostaglandin E, EP3 Subtype ; *Sex Characteristics
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    Innate immune recognition of infected apoptotic cells directs T(H)17 cell differentiation (2009)
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    Publication Date: 2009-03-06
    Description: Adaptive immune responses rely on differentiation of CD4 T helper cells into subsets with distinct effector functions best suited for host defence against the invading pathogen. Interleukin (IL)-17-producing T helper cells (T(H)17) are a recently identified subset, separate from the T helper type 1 (T(H)1) and T helper type 2 (T(H)2) subsets. Synergy between the cytokines transforming growth factor-beta and IL-6 in vitro induces development of T(H)17 cells in mouse and human systems, whereas IL-23 supports expansion of these cells. However, it is not known which conditions in vivo would induce this combination of cytokines. Furthermore, it is enigmatic that a combination of pro-inflammatory and anti-inflammatory cytokines would be required to generate an effector T(H)17 response. Here we show that the relevant physiological stimulus triggering this combination of cytokines is the recognition and phagocytosis of infected apoptotic cells by dendritic cells. Phagocytosis of infected apoptotic cells uniquely triggers the combination of IL-6 and transforming growth factor-beta through recognition of pathogen-associated molecular patterns and phosphatidylserine exposed on apoptotic cells, respectively. Conversely, phagocytosis of apoptotic cells in the absence of microbial signals induces differentiation of the closely related regulatory T cells, which are important for controlling autoimmunity. Blocking apoptosis during infection of the mouse intestinal epithelium with the rodent pathogen Citrobacter rodentium, which models human infections with the attaching and effacing enteropathogenic and enterohaemorrhagic Escherichia coli, impairs the characteristic T(H)17 response in the lamina propria. Our results demonstrate that infected apoptotic cells are a critical component of the innate immune signals instructing T(H)17 differentiation, and point to pathogens particularly adept at triggering apoptosis that might preferentially induce T(H)17-mediated immunity. Because T(H)17 cells have been correlated with autoimmune diseases, investigation of the pathways of innate recognition of infected apoptotic cells might lead to improved understanding of the causative defects in autoimmunity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Torchinsky, Miriam Beer -- Garaude, Johan -- Martin, Andrea P -- Blander, J Magarian -- AI073899/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Mar 5;458(7234):78-82. doi: 10.1038/nature07781.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunology Institute, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19262671" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Apoptosis ; *Cell Differentiation ; Citrobacter rodentium/*immunology/physiology ; Dendritic Cells/immunology/metabolism ; Immunity, Innate/*immunology ; Interleukin-10/biosynthesis/immunology ; Interleukin-17/*immunology/metabolism ; Interleukin-23/immunology ; Interleukin-6/biosynthesis ; Ligands ; Mice ; Mice, Inbred C57BL ; Phagocytosis ; T-Lymphocytes, Helper-Inducer/*cytology/*immunology/metabolism ; Toll-Like Receptors/immunology/metabolism ; Transforming Growth Factor beta/immunology
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    Structural basis for translational fidelity ensured by transfer RNA lysidine synthetase (2009)
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    Publication Date: 2009-10-23
    Description: Maturation of precursor transfer RNA (pre-tRNA) includes excision of the 5' leader and 3' trailer sequences, removal of introns and addition of the CCA terminus. Nucleotide modifications are incorporated at different stages of tRNA processing, after the RNA molecule adopts the proper conformation. In bacteria, tRNA(Ile2) lysidine synthetase (TilS) modifies cytidine into lysidine (L; 2-lysyl-cytidine) at the first anticodon of tRNA(Ile2) (refs 4-9). This modification switches tRNA(Ile2) from a methionine-specific to an isoleucine-specific tRNA. However, the aminoacylation of tRNA(Ile2) by methionyl-tRNA synthetase (MetRS), before the modification by TilS, might lead to the misincorporation of methionine in response to isoleucine codons. The mechanism used by bacteria to avoid this pitfall is unknown. Here we show that the TilS enzyme specifically recognizes and modifies tRNA(Ile2) in its precursor form, thereby avoiding translation errors. We identified the lysidine modification in pre-tRNA(Ile2) isolated from RNase-E-deficient Escherichia coli and did not detect mature tRNA(Ile2) lacking this modification. Our kinetic analyses revealed that TilS can modify both types of RNA molecule with comparable efficiencies. X-ray crystallography and mutational analyses revealed that TilS specifically recognizes the entire L-shape structure in pre-tRNA(Ile2) through extensive interactions coupled with sequential domain movements. Our results demonstrate how TilS prevents the recognition of tRNA(Ile2) by MetRS and achieves high specificity for its substrate. These two key points form the basis for maintaining the fidelity of isoleucine codon translation in bacteria. Our findings also provide a rationale for the necessity of incorporating specific modifications at the precursor level during tRNA biogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakanishi, Kotaro -- Bonnefond, Luc -- Kimura, Satoshi -- Suzuki, Tsutomu -- Ishitani, Ryuichiro -- Nureki, Osamu -- England -- Nature. 2009 Oct 22;461(7267):1144-8. doi: 10.1038/nature08474.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 225-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847269" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acyl-tRNA Synthetases/*chemistry/genetics/*metabolism ; Apoproteins/genetics/metabolism ; Bacillus subtilis ; Bacterial Proteins/*chemistry/genetics/*metabolism ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; Escherichia coli ; Geobacillus ; Kinetics ; Lysine/analogs & derivatives/metabolism ; Mass Spectrometry ; Models, Molecular ; Molecular Sequence Data ; *Protein Biosynthesis ; Pyrimidine Nucleosides/metabolism ; RNA, Transfer, Ile/genetics/metabolism ; Substrate Specificity
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    CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help (2009)
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    Publication Date: 2009-11-10
    Description: CD4(+) T helper cells are well known for their role in providing critical signals during priming of cytotoxic CD8(+) T lymphocyte (CTL) responses in vivo. T-cell help is required for the generation of primary CTL responses as well as in promoting protective CD8(+) memory T-cell development. However, the role of CD4 help in the control of CTL responses at the effector stage is unknown. Here we show that fully helped effector CTLs are themselves not self-sufficient for entry into the infected tissue, but rely on the CD4(+) T cells to provide the necessary cue. CD4(+) T helper cells control the migration of CTL indirectly through the secretion of IFN-gamma and induction of local chemokine secretion in the infected tissue. Our results reveal a previously unappreciated role of CD4 help in mobilizing effector CTL to the peripheral sites of infection where they help to eliminate infected cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789415/" 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/PMC2789415/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakanishi, Yusuke -- Lu, Bao -- Gerard, Craig -- Iwasaki, Akiko -- AI054359/AI/NIAID NIH HHS/ -- AI062428/AI/NIAID NIH HHS/ -- AI39759/AI/NIAID NIH HHS/ -- HL51366/HL/NHLBI NIH HHS/ -- R01 AI054359/AI/NIAID NIH HHS/ -- R01 AI054359-06A2/AI/NIAID NIH HHS/ -- R01 AI062428/AI/NIAID NIH HHS/ -- R01 AI062428-05/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Nov 26;462(7272):510-3. doi: 10.1038/nature08511. Epub 2009 Nov 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19898495" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; Chemokines/immunology/secretion ; *Chemotaxis ; Female ; Herpes Simplex/immunology/virology ; Herpesvirus 2, Human/*immunology ; Immunity, Mucosal/immunology ; Interferon-gamma/antagonists & inhibitors/immunology/secretion ; Mice ; Mice, Inbred C57BL ; Models, Immunological ; Mucous Membrane/immunology/virology ; Receptors, CXCR3/metabolism ; T-Lymphocytes, Cytotoxic/*cytology/*immunology ; T-Lymphocytes, Helper-Inducer/*immunology/secretion ; Vagina/*immunology/*virology
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    Membrane-bound Fas ligand only is essential for Fas-induced apoptosis (2009)
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    Publication Date: 2009-10-02
    Description: Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice and humans. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasL(Deltas/Deltas)) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasL(Deltam/Deltam)) could not kill cells through Fas activation. FasL(Deltam/Deltam) mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL(gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL(Deltam/Deltam) mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL(gld/gld) mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785124/" 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/PMC2785124/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O' Reilly, Lorraine A -- Tai, Lin -- Lee, Lily -- Kruse, Elizabeth A -- Grabow, Stephanie -- Fairlie, W Douglas -- Haynes, Nicole M -- Tarlinton, David M -- Zhang, Jian-Guo -- Belz, Gabrielle T -- Smyth, Mark J -- Bouillet, Philippe -- Robb, Lorraine -- Strasser, Andreas -- CA043540-18/CA/NCI NIH HHS/ -- CA80188-6/CA/NCI NIH HHS/ -- R01 CA043540/CA/NCI NIH HHS/ -- R01 CA043540-18/CA/NCI NIH HHS/ -- R01 CA080188-06/CA/NCI NIH HHS/ -- England -- Nature. 2009 Oct 1;461(7264):659-63. doi: 10.1038/nature08402.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794494" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Antinuclear/immunology ; Antigens, CD95/*metabolism ; *Apoptosis ; Cell Membrane/*metabolism ; Cytidine Deaminase/metabolism ; Cytotoxicity, Immunologic ; Fas Ligand Protein/deficiency/genetics/*metabolism/secretion ; Glomerulonephritis/metabolism ; Histiocytic Sarcoma/metabolism ; Hypergammaglobulinemia/metabolism ; Lupus Erythematosus, Systemic/metabolism ; Lymphatic Diseases/metabolism ; Mice ; Mice, Inbred C57BL ; Mutation ; Splenomegaly/metabolism ; T-Lymphocytes/immunology/metabolism
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    Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment (2009)
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    Publication Date: 2009-06-12
    Description: Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow. Adult bone marrow also contains adipocytes, the number of which correlates inversely with the haematopoietic activity of the marrow. Fatty infiltration of haematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia. To explore whether adipocytes influence haematopoiesis or simply fill marrow space, we compared the haematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. Here we show, by flow cytometry, colony-forming activity and competitive repopulation assay, that haematopoietic stem cells and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 'fatless' mice, which are genetically incapable of forming adipocytes, and in mice treated with the peroxisome proliferator-activated receptor-gamma inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis, marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone-marrow microenvironment, and indicate that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831539/" 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/PMC2831539/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naveiras, Olaia -- Nardi, Valentina -- Wenzel, Pamela L -- Hauschka, Peter V -- Fahey, Frederic -- Daley, George Q -- DP1 OD000256/OD/NIH HHS/ -- DP1 OD000256-01/OD/NIH HHS/ -- R01 DK059279/DK/NIDDK NIH HHS/ -- R01 DK059279-06/DK/NIDDK NIH HHS/ -- R01 DK070055/DK/NIDDK NIH HHS/ -- R01 DK070055-01/DK/NIDDK NIH HHS/ -- T32- HL -7623/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jul 9;460(7252):259-63. doi: 10.1038/nature08099. Epub 2009 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516257" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/cytology/drug effects/*physiology ; Adipogenesis/drug effects ; Adiposity/physiology ; Animals ; Benzhydryl Compounds ; Bone Marrow Cells/*cytology/*metabolism ; Bone Marrow Transplantation ; Cell Line ; Epoxy Compounds/pharmacology ; Femur ; *Hematopoiesis/drug effects ; Hematopoietic Stem Cells/cytology/metabolism ; Homeostasis ; Mice ; Mice, Inbred C57BL ; Osteogenesis ; Spine/cytology/metabolism ; Stromal Cells ; Tail ; Thorax ; Tibia
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    Flipping of alkylated DNA damage bridges base and nucleotide excision repair (2009)
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    Publication Date: 2009-06-12
    Description: Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O(6)-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O(6)-methylguanine or cigarette-smoke-derived O(6)-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729916/" 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/PMC2729916/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tubbs, Julie L -- Latypov, Vitaly -- Kanugula, Sreenivas -- Butt, Amna -- Melikishvili, Manana -- Kraehenbuehl, Rolf -- Fleck, Oliver -- Marriott, Andrew -- Watson, Amanda J -- Verbeek, Barbara -- McGown, Gail -- Thorncroft, Mary -- Santibanez-Koref, Mauro F -- Millington, Christopher -- Arvai, Andrew S -- Kroeger, Matthew D -- Peterson, Lisa A -- Williams, David M -- Fried, Michael G -- Margison, Geoffrey P -- Pegg, Anthony E -- Tainer, John A -- CA018137/CA/NCI NIH HHS/ -- CA097209/CA/NCI NIH HHS/ -- CA59887/CA/NCI NIH HHS/ -- GM070662/GM/NIGMS NIH HHS/ -- R01 CA059887/CA/NCI NIH HHS/ -- R01 CA059887-12/CA/NCI NIH HHS/ -- R01 CA059887-13/CA/NCI NIH HHS/ -- R01 GM070662/GM/NIGMS NIH HHS/ -- R01 GM070662-01/GM/NIGMS NIH HHS/ -- R01 GM070662-02/GM/NIGMS NIH HHS/ -- R01 GM070662-03/GM/NIGMS NIH HHS/ -- R01 GM070662-04/GM/NIGMS NIH HHS/ -- R01 GM070662-05/GM/NIGMS NIH HHS/ -- R01 GM070662-06/GM/NIGMS NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Jun 11;459(7248):808-13. doi: 10.1038/nature08076.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516334" target="_blank"〉PubMed〈/a〉
    Keywords: Alkyl and Aryl Transferases/*chemistry/*metabolism ; Alkylation ; Binding Sites ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; *DNA Damage ; *DNA Repair ; Guanine/analogs & derivatives/chemistry/metabolism ; Humans ; Models, Molecular ; Protein Binding ; Protein Conformation
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    Haematopoietic stem cells depend on Galpha(s)-mediated signalling to engraft bone marrow (2009)
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    Publication Date: 2009-03-27
    Description: Haematopoietic stem and progenitor cells (HSPCs) change location during development and circulate in mammals throughout life, moving into and out of the bloodstream to engage bone marrow niches in sequential steps of homing, engraftment and retention. Here we show that HSPC engraftment of bone marrow in fetal development is dependent on the guanine-nucleotide-binding protein stimulatory alpha subunit (Galpha(s)). HSPCs from adult mice deficient in Galpha(s) (Galpha(s)(-/-)) differentiate and undergo chemotaxis, but also do not home to or engraft in the bone marrow in adult mice and demonstrate a marked inability to engage the marrow microvasculature. If deleted after engraftment, Galpha(s) deficiency did not lead to lack of retention in the marrow, rather cytokine-induced mobilization into the blood was impaired. Testing whether activation of Galpha(s) affects HSPCs, pharmacological activators enhanced homing and engraftment in vivo. Galpha(s) governs specific aspects of HSPC localization under physiological conditions in vivo and may be pharmacologically targeted to improve transplantation efficiency.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761017/" 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/PMC2761017/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adams, Gregor B -- Alley, Ian R -- Chung, Ung-Il -- Chabner, Karissa T -- Jeanson, Nathaniel T -- Lo Celso, Cristina -- Marsters, Emily S -- Chen, Min -- Weinstein, Lee S -- Lin, Charles P -- Kronenberg, Henry M -- Scadden, David T -- U54 HL081030/HL/NHLBI NIH HHS/ -- U54 HL081030-01/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 May 7;459(7243):103-7. doi: 10.1038/nature07859. Epub 2009 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19322176" target="_blank"〉PubMed〈/a〉
    Keywords: Adjuvants, Immunologic/pharmacology ; Animals ; Bone Marrow/drug effects/embryology/*physiology ; Bone Marrow Transplantation/physiology ; Cell Movement/drug effects/physiology ; Cholera Toxin/pharmacology ; GTP-Binding Protein alpha Subunits, Gs/genetics/*metabolism ; Granulocyte Colony-Stimulating Factor/metabolism ; Hematopoietic Stem Cells/*physiology ; Mice ; Mice, Inbred C57BL ; Signal Transduction/*physiology
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    Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance (2009)
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    Publication Date: 2009-09-11
    Description: Phagocytic removal of apoptotic cells occurs efficiently in vivo such that even in tissues with significant apoptosis, very few apoptotic cells are detectable. This is thought to be due to the release of 'find-me' signals by apoptotic cells that recruit motile phagocytes such as monocytes, macrophages and dendritic cells, leading to the prompt clearance of the dying cells. However, the identity and in vivo relevance of such find-me signals are not well understood. Here, through several lines of evidence, we identify extracellular nucleotides as a critical apoptotic cell find-me signal. We demonstrate the caspase-dependent release of ATP and UTP (in equimolar quantities) during the early stages of apoptosis by primary thymocytes and cell lines. Purified nucleotides at these concentrations were sufficient to induce monocyte recruitment comparable to that of apoptotic cell supernatants. Enzymatic removal of ATP and UTP (by apyrase or the expression of ectopic CD39) abrogated the ability of apoptotic cell supernatants to recruit monocytes in vitro and in vivo. We then identified the ATP/UTP receptor P2Y(2) as a critical sensor of nucleotides released by apoptotic cells using RNA interference-mediated depletion studies in monocytes, and macrophages from P2Y(2)-null mice. The relevance of nucleotides in apoptotic cell clearance in vivo was revealed by two approaches. First, in a murine air-pouch model, apoptotic cell supernatants induced a threefold greater recruitment of monocytes and macrophages than supernatants from healthy cells did; this recruitment was abolished by depletion of nucleotides and was significantly decreased in P2Y(2)(-/-) (also known as P2ry2(-/-)) mice. Second, clearance of apoptotic thymocytes was significantly impaired by either depletion of nucleotides or interference with P2Y receptor function (by pharmacological inhibition or in P2Y(2)(-/-) mice). These results identify nucleotides as a critical find-me cue released by apoptotic cells to promote P2Y(2)-dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851546/" 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/PMC2851546/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elliott, Michael R -- Chekeni, Faraaz B -- Trampont, Paul C -- Lazarowski, Eduardo R -- Kadl, Alexandra -- Walk, Scott F -- Park, Daeho -- Woodson, Robin I -- Ostankovich, Marina -- Sharma, Poonam -- Lysiak, Jeffrey J -- Harden, T Kendall -- Leitinger, Norbert -- Ravichandran, Kodi S -- R01 GM064709/GM/NIGMS NIH HHS/ -- R01 GM064709-07/GM/NIGMS NIH HHS/ -- R01 GM069998/GM/NIGMS NIH HHS/ -- R01 GM069998-04/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Sep 10;461(7261):282-6. doi: 10.1038/nature08296.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19741708" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/*metabolism/pharmacology/secretion ; Animals ; Apoptosis/*physiology ; Cell Line ; Cells, Cultured ; Chemotactic Factors/metabolism/pharmacology/secretion ; Chemotaxis/drug effects ; Culture Media, Conditioned/chemistry/metabolism/pharmacology ; Humans ; Jurkat Cells ; Macrophage Activation/drug effects ; Macrophages/cytology/drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Monocytes/cytology/drug effects/metabolism ; Phagocytes/*cytology/drug effects/metabolism ; Phagocytosis/drug effects/*physiology ; Purinergic P2 Receptor Antagonists ; Receptors, Purinergic P2/deficiency/genetics/metabolism ; Receptors, Purinergic P2Y2 ; *Signal Transduction/drug effects ; Thymus Gland/*cytology ; Uridine Triphosphate/*metabolism/pharmacology/secretion
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    Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase (2009)
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    Publication Date: 2009-06-12
    Description: With 8.9 million new cases and 1.7 million deaths per year, tuberculosis is a leading global killer that has not been effectively controlled. The causative agent, Mycobacterium tuberculosis, proliferates within host macrophages where it modifies both its intracellular and local tissue environment, resulting in caseous granulomas with incomplete bacterial sterilization. Although infection by various mycobacterial species produces a cyclic AMP burst within macrophages that influences cell signalling, the underlying mechanism for the cAMP burst remains unclear. Here we show that among the 17 adenylate cyclase genes present in M. tuberculosis, at least one (Rv0386) is required for virulence. Furthermore, we demonstrate that the Rv0386 adenylate cyclase facilitates delivery of bacterial-derived cAMP into the macrophage cytoplasm. Loss of Rv0386 and the intramacrophage cAMP it delivers results in reductions in TNF-alpha production via the protein kinase A and cAMP response-element-binding protein pathway, decreased immunopathology in animal tissues, and diminished bacterial survival. Direct intoxication of host cells by bacterial-derived cAMP may enable M. tuberculosis to modify both its intracellular and tissue environments to facilitate its long-term survival.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Agarwal, Nisheeth -- Lamichhane, Gyanu -- Gupta, Radhika -- Nolan, Scott -- Bishai, William R -- AI30036/AI/NIAID NIH HHS/ -- AI36973/AI/NIAID NIH HHS/ -- AI37856/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Jul 2;460(7251):98-102. doi: 10.1038/nature08123. Epub 2009 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Johns Hopkins School of Medicine, CRB2, Room 1.08, 1550 Orleans Street, Baltimore, Maryland 21231-1044, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516256" target="_blank"〉PubMed〈/a〉
    Keywords: Adenylyl Cyclases/genetics/*metabolism ; Animals ; Cell Line ; Cyclic AMP/*metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cytosol/metabolism/microbiology ; Macrophages/immunology/*metabolism/microbiology/*pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mycobacterium tuberculosis/*enzymology/genetics/growth & ; development/*pathogenicity ; Phosphoric Diester Hydrolases/genetics/metabolism ; Phosphorylation ; Tuberculosis/immunology/microbiology/*pathology ; Tumor Necrosis Factor-alpha/biosynthesis/secretion ; Virulence/genetics
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    Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response (2009)
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    Publication Date: 2009-11-13
    Description: The mucosal immune system forms the largest part of the entire immune system, containing about three-quarters of all lymphocytes and producing grams of secretory IgA daily to protect the mucosal surface from pathogens. To evoke the mucosal immune response, antigens on the mucosal surface must be transported across the epithelial barrier into organized lymphoid structures such as Peyer's patches. This function, called antigen transcytosis, is mediated by specialized epithelial M cells. The molecular mechanisms promoting this antigen uptake, however, are largely unknown. Here we report that glycoprotein 2 (GP2), specifically expressed on the apical plasma membrane of M cells among enterocytes, serves as a transcytotic receptor for mucosal antigens. Recombinant GP2 protein selectively bound a subset of commensal and pathogenic enterobacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (S. Typhimurium), by recognizing FimH, a component of type I pili on the bacterial outer membrane. Consistently, these bacteria were colocalized with endogenous GP2 on the apical plasma membrane as well as in cytoplasmic vesicles in M cells. Moreover, deficiency of bacterial FimH or host GP2 led to defects in transcytosis of type-I-piliated bacteria through M cells, resulting in an attenuation of antigen-specific immune responses in Peyer's patches. GP2 is therefore a previously unrecognized transcytotic receptor on M cells for type-I-piliated bacteria and is a prerequisite for the mucosal immune response to these bacteria. Given that M cells are considered a promising target for oral vaccination against various infectious diseases, the GP2-dependent transcytotic pathway could provide a new target for the development of M-cell-targeted mucosal vaccines.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hase, Koji -- Kawano, Kazuya -- Nochi, Tomonori -- Pontes, Gemilson Soares -- Fukuda, Shinji -- Ebisawa, Masashi -- Kadokura, Kazunori -- Tobe, Toru -- Fujimura, Yumiko -- Kawano, Sayaka -- Yabashi, Atsuko -- Waguri, Satoshi -- Nakato, Gaku -- Kimura, Shunsuke -- Murakami, Takaya -- Iimura, Mitsutoshi -- Hamura, Kimiyo -- Fukuoka, Shin-Ichi -- Lowe, Anson W -- Itoh, Kikuji -- Kiyono, Hiroshi -- Ohno, Hiroshi -- DK43294/DK/NIDDK NIH HHS/ -- DK56339/DK/NIDDK NIH HHS/ -- England -- Nature. 2009 Nov 12;462(7270):226-30. doi: 10.1038/nature08529.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Epithelial Immunobiology, Research Center for Allergy and Immunology, RIKEN, Kanagawa 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907495" target="_blank"〉PubMed〈/a〉
    Keywords: Adhesins, Escherichia coli/genetics/immunology/*metabolism ; Animals ; Antigens, Bacterial/genetics/immunology/*metabolism ; Cell Line ; Epithelial Cells/*immunology/metabolism ; Escherichia coli/immunology/metabolism ; Fimbriae Proteins/genetics/immunology/*metabolism ; GPI-Linked Proteins ; Glycoproteins ; HeLa Cells ; Humans ; Immunity, Mucosal/*immunology ; Intestines/cytology ; Membrane Glycoproteins/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Peyer's Patches/*cytology/immunology ; Salmonella typhimurium/genetics/immunology/metabolism ; Substrate Specificity
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    Intracellular dynamics of hippocampal place cells during virtual navigation (2009)
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    Publication Date: 2009-10-16
    Description: Hippocampal place cells encode spatial information in rate and temporal codes. To examine the mechanisms underlying hippocampal coding, here we measured the intracellular dynamics of place cells by combining in vivo whole-cell recordings with a virtual-reality system. Head-restrained mice, running on a spherical treadmill, interacted with a computer-generated visual environment to perform spatial behaviours. Robust place-cell activity was present during movement along a virtual linear track. From whole-cell recordings, we identified three subthreshold signatures of place fields: an asymmetric ramp-like depolarization of the baseline membrane potential, an increase in the amplitude of intracellular theta oscillations, and a phase precession of the intracellular theta oscillation relative to the extracellularly recorded theta rhythm. These intracellular dynamics underlie the primary features of place-cell rate and temporal codes. The virtual-reality system developed here will enable new experimental approaches to study the neural circuits underlying navigation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771429/" 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/PMC2771429/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harvey, Christopher D -- Collman, Forrest -- Dombeck, Daniel A -- Tank, David W -- 1R01MH083686-01/MH/NIMH NIH HHS/ -- 5R01MH060651-09/MH/NIMH NIH HHS/ -- R01 MH060651/MH/NIMH NIH HHS/ -- R01 MH060651-09/MH/NIMH NIH HHS/ -- R01 MH083686/MH/NIMH NIH HHS/ -- R01 MH083686-02/MH/NIMH NIH HHS/ -- R01 MH083686-02S1/MH/NIMH NIH HHS/ -- England -- Nature. 2009 Oct 15;461(7266):941-6. doi: 10.1038/nature08499.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Princeton Neuroscience Institute, New Jersey 08544, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19829374" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Behavior, Animal/physiology ; Hippocampus/*cytology/physiology ; Intracellular Space/*metabolism ; Locomotion/physiology ; Male ; Membrane Potentials/physiology ; Mice ; Mice, Inbred C57BL ; Neurons/*metabolism ; Pyramidal Cells/metabolism ; Space Perception/*physiology ; Theta Rhythm ; *User-Computer Interface
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    Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers (2009)
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    Publication Date: 2009-02-27
    Description: A pathological hallmark of Alzheimer's disease is an accumulation of insoluble plaque containing the amyloid-beta peptide of 40-42 amino acid residues. Prefibrillar, soluble oligomers of amyloid-beta have been recognized to be early and key intermediates in Alzheimer's-disease-related synaptic dysfunction. At nanomolar concentrations, soluble amyloid-beta oligomers block hippocampal long-term potentiation, cause dendritic spine retraction from pyramidal cells and impair rodent spatial memory. Soluble amyloid-beta oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer's disease brain. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-beta oligomers on neurons-one that is central to the pathophysiological process in Alzheimer's disease. Here we identify the cellular prion protein (PrP(C)) as an amyloid-beta-oligomer receptor by expression cloning. Amyloid-beta oligomers bind with nanomolar affinity to PrP(C), but the interaction does not require the infectious PrP(Sc) conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-beta oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-beta-oligomer binding to PrP(C) and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-beta. Thus, PrP(C) is a mediator of amyloid-beta-oligomer-induced synaptic dysfunction, and PrP(C)-specific pharmaceuticals may have therapeutic potential for Alzheimer's disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748841/" 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/PMC2748841/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lauren, Juha -- Gimbel, David A -- Nygaard, Haakon B -- Gilbert, John W -- Strittmatter, Stephen M -- 5T32GN07205/PHS HHS/ -- P30 DA018343/DA/NIDA NIH HHS/ -- R01 NS039962/NS/NINDS NIH HHS/ -- R01 NS039962-09/NS/NINDS NIH HHS/ -- R01 NS042304/NS/NINDS NIH HHS/ -- R01 NS042304-08/NS/NINDS NIH HHS/ -- R37 NS033020/NS/NINDS NIH HHS/ -- R37 NS033020-17/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Feb 26;457(7233):1128-32. doi: 10.1038/nature07761.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, Connecticut 06536, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242475" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism/pathology/physiopathology ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/*chemistry/*metabolism ; Amyloidosis/metabolism ; Animals ; COS Cells ; Cercopithecus aethiops ; Hippocampus/cytology/metabolism ; Humans ; Long-Term Potentiation/physiology ; Mice ; Mice, Inbred C57BL ; *Neuronal Plasticity ; Neurons/metabolism ; Peptide Fragments/*chemistry/*metabolism ; Prions/genetics/*metabolism ; Protein Binding ; *Protein Multimerization ; Receptors, Cell Surface/genetics/metabolism ; Synapses/*metabolism/*pathology
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    Cell biology: How to combat stress (2009)
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    Publication Date: 2009-02-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nicchitta, Christopher V -- England -- Nature. 2009 Feb 5;457(7230):668-9. doi: 10.1038/457668a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194438" target="_blank"〉PubMed〈/a〉
    Keywords: Basic-Leucine Zipper Transcription Factors/*genetics ; Crystallography, X-Ray ; Endoplasmic Reticulum/*metabolism ; Membrane Glycoproteins/chemistry/*metabolism ; Protein Biosynthesis ; Protein-Serine-Threonine Kinases/chemistry/*metabolism ; RNA, Fungal/genetics/metabolism ; RNA, Messenger/genetics/*metabolism ; Repressor Proteins/*genetics ; Saccharomyces cerevisiae/*cytology/*genetics ; Saccharomyces cerevisiae Proteins/chemistry/*genetics/*metabolism ; *Stress, Physiological/genetics
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    Surface hydrophobin prevents immune recognition of airborne fungal spores (2009)
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    Publication Date: 2009-08-29
    Description: The air we breathe is filled with thousands of fungal spores (conidia) per cubic metre, which in certain composting environments can easily exceed 10(9) per cubic metre. They originate from more than a hundred fungal species belonging mainly to the genera Cladosporium, Penicillium, Alternaria and Aspergillus. Although these conidia contain many antigens and allergens, it is not known why airborne fungal microflora do not activate the host innate immune cells continuously and do not induce detrimental inflammatory responses following their inhalation. Here we show that the surface layer on the dormant conidia masks their recognition by the immune system and hence prevents immune response. To explore this, we used several fungal members of the airborne microflora, including the human opportunistic fungal pathogen Aspergillus fumigatus, in in vitro assays with dendritic cells and alveolar macrophages and in in vivo murine experiments. In A. fumigatus, this surface 'rodlet layer' is composed of hydrophobic RodA protein covalently bound to the conidial cell wall through glycosylphosphatidylinositol-remnants. RodA extracted from conidia of A. fumigatus was immunologically inert and did not induce dendritic cell or alveolar macrophage maturation and activation, and failed to activate helper T-cell immune responses in vivo. The removal of this surface 'rodlet/hydrophobin layer' either chemically (using hydrofluoric acid), genetically (DeltarodA mutant) or biologically (germination) resulted in conidial morphotypes inducing immune activation. All these observations show that the hydrophobic rodlet layer on the conidial cell surface immunologically silences airborne moulds.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aimanianda, Vishukumar -- Bayry, Jagadeesh -- Bozza, Silvia -- Kniemeyer, Olaf -- Perruccio, Katia -- Elluru, Sri Ramulu -- Clavaud, Cecile -- Paris, Sophie -- Brakhage, Axel A -- Kaveri, Srini V -- Romani, Luigina -- Latge, Jean-Paul -- England -- Nature. 2009 Aug 27;460(7259):1117-21. doi: 10.1038/nature08264.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Unite des Aspergillus, Institut Pasteur, Paris F-75015, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19713928" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Air Microbiology ; Allergens ; Animals ; Antigens, Fungal/chemistry/genetics/*immunology ; Antigens, Plant ; Aspergillus fumigatus/chemistry/immunology/physiology ; CD4-Positive T-Lymphocytes/immunology ; Cathepsins ; Cells, Cultured ; Dendritic Cells/cytology/immunology/transplantation ; Fungal Proteins ; Humans ; Hydrofluoric Acid/chemistry ; Immune System/immunology ; Lymphocyte Activation ; Macrophages, Alveolar/immunology ; Mice ; Mice, Inbred C57BL ; Spores, Fungal/chemistry/genetics/*immunology
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    IFNalpha activates dormant haematopoietic stem cells in vivo (2009)
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    Publication Date: 2009-02-13
    Description: Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly re-establish homeostasis. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFNalpha), HSCs efficiently exit G(0) and enter an active cell cycle. HSCs respond to IFNalpha treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNalpha target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNalpha/beta receptor (IFNAR), STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNalpha stimulation, demonstrating that STAT1 and Sca-1 mediate IFNalpha-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil, HSCs pre-treated (primed) with IFNalpha and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNalpha are functionally compromised and are rapidly out-competed by non-activatable Ifnar(-/-) cells in competitive repopulation assays. Whereas chronic activation of the IFNalpha pathway in HSCs impairs their function, acute IFNalpha treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNalpha on leukaemic cells, and raise the possibility for new applications of type I interferons to target cancer stem cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Essers, Marieke A G -- Offner, Sandra -- Blanco-Bose, William E -- Waibler, Zoe -- Kalinke, Ulrich -- Duchosal, Michel A -- Trumpp, Andreas -- England -- Nature. 2009 Apr 16;458(7240):904-8. doi: 10.1038/nature07815. Epub 2009 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19212321" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Ly/metabolism ; Cell Count ; Cell Cycle/*drug effects ; Cell Proliferation/drug effects ; Fluorouracil/pharmacology ; Hematopoietic Stem Cells/*cytology/*drug effects ; Interferon-alpha/*pharmacology ; Membrane Proteins/deficiency/metabolism ; Mice ; Mice, Inbred C57BL ; Phosphorylation/drug effects ; Receptor, Interferon alpha-beta/deficiency/metabolism ; STAT1 Transcription Factor/deficiency/metabolism ; Signal Transduction/drug effects ; Up-Regulation/drug effects
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    A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome (2009)
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    Publication Date: 2009-06-02
    Description: Diverse histone modifications are catalysed and recognized by various specific proteins, establishing unique modification patterns that act as transcription signals. In particular, histone H3 trimethylation at lysine 36 (H3K36me3) is associated with actively transcribed regions and has been proposed to provide landmarks for continuing transcription; however, the control mechanisms and functions of H3K36me3 in higher eukaryotes are unknown. Here we show that the H3K36me3-specific histone methyltransferase (HMTase) Wolf-Hirschhorn syndrome candidate 1 (WHSC1, also known as NSD2 or MMSET) functions in transcriptional regulation together with developmental transcription factors whose defects overlap with the human disease Wolf-Hirschhorn syndrome (WHS). We found that mouse Whsc1, one of five putative Set2 homologues, governed H3K36me3 along euchromatin by associating with the cell-type-specific transcription factors Sall1, Sall4 and Nanog in embryonic stem cells, and Nkx2-5 in embryonic hearts, regulating the expression of their target genes. Whsc1-deficient mice showed growth retardation and various WHS-like midline defects, including congenital cardiovascular anomalies. The effects of Whsc1 haploinsufficiency were increased in Nkx2-5 heterozygous mutant hearts, indicating their functional link. We propose that WHSC1 functions together with developmental transcription factors to prevent the inappropriate transcription that can lead to various pathophysiologies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nimura, Keisuke -- Ura, Kiyoe -- Shiratori, Hidetaka -- Ikawa, Masato -- Okabe, Masaru -- Schwartz, Robert J -- Kaneda, Yasufumi -- England -- Nature. 2009 Jul 9;460(7252):287-91. doi: 10.1038/nature08086. Epub 2009 May 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19483677" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation ; Histone-Lysine N-Methyltransferase/deficiency/genetics/*metabolism ; Histones/*metabolism ; Homeodomain Proteins/genetics/*metabolism ; Lysine/metabolism ; Methylation ; Mice ; Mice, Inbred C57BL ; Protein Binding ; Repressor Proteins/metabolism ; Transcription Factors/genetics/*metabolism ; Transcription, Genetic ; Wolf-Hirschhorn Syndrome/*metabolism
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    ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor (2009)
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    Publication Date: 2009-09-01
    Description: The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed, and it is an important therapeutic target in human cancer. Structural studies have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular 'tether' in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor. Although ErbB2 is unique among the four human ErbB receptors, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762480/" 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/PMC2762480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alvarado, Diego -- Klein, Daryl E -- Lemmon, Mark A -- R01 CA079992/CA/NCI NIH HHS/ -- R01 CA079992-09/CA/NCI NIH HHS/ -- R01 CA079992-10/CA/NCI NIH HHS/ -- R01 CA125432/CA/NCI NIH HHS/ -- R01 CA125432-01A1/CA/NCI NIH HHS/ -- R01 CA125432-02/CA/NCI NIH HHS/ -- R01 CA125432-03/CA/NCI NIH HHS/ -- England -- Nature. 2009 Sep 10;461(7261):287-91. doi: 10.1038/nature08297. Epub 2009 Aug 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19718021" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Crystallography, X-Ray ; Drosophila Proteins/*antagonists & inhibitors/chemistry/genetics/*metabolism ; Drosophila melanogaster/chemistry/*metabolism ; Enzyme Activation ; Humans ; Ligands ; Models, Molecular ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Receptor, ErbB-2/antagonists & inhibitors/*chemistry/*metabolism ; Receptors, Invertebrate Peptide/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Scattering, Small Angle ; Solubility ; X-Ray Diffraction
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    Structure of a prokaryotic virtual proton pump at 3.2 A resolution (2009)
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    Publication Date: 2009-07-07
    Description: To reach the mammalian gut, enteric bacteria must pass through the stomach. Many such organisms survive exposure to the harsh gastric environment (pH 1.5-4) by mounting extreme acid-resistance responses, one of which, the arginine-dependent system of Escherichia coli, has been studied at levels of cellular physiology, molecular genetics and protein biochemistry. This multiprotein system keeps the cytoplasm above pH 5 during acid challenge by continually pumping protons out of the cell using the free energy of arginine decarboxylation. At the heart of the process is a 'virtual proton pump' in the inner membrane, called AdiC, that imports L-arginine from the gastric juice and exports its decarboxylation product agmatine. AdiC belongs to the APC superfamily of membrane proteins, which transports amino acids, polyamines and organic cations in a multitude of biological roles, including delivery of arginine for nitric oxide synthesis, facilitation of insulin release from pancreatic beta-cells, and, when inappropriately overexpressed, provisioning of certain fast-growing neoplastic cells with amino acids. High-resolution structures and detailed transport mechanisms of APC transporters are currently unknown. Here we describe a crystal structure of AdiC at 3.2 A resolution. The protein is captured in an outward-open, substrate-free conformation with transmembrane architecture remarkably similar to that seen in four other families of apparently unrelated transport proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745212/" 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/PMC2745212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fang, Yiling -- Jayaram, Hariharan -- Shane, Tania -- Kolmakova-Partensky, Ludmila -- Wu, Fang -- Williams, Carole -- Xiong, Yong -- Miller, Christopher -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 GM031768/GM/NIGMS NIH HHS/ -- R01 GM031768-26/GM/NIGMS NIH HHS/ -- R01 GM089688/GM/NIGMS NIH HHS/ -- T32 NS 07292/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Aug 20;460(7258):1040-3. doi: 10.1038/nature08201. Epub 2009 Jul 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, Massachusetts 02454, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19578361" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Transport Systems/*chemistry/metabolism ; Antiporters/*chemistry/metabolism ; Bacterial Proteins/*chemistry ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Multigene Family ; Protein Conformation ; Salmonella typhi/*chemistry ; Structural Homology, Protein
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    Structural basis of inter-protein electron transfer for nitrite reduction in denitrification (2009)
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    Publication Date: 2009-11-06
    Description: Recent earth science studies have pointed out that massive acceleration of the global nitrogen cycle by anthropogenic addition of bio-available nitrogen has led to a host of environmental problems. Nitrous oxide (N(2)O) is a greenhouse gas that is an intermediate during the biological process known as denitrification. Copper-containing nitrite reductase (CuNIR) is a key enzyme in the process; it produces a precursor for N(2)O by catalysing the one-electron reduction of nitrite (NO2-) to nitric oxide (NO). The reduction step is performed by an efficient electron-transfer reaction with a redox-partner protein. However, details of the mechanism during the electron-transfer reaction are still unknown. Here we show the high-resolution crystal structure of the electron-transfer complex for CuNIR with its cognate cytochrome c as the electron donor. The hydrophobic electron-transfer path is formed at the docking interface by desolvation owing to close contact between the two proteins. Structural analysis of the interface highlights an essential role for the loop region with a hydrophobic patch for protein-protein recognition; it also shows how interface construction allows the variation in atomic components to achieve diverse biological electron transfers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nojiri, Masaki -- Koteishi, Hiroyasu -- Nakagami, Takuya -- Kobayashi, Kazuo -- Inoue, Tsuyoshi -- Yamaguchi, Kazuya -- Suzuki, Shinnichiro -- England -- Nature. 2009 Nov 5;462(7269):117-20. doi: 10.1038/nature08507.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan. nojiri@ch.wani.osaka-u.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19890332" target="_blank"〉PubMed〈/a〉
    Keywords: Achromobacter denitrificans/*enzymology ; Crystallography, X-Ray ; Cytochromes c/chemistry/metabolism ; Electron Transport ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Nitric Oxide/metabolism ; Nitrite Reductases/*chemistry/*metabolism ; Nitrites/metabolism ; Nitrous Oxide/metabolism ; Protein Conformation ; Structure-Activity Relationship
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    Transmembrane passage of hydrophobic compounds through a protein channel wall (2009)
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    Publication Date: 2009-02-03
    Description: Membrane proteins that transport hydrophobic compounds have important roles in multi-drug resistance and can cause a number of diseases, underscoring the importance of protein-mediated transport of hydrophobic compounds. Hydrophobic compounds readily partition into regular membrane lipid bilayers, and their transport through an aqueous protein channel is energetically unfavourable. Alternative transport models involving acquisition from the lipid bilayer by lateral diffusion have been proposed for hydrophobic substrates. So far, all transport proteins for which a lateral diffusion mechanism has been proposed function as efflux pumps. Here we present the first example of a lateral diffusion mechanism for the uptake of hydrophobic substrates by the Escherichia coli outer membrane long-chain fatty acid transporter FadL. A FadL mutant in which a lateral opening in the barrel wall is constricted, but which is otherwise structurally identical to wild-type FadL, does not transport substrates. A crystal structure of FadL from Pseudomonas aeruginosa shows that the opening in the wall of the beta-barrel is conserved and delineates a long, hydrophobic tunnel that could mediate substrate passage from the extracellular environment, through the polar lipopolysaccharide layer and, by means of the lateral opening in the barrel wall, into the lipid bilayer from where the substrate can diffuse into the periplasm. Because FadL homologues are found in pathogenic and biodegrading bacteria, our results have implications for combating bacterial infections and bioremediating xenobiotics in the environment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658730/" 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/PMC2658730/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hearn, Elizabeth M -- Patel, Dimki R -- Lepore, Bryan W -- Indic, Mridhu -- van den Berg, Bert -- 1R01GM074824/GM/NIGMS NIH HHS/ -- F32 GM079820-01/GM/NIGMS NIH HHS/ -- F32 GM079820-02/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 GM074824/GM/NIGMS NIH HHS/ -- R01 GM074824-01/GM/NIGMS NIH HHS/ -- R01 GM074824-02/GM/NIGMS NIH HHS/ -- R01 GM074824-03/GM/NIGMS NIH HHS/ -- R01 GM074824-04/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Mar 19;458(7236):367-70. doi: 10.1038/nature07678. Epub 2009 Feb 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19182779" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*chemistry/genetics/*metabolism ; Cloning, Molecular ; Crystallography, X-Ray ; Diffusion ; Escherichia coli/*chemistry/genetics ; Escherichia coli Proteins/*chemistry/genetics/*metabolism ; Fatty Acid Transport Proteins/*chemistry/genetics/*metabolism ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/metabolism ; Models, Molecular ; Pseudomonas aeruginosa/*chemistry/genetics
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    Characterization of two classes of small molecule inhibitors of Arp2/3 complex (2009)
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    Publication Date: 2009-08-04
    Description: Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements. However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780427/" 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/PMC2780427/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nolen, B J -- Tomasevic, N -- Russell, A -- Pierce, D W -- Jia, Z -- McCormick, C D -- Hartman, J -- Sakowicz, R -- Pollard, T D -- F32 GM074374-02/GM/NIGMS NIH HHS/ -- GM-066311/GM/NIGMS NIH HHS/ -- GM074374-02/GM/NIGMS NIH HHS/ -- P01 GM066311/GM/NIGMS NIH HHS/ -- P01 GM066311-01A1/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- England -- Nature. 2009 Aug 20;460(7258):1031-4. doi: 10.1038/nature08231. Epub 2009 Aug 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19648907" target="_blank"〉PubMed〈/a〉
    Keywords: Actin Cytoskeleton/drug effects/metabolism ; Actin-Related Protein 2/antagonists & inhibitors/chemistry/metabolism ; Actin-Related Protein 2-3 Complex/*antagonists & inhibitors/chemistry/metabolism ; Actin-Related Protein 3/antagonists & inhibitors/chemistry/metabolism ; Actins/chemistry/metabolism ; Animals ; Biopolymers/chemistry/metabolism ; Cattle ; Cell Line ; Crystallography, X-Ray ; Humans ; Hydrophobic and Hydrophilic Interactions ; Indoles/classification/metabolism/pharmacology ; Listeria/physiology ; Models, Molecular ; Monocytes/immunology ; Protein Conformation/drug effects ; Schizosaccharomyces ; Thiazoles/chemistry/classification/metabolism/pharmacology ; Thiophenes/classification/metabolism/pharmacology
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    Structural biology: Highly charged meetings (2009)
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    Publication Date: 2009-11-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Anthony G -- England -- Nature. 2009 Nov 26;462(7272):420-1. doi: 10.1038/462420a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940907" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/*chemistry/*metabolism ; Models, Molecular ; Molecular Dynamics Simulation ; Neutron Diffraction ; Potassium Channels, Voltage-Gated/*chemistry/*metabolism ; Protein Structure, Tertiary ; Static Electricity
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    Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter (2009)
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    Publication Date: 2009-01-09
    Description: Haematopoietic stem cells (HSCs) are the founder cells of the adult haematopoietic system, and thus knowledge of the molecular program directing their generation during development is important for regenerative haematopoietic strategies. Runx1 is a pivotal transcription factor required for HSC generation in the vascular regions of the mouse conceptus-the aorta, vitelline and umbilical arteries, yolk sac and placenta. It is thought that HSCs emerge from vascular endothelial cells through the formation of intra-arterial clusters and that Runx1 functions during the transition from 'haemogenic endothelium' to HSCs. Here we show by conditional deletion that Runx1 activity in vascular-endothelial-cadherin-positive endothelial cells is indeed essential for intra-arterial cluster, haematopoietic progenitor and HSC formation in mice. In contrast, Runx1 is not required in cells expressing Vav1, one of the first pan-haematopoietic genes expressed in HSCs. Collectively these data show that Runx1 function is essential in endothelial cells for haematopoietic progenitor and HSC formation from the vasculature, but its requirement ends once or before Vav is expressed.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744041/" 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/PMC2744041/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Michael J -- Yokomizo, Tomomasa -- Zeigler, Brandon M -- Dzierzak, Elaine -- Speck, Nancy A -- CA23108/CA/NCI NIH HHS/ -- R01 CA058343/CA/NCI NIH HHS/ -- R01DK54077/DK/NIDDK NIH HHS/ -- R01HL091724/HL/NHLBI NIH HHS/ -- R37 DK054077/DK/NIDDK NIH HHS/ -- R37 DK054077-09/DK/NIDDK NIH HHS/ -- T32 AI-07519/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Feb 12;457(7231):887-91. doi: 10.1038/nature07619. Epub 2009 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19129762" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/metabolism ; Cadherins/metabolism ; *Cell Differentiation ; Core Binding Factor Alpha 2 Subunit/genetics/*metabolism ; Endothelial Cells/*cytology ; Female ; *Gene Expression Regulation, Developmental ; Hematopoietic Stem Cells/*cytology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Proto-Oncogene Proteins c-vav/metabolism
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    Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation (2009)
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    Publication Date: 2009-05-02
    Description: Gene silencing by double-stranded RNA, denoted RNA interference, represents a new paradigm for rational drug design. However, the transformative therapeutic potential of short interfering RNA (siRNA) has been stymied by a key obstacle-safe delivery to specified target cells in vivo. Macrophages are particularly attractive targets for RNA interference therapy because they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and diabetes. Here we report the engineering of beta1,3-D-glucan-encapsulated siRNA particles (GeRPs) as efficient oral delivery vehicles that potently silence genes in mouse macrophages in vitro and in vivo. Oral gavage of mice with GeRPs containing as little as 20 microg kg(-1) siRNA directed against tumour necrosis factor alpha (Tnf-alpha) depleted its messenger RNA in macrophages recovered from the peritoneum, spleen, liver and lung, and lowered serum Tnf-alpha levels. Screening with GeRPs for inflammation genes revealed that the mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) is a previously unknown mediator of cytokine expression. Importantly, silencing Map4k4 in macrophages in vivo protected mice from lipopolysaccharide-induced lethality by inhibiting Tnf-alpha and interleukin-1beta production. This technology defines a new strategy for oral delivery of siRNA to attenuate inflammatory responses in human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879154/" 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/PMC2879154/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aouadi, Myriam -- Tesz, Gregory J -- Nicoloro, Sarah M -- Wang, Mengxi -- Chouinard, My -- Soto, Ernesto -- Ostroff, Gary R -- Czech, Michael P -- DK 30898/DK/NIDDK NIH HHS/ -- DK 32520/DK/NIDDK NIH HHS/ -- DK 60837/DK/NIDDK NIH HHS/ -- P30 DK032520/DK/NIDDK NIH HHS/ -- P30 DK032520-25/DK/NIDDK NIH HHS/ -- R01 DK030898/DK/NIDDK NIH HHS/ -- R01 DK030898-26/DK/NIDDK NIH HHS/ -- R01 DK060837/DK/NIDDK NIH HHS/ -- R01 DK060837-01A1/DK/NIDDK NIH HHS/ -- R37 DK030898/DK/NIDDK NIH HHS/ -- England -- Nature. 2009 Apr 30;458(7242):1180-4. doi: 10.1038/nature07774.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19407801" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Oral ; Animals ; *Drug Delivery Systems ; Enzyme Activation/drug effects ; *Gene Silencing ; Glucans/metabolism ; Inflammation/genetics/*prevention & control ; Interleukin-1beta/biosynthesis ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lipopolysaccharides/pharmacology ; MAP Kinase Signaling System/drug effects ; Macrophages/drug effects/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Organ Specificity ; Protein-Serine-Threonine Kinases/*deficiency/*genetics/metabolism ; RNA, Small Interfering/*administration & dosage/genetics/metabolism ; Substrate Specificity ; Tumor Necrosis Factor-alpha/biosynthesis/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
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    mTOR regulates memory CD8 T-cell differentiation (2009)
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    Publication Date: 2009-06-23
    Description: Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2710807/" 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/PMC2710807/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Araki, Koichi -- Turner, Alexandra P -- Shaffer, Virginia Oliva -- Gangappa, Shivaprakash -- Keller, Susanne A -- Bachmann, Martin F -- Larsen, Christian P -- Ahmed, Rafi -- AI030048/AI/NIAID NIH HHS/ -- AI040519/AI/NIAID NIH HHS/ -- N01-AI-50025/AI/NIAID NIH HHS/ -- R01 AI073707/AI/NIAID NIH HHS/ -- R01 AI073707-01A2/AI/NIAID NIH HHS/ -- R37 AI040519/AI/NIAID NIH HHS/ -- R37 AI040519-13/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Jul 2;460(7251):108-12. doi: 10.1038/nature08155. Epub 2009 Jun 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center and Department of Microbiology and Immunology, Atlanta, Georgia, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19543266" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Viral/immunology ; CD8-Positive T-Lymphocytes/*cytology/*immunology ; *Cell Differentiation ; Cells, Cultured ; Immunologic Memory/drug effects/*immunology ; Lymphocyte Count ; Lymphocytic choriomeningitis virus/immunology ; Macaca mulatta/immunology ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes ; Protein Kinases/*metabolism ; Proteins ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases ; Transcription Factors/metabolism
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    Structural biology: A channel with a twist (2009)
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    Publication Date: 2009-09-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vasquez, Valeria -- Perozo, Eduardo -- England -- Nature. 2009 Sep 3;461(7260):47-9. doi: 10.1038/461047a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19727188" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; Ion Channel Gating/*physiology ; Ion Channels/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Mycobacterium tuberculosis/chemistry ; Pressure ; Protein Structure, Quaternary ; Staphylococcus aureus/*chemistry
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    Pyrrolysyl-tRNA synthetase-tRNA(Pyl) structure reveals the molecular basis of orthogonality (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-01-02
    Description: Pyrrolysine (Pyl), the 22nd natural amino acid, is genetically encoded by UAG and inserted into proteins by the unique suppressor tRNA(Pyl) (ref. 1). The Methanosarcinaceae produce Pyl and express Pyl-containing methyltransferases that allow growth on methylamines. Homologous methyltransferases and the Pyl biosynthetic and coding machinery are also found in two bacterial species. Pyl coding is maintained by pyrrolysyl-tRNA synthetase (PylRS), which catalyses the formation of Pyl-tRNA(Pyl) (refs 4, 5). Pyl is not a recent addition to the genetic code. PylRS was already present in the last universal common ancestor; it then persisted in organisms that utilize methylamines as energy sources. Recent protein engineering efforts added non-canonical amino acids to the genetic code. This technology relies on the directed evolution of an 'orthogonal' tRNA synthetase-tRNA pair in which an engineered aminoacyl-tRNA synthetase (aaRS) specifically and exclusively acylates the orthogonal tRNA with a non-canonical amino acid. For Pyl the natural evolutionary process developed such a system some 3 billion years ago. When transformed into Escherichia coli, Methanosarcina barkeri PylRS and tRNA(Pyl) function as an orthogonal pair in vivo. Here we show that Desulfitobacterium hafniense PylRS-tRNA(Pyl) is an orthogonal pair in vitro and in vivo, and present the crystal structure of this orthogonal pair. The ancient emergence of PylRS-tRNA(Pyl) allowed the evolution of unique structural features in both the protein and the tRNA. These structural elements manifest an intricate, specialized aaRS-tRNA interaction surface that is highly distinct from those observed in any other known aaRS-tRNA complex; it is this general property that underlies the molecular basis of orthogonality.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2648862/" 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/PMC2648862/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nozawa, Kayo -- O'Donoghue, Patrick -- Gundllapalli, Sarath -- Araiso, Yuhei -- Ishitani, Ryuichiro -- Umehara, Takuya -- Soll, Dieter -- Nureki, Osamu -- R01 GM022854/GM/NIGMS NIH HHS/ -- R01 GM022854-33/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Feb 26;457(7233):1163-7. doi: 10.1038/nature07611. Epub 2008 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, B34 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa 226-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19118381" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acyl-tRNA Synthetases/*chemistry/genetics/*metabolism ; Aminoacylation ; Crystallography, X-Ray ; Desulfitobacterium/*enzymology/genetics ; Escherichia coli/genetics ; Lysine/*analogs & derivatives/biosynthesis/genetics/metabolism ; Methanosarcina barkeri/enzymology/genetics ; Models, Molecular ; RNA, Transfer, Amino Acid-Specific/genetics/metabolism ; Structural Homology, Protein
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    Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates (2009)
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    Publication Date: 2009-02-20
    Description: The complement system is an essential component of the innate and acquired immune system, and consists of a series of proteolytic cascades that are initiated by the presence of microorganisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including complement factor H (fH; ref. 2), a 155 kDa protein composed of 20 domains (termed complement control protein repeats). Many pathogens have evolved the ability to avoid immune-killing by recruiting host complement regulators and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface. Here we present the structure of a complement regulator in complex with its pathogen surface-protein ligand. This reveals how the important human pathogen Neisseria meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, fH. The structure also indicates the molecular basis of the host-specificity of the interaction between fH and the meningococcus, and informs attempts to develop novel therapeutics and vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670278/" 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/PMC2670278/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schneider, Muriel C -- Prosser, Beverly E -- Caesar, Joseph J E -- Kugelberg, Elisabeth -- Li, Su -- Zhang, Qian -- Quoraishi, Sadik -- Lovett, Janet E -- Deane, Janet E -- Sim, Robert B -- Roversi, Pietro -- Johnson, Steven -- Tang, Christoph M -- Lea, Susan M -- 083599/Wellcome Trust/United Kingdom -- G0400775/Medical Research Council/United Kingdom -- G0400775(71657)/Medical Research Council/United Kingdom -- G0500367/Medical Research Council/United Kingdom -- G0601195/Medical Research Council/United Kingdom -- G0601195(79743)/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2009 Apr 16;458(7240):890-3. doi: 10.1038/nature07769. Epub 2009 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Molecular Microbiology and Infection, Imperial College, London SW7 2AZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19225461" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Bacterial/*chemistry/*metabolism ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Carbohydrates/*chemistry ; Complement Factor H/*chemistry/immunology/*metabolism ; Crystallography, X-Ray ; Ligands ; Models, Molecular ; *Molecular Mimicry ; Neisseria meningitidis/chemistry/immunology/*metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Conformation ; Structure-Activity Relationship ; Substrate Specificity
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    Sleep deprivation impairs cAMP signalling in the hippocampus (2009)
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    Publication Date: 2009-10-23
    Description: Millions of people regularly obtain insufficient sleep. Given the effect of sleep deprivation on our lives, understanding the cellular and molecular pathways affected by sleep deprivation is clearly of social and clinical importance. One of the major effects of sleep deprivation on the brain is to produce memory deficits in learning models that are dependent on the hippocampus. Here we have identified a molecular mechanism by which brief sleep deprivation alters hippocampal function. Sleep deprivation selectively impaired 3', 5'-cyclic AMP (cAMP)- and protein kinase A (PKA)-dependent forms of synaptic plasticity in the mouse hippocampus, reduced cAMP signalling, and increased activity and protein levels of phosphodiesterase 4 (PDE4), an enzyme that degrades cAMP. Treatment of mice with phosphodiesterase inhibitors rescued the sleep-deprivation-induced deficits in cAMP signalling, synaptic plasticity and hippocampus-dependent memory. These findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signalling through increased PDE4 activity. Thus, drugs that enhance cAMP signalling may provide a new therapeutic approach to counteract the cognitive effects of sleep deprivation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783639/" 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/PMC2783639/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vecsey, Christopher G -- Baillie, George S -- Jaganath, Devan -- Havekes, Robbert -- Daniels, Andrew -- Wimmer, Mathieu -- Huang, Ted -- Brown, Kim M -- Li, Xiang-Yao -- Descalzi, Giannina -- Kim, Susan S -- Chen, Tao -- Shang, Yu-Ze -- Zhuo, Min -- Houslay, Miles D -- Abel, Ted -- 84256/Canadian Institutes of Health Research/Canada -- AG017628/AG/NIA NIH HHS/ -- G0600765/Medical Research Council/United Kingdom -- GM07517/GM/NIGMS NIH HHS/ -- HL060287/HL/NHLBI NIH HHS/ -- HL07953/HL/NHLBI NIH HHS/ -- P01 AG017628/AG/NIA NIH HHS/ -- P01 AG017628-080006/AG/NIA NIH HHS/ -- P50 HL060287/HL/NHLBI NIH HHS/ -- P50 HL060287-100006/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Oct 22;461(7267):1122-5. doi: 10.1038/nature08488.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847264" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Colforsin/pharmacology ; Cyclic AMP/*metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Hippocampus/drug effects/enzymology/*metabolism/physiology ; Long-Term Potentiation/drug effects ; Male ; Memory/drug effects/physiology ; Mice ; Mice, Inbred C57BL ; Neuronal Plasticity ; Phosphodiesterase 4 Inhibitors ; Rolipram/pharmacology ; *Second Messenger Systems/drug effects ; Sleep Deprivation/*physiopathology ; Time Factors
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    Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells (2009)
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    Publication Date: 2009-01-06
    Description: Rare cells with the properties of stem cells are integral to the development and perpetuation of leukaemias. A defining characteristic of stem cells is their capacity to self-renew, which is markedly extended in leukaemia stem cells. The underlying molecular mechanisms, however, are largely unknown. Here we demonstrate that expression of the cell-cycle inhibitor p21 is indispensable for maintaining self-renewal of leukaemia stem cells. Expression of leukaemia-associated oncogenes in mouse haematopoietic stem cells (HSCs) induces DNA damage and activates a p21-dependent cellular response, which leads to reversible cell-cycle arrest and DNA repair. Activated p21 is critical in preventing excess DNA-damage accumulation and functional exhaustion of leukaemic stem cells. These data unravel the oncogenic potential of p21 and suggest that inhibition of DNA repair mechanisms might function as potent strategy for the eradication of the slowly proliferating leukaemia stem cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Viale, Andrea -- De Franco, Francesca -- Orleth, Annette -- Cambiaghi, Valeria -- Giuliani, Virginia -- Bossi, Daniela -- Ronchini, Chiara -- Ronzoni, Simona -- Muradore, Ivan -- Monestiroli, Silvia -- Gobbi, Alberto -- Alcalay, Myriam -- Minucci, Saverio -- Pelicci, Pier Giuseppe -- England -- Nature. 2009 Jan 1;457(7225):51-6. doi: 10.1038/nature07618.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Experimental Oncology at the IFOM-IEO Campus, European Institute of Oncology, IEO, 20141 Milan, Italy. andrea.viale@ifom-ieo-campus.it〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19122635" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Count ; *Cell Cycle/genetics ; Cell Division ; Core Binding Factor Alpha 2 Subunit/genetics/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/deficiency/genetics/*metabolism ; *DNA Damage/genetics ; DNA Repair ; Fibroblasts ; Gene Expression Regulation, Neoplastic ; Leukemia/*pathology ; Mice ; Mice, Inbred C57BL ; Neoplastic Stem Cells/cytology/*pathology ; Oncogene Proteins, Fusion/genetics/metabolism ; Up-Regulation
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    An unusual carbon-carbon bond cleavage reaction during phosphinothricin biosynthesis (2009)
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    Publication Date: 2009-06-12
    Description: Natural products containing phosphorus-carbon bonds have found widespread use in medicine and agriculture. One such compound, phosphinothricin tripeptide, contains the unusual amino acid phosphinothricin attached to two alanine residues. Synthetic phosphinothricin (glufosinate) is a component of two top-selling herbicides (Basta and Liberty), and is widely used with resistant transgenic crops including corn, cotton and canola. Recent genetic and biochemical studies showed that during phosphinothricin tripeptide biosynthesis 2-hydroxyethylphosphonate (HEP) is converted to hydroxymethylphosphonate (HMP). Here we report the in vitro reconstitution of this unprecedented C(sp(3))-C(sp(3)) bond cleavage reaction and X-ray crystal structures of the enzyme. The protein is a mononuclear non-haem iron(ii)-dependent dioxygenase that converts HEP to HMP and formate. In contrast to most other members of this family, the oxidative consumption of HEP does not require additional cofactors or the input of exogenous electrons. The current study expands the scope of reactions catalysed by the 2-His-1-carboxylate mononuclear non-haem iron family of enzymes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874955/" 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/PMC2874955/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cicchillo, Robert M -- Zhang, Houjin -- Blodgett, Joshua A V -- Whitteck, John T -- Li, Gongyong -- Nair, Satish K -- van der Donk, Wilfred A -- Metcalf, William W -- P01 GM077596/GM/NIGMS NIH HHS/ -- P01 GM077596-03/GM/NIGMS NIH HHS/ -- R01 GM059334/GM/NIGMS NIH HHS/ -- R01 GM059334-09/GM/NIGMS NIH HHS/ -- R01 GM59334/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):871-4. doi: 10.1038/nature07972.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516340" target="_blank"〉PubMed〈/a〉
    Keywords: Aminobutyrates/*chemistry/*metabolism ; Biocatalysis ; Crystallography, X-Ray ; Dioxygenases/chemistry/genetics/*metabolism ; Escherichia coli ; Formates/metabolism ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Models, Biological ; Models, Molecular ; Molecular Conformation ; Organophosphonates/metabolism
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    Crystal structure of a bacterial homologue of the kidney urea transporter (2009)
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    Publication Date: 2009-10-30
    Description: Urea is highly concentrated in the mammalian kidney to produce the osmotic gradient necessary for water re-absorption. Free diffusion of urea across cell membranes is slow owing to its high polarity, and specialized urea transporters have evolved to achieve rapid and selective urea permeation. Here we present the 2.3 A structure of a functional urea transporter from the bacterium Desulfovibrio vulgaris. The transporter is a homotrimer, and each subunit contains a continuous membrane-spanning pore formed by the two homologous halves of the protein. The pore contains a constricted selectivity filter that can accommodate several dehydrated urea molecules in single file. Backbone and side-chain oxygen atoms provide continuous coordination of urea as it progresses through the filter, and well-placed alpha-helix dipoles provide further compensation for dehydration energy. These results establish that the urea transporter operates by a channel-like mechanism and reveal the physical and chemical basis of urea selectivity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871279/" 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/PMC2871279/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Levin, Elena J -- Quick, Matthias -- Zhou, Ming -- GM075026/GM/NIGMS NIH HHS/ -- HL086392/HL/NHLBI NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- R01 HL086392-04/HL/NHLBI NIH HHS/ -- R01 HL086392-04S1/HL/NHLBI NIH HHS/ -- R01 HL086392-05/HL/NHLBI NIH HHS/ -- T32 HL087745/HL/NHLBI NIH HHS/ -- T32 HL087745-03/HL/NHLBI NIH HHS/ -- T32HL087745/HL/NHLBI NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM075026-040007/GM/NIGMS NIH HHS/ -- U54 GM075026-050007/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Dec 10;462(7274):757-61. doi: 10.1038/nature08558. Epub .〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19865084" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; Desulfovibrio vulgaris/*chemistry ; Humans ; Kidney/*chemistry ; Membrane Transport Proteins/*chemistry/*metabolism ; Models, Molecular ; Oocytes/metabolism ; Protein Folding ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship ; Urea/metabolism ; Xenopus laevis
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    The origin of the electrostatic perturbation in acetoacetate decarboxylase (2009)
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    Publication Date: 2009-05-22
    Description: Acetoacetate decarboxylase (AADase) has long been cited as the prototypical example of the marked shifts in the pK(a) values of ionizable groups that can occur in an enzyme active site. In 1966, it was hypothesized that in AADase the origin of the large pK(a) perturbation (-4.5 log units) observed in the nucleophilic Lys 115 results from the proximity of Lys 116, marking the first proposal of microenvironment effects in enzymology. The electrostatic perturbation hypothesis has been demonstrated in a number of enzymes, but never for the enzyme that inspired its conception, owing to the lack of a three-dimensional structure. Here we present the X-ray crystal structures of AADase and of the enamine adduct with the substrate analogue 2,4-pentanedione. Surprisingly, the shift of the pK(a) of Lys 115 is not due to the proximity of Lys 116, the side chain of which is oriented away from the active site. Instead, Lys 116 participates in the structural anchoring of Lys 115 in a long, hydrophobic funnel provided by the novel fold of the enzyme. Thus, AADase perturbs the pK(a) of the nucleophile by means of a desolvation effect by placement of the side chain into the protein core while enforcing the proximity of polar residues, which facilitate decarboxylation through electrostatic and steric effects.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ho, Meng-Chiao -- Menetret, Jean-Francois -- Tsuruta, Hiro -- Allen, Karen N -- England -- Nature. 2009 May 21;459(7245):393-7. doi: 10.1038/nature07938.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19458715" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Carboxy-Lyases/*chemistry ; Catalytic Domain ; Chromobacterium/*enzymology ; Clostridium acetobutylicum/*enzymology ; Crystallography, X-Ray ; Decarboxylation ; Hydrophobic and Hydrophilic Interactions ; Lysine/chemistry/metabolism ; Models, Molecular ; Pentanones/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Static Electricity
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    The Fas-FADD death domain complex structure unravels signalling by receptor clustering (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-01-02
    Description: The death inducing signalling complex (DISC) formed by Fas receptor, FADD (Fas-associated death domain protein) and caspase 8 is a pivotal trigger of apoptosis. The Fas-FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains of Fas and FADD is at the centre of DISC formation. Thus, characterizing the mechanistic basis for the Fas-FADD interaction is crucial for understanding DISC signalling but has remained unclear largely because of a lack of structural data. We have successfully formed and isolated the human Fas-FADD death domain complex and report the 2.7 A crystal structure. The complex shows a tetrameric arrangement of four FADD death domains bound to four Fas death domains. We show that an opening of the Fas death domain exposes the FADD binding site and simultaneously generates a Fas-Fas bridge. The result is a regulatory Fas-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. In addition to depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signalling solely by oligomerization and clustering events.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661029/" 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/PMC2661029/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scott, Fiona L -- Stec, Boguslaw -- Pop, Cristina -- Dobaczewska, Malgorzata K -- Lee, JeongEun J -- Monosov, Edward -- Robinson, Howard -- Salvesen, Guy S -- Schwarzenbacher, Robert -- Riedl, Stefan J -- P01 CA069381/CA/NCI NIH HHS/ -- P01 CA069381-130009/CA/NCI NIH HHS/ -- P01CA69381/CA/NCI NIH HHS/ -- P30 CA030199/CA/NCI NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01AA017238/AA/NIAAA NIH HHS/ -- England -- Nature. 2009 Feb 19;457(7232):1019-22. doi: 10.1038/nature07606. Epub 2008 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Apoptosis and Cell Death Research, The Burnham Institute for Medical Research, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19118384" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, CD95/*chemistry/*metabolism ; Crystallography, X-Ray ; Death Domain Receptor Signaling Adaptor Proteins/chemistry/metabolism ; Fas-Associated Death Domain Protein/*chemistry/*metabolism ; Humans ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; *Receptor Aggregation ; *Signal Transduction
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    The Ink4/Arf locus is a barrier for iPS cell reprogramming (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-08-12
    Description: The mechanisms involved in the reprogramming of differentiated cells into induced pluripotent stem (iPS) cells by the three transcription factors Oct4 (also known as Pou5f1), Klf4 and Sox2 remain poorly understood. The Ink4/Arf locus comprises the Cdkn2a-Cdkn2b genes encoding three potent tumour suppressors, namely p16(Ink4a), p19(Arf) and p15(Ink4b), which are basally expressed in differentiated cells and upregulated by aberrant mitogenic signals. Here we show that the locus is completely silenced in iPS cells, as well as in embryonic stem (ES) cells, acquiring the epigenetic marks of a bivalent chromatin domain, and retaining the ability to be reactivated after differentiation. Cell culture conditions during reprogramming enhance the expression of the Ink4/Arf locus, further highlighting the importance of silencing the locus to allow proliferation and reprogramming. Indeed, the three factors together repress the Ink4/Arf locus soon after their expression and concomitant with the appearance of the first molecular markers of 'stemness'. This downregulation also occurs in cells carrying the oncoprotein large-T, which functionally inactivates the pathways regulated by the Ink4/Arf locus, thus indicating that the silencing of the locus is intrinsic to reprogramming and not the result of a selective process. Genetic inhibition of the Ink4/Arf locus has a profound positive effect on the efficiency of iPS cell generation, increasing both the kinetics of reprogramming and the number of emerging iPS cell colonies. In murine cells, Arf, rather than Ink4a, is the main barrier to reprogramming by activation of p53 (encoded by Trp53) and p21 (encoded by Cdkn1a); whereas, in human fibroblasts, INK4a is more important than ARF. Furthermore, organismal ageing upregulates the Ink4/Arf locus and, accordingly, reprogramming is less efficient in cells from old organisms, but this defect can be rescued by inhibiting the locus with a short hairpin RNA. All together, we conclude that the silencing of Ink4/Arf locus is rate-limiting for reprogramming, and its transient inhibition may significantly improve the generation of iPS cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578184/" 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/PMC3578184/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Han -- Collado, Manuel -- Villasante, Aranzazu -- Strati, Katerina -- Ortega, Sagrario -- Canamero, Marta -- Blasco, Maria A -- Serrano, Manuel -- 233270/European Research Council/International -- England -- Nature. 2009 Aug 27;460(7259):1136-9. doi: 10.1038/nature08290. Epub 2009 Aug 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), 3 Melchor Fernandez Almagro Street, Madrid E-28029, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19668188" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/physiology ; Animals ; Cell Count ; Cell Differentiation ; Cellular Reprogramming/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/deficiency/genetics/*metabolism ; Embryonic Stem Cells/cytology ; Epigenesis, Genetic ; Fibroblasts/cytology/metabolism ; Gene Silencing ; Humans ; Keratinocytes ; Kinetics ; Mice ; Mice, Inbred C57BL ; Pluripotent Stem Cells/*cytology/*metabolism
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    Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-17
    Description: Mechanical pain contributes to the morbidity associated with inflammation and trauma, but primary sensory neurons that convey the sensation of acute and persistent mechanical pain have not been identified. Dorsal root ganglion (DRG) neurons transmit sensory information to the spinal cord using the excitatory transmitter glutamate, a process that depends on glutamate transport into synaptic vesicles for regulated exocytotic release. Here we report that a small subset of cells in the DRG expresses the low abundance vesicular glutamate transporter VGLUT3 (also known as SLC17A8). In the dorsal horn of the spinal cord, these afferents project to lamina I and the innermost layer of lamina II, which has previously been implicated in persistent pain caused by injury. Because the different VGLUT isoforms generally have a non-redundant pattern of expression, we used Vglut3 knockout mice to assess the role of VGLUT3(+) primary afferents in the behavioural response to somatosensory input. The loss of VGLUT3 specifically impairs mechanical pain sensation, and in particular the mechanical hypersensitivity to normally innocuous stimuli that accompanies inflammation, nerve injury and trauma. Direct recording from VGLUT3(+) neurons in the DRG further identifies them as a poorly understood population of unmyelinated, low threshold mechanoreceptors (C-LTMRs). The analysis of Vglut3(-/-) mice now indicates a critical role for C-LTMRs in the mechanical hypersensitivity caused by injury.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810205/" 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/PMC2810205/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seal, Rebecca P -- Wang, Xidao -- Guan, Yun -- Raja, Srinivasa N -- Woodbury, C Jeffery -- Basbaum, Allan I -- Edwards, Robert H -- F32 MH068085/MH/NIMH NIH HHS/ -- F32 MH068085-02/MH/NIMH NIH HHS/ -- R01 MH050712/MH/NIMH NIH HHS/ -- R01 MH050712-17/MH/NIMH NIH HHS/ -- R01 NS044094/NS/NINDS NIH HHS/ -- R01 NS044094-06/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Dec 3;462(7273):651-5. doi: 10.1038/nature08505. Epub 2009 Nov 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, University of California, San Francisco School of Medicine, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19915548" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Transport Systems, Acidic/genetics/*metabolism ; Animals ; Behavior, Animal/physiology ; Female ; Ganglia, Spinal/*metabolism ; Gene Expression Regulation ; Hypersensitivity/*genetics/*physiopathology ; Mechanoreceptors/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pain/*genetics ; Wounds and Injuries/*physiopathology
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    Structure and mechanism of a bacterial light-regulated cyclic nucleotide phosphodiesterase (2009)
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    Publication Date: 2009-06-19
    Description: The ability to respond to light is crucial for most organisms. BLUF is a recently identified photoreceptor protein domain that senses blue light using a FAD chromophore. BLUF domains are present in various proteins from the Bacteria, Euglenozoa and Fungi. Although structures of single-domain BLUF proteins have been determined, none are available for a BLUF protein containing a functional output domain; the mechanism of light activation in this new class of photoreceptors has thus remained poorly understood. Here we report the biochemical, structural and mechanistic characterization of a full-length, active photoreceptor, BlrP1 (also known as KPN_01598), from Klebsiella pneumoniae. BlrP1 consists of a BLUF sensor domain and a phosphodiesterase EAL output domain which hydrolyses cyclic dimeric GMP (c-di-GMP). This ubiquitous second messenger controls motility, biofilm formation, virulence and antibiotic resistance in the Bacteria. Crystal structures of BlrP1 complexed with its substrate and metal ions involved in catalysis or in enzyme inhibition provide a detailed understanding of the mechanism of the EAL-domain c-di-GMP phosphodiesterases. These structures also sketch out a path of light activation of the phosphodiesterase output activity. Photon absorption by the BLUF domain of one subunit of the antiparallel BlrP1 homodimer activates the EAL domain of the second subunit through allosteric communication transmitted through conserved domain-domain interfaces.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barends, Thomas R M -- Hartmann, Elisabeth -- Griese, Julia J -- Beitlich, Thorsten -- Kirienko, Natalia V -- Ryjenkov, Dmitri A -- Reinstein, Jochen -- Shoeman, Robert L -- Gomelsky, Mark -- Schlichting, Ilme -- England -- Nature. 2009 Jun 18;459(7249):1015-8. doi: 10.1038/nature07966.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Medical Research, Department of Biomolecular Mechanisms, Jahnstrasse 29, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536266" target="_blank"〉PubMed〈/a〉
    Keywords: 3',5'-Cyclic-GMP Phosphodiesterases/*chemistry/metabolism/*radiation effects ; Allosteric Regulation/radiation effects ; Biocatalysis/radiation effects ; Catalytic Domain ; Crystallography, X-Ray ; Cyclic GMP/analogs & derivatives/metabolism ; Klebsiella pneumoniae/*enzymology ; *Light ; Metals/metabolism ; Models, Molecular ; Phosphorus/metabolism ; Photons ; Photoreceptors, Microbial/*chemistry/metabolism/*radiation effects ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary
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    The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex (2009)
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    Publication Date: 2009-03-03
    Description: The lipopolysaccharide (LPS) of Gram negative bacteria is a well-known inducer of the innate immune response. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules. To understand the ligand specificity and receptor activation mechanism of the TLR4-MD-2-LPS complex we determined its crystal structure. LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically. LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2, forming a hydrophobic interaction with the conserved phenylalanines of TLR4. The F126 loop of MD-2 undergoes localized structural change and supports this core hydrophobic interface by making hydrophilic interactions with TLR4. Comparison with the structures of tetra-acylated antagonists bound to MD-2 indicates that two other lipid chains in LPS displace the phosphorylated glucosamine backbone by approximately 5 A towards the solvent area. This structural shift allows phosphate groups of LPS to contribute to receptor multimerization by forming ionic interactions with a cluster of positively charged residues in TLR4 and MD-2. The TLR4-MD-2-LPS structure illustrates the remarkable versatility of the ligand recognition mechanisms employed by the TLR family, which is essential for defence against diverse microbial infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Beom Seok -- Song, Dong Hyun -- Kim, Ho Min -- Choi, Byong-Seok -- Lee, Hayyoung -- Lee, Jie-Oh -- England -- Nature. 2009 Apr 30;458(7242):1191-5. doi: 10.1038/nature07830. Epub 2009 Mar 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, KAIST, Daejeon, 305-701, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19252480" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Escherichia coli/chemistry ; Humans ; Hydrophobic and Hydrophilic Interactions ; Lipopolysaccharides/*chemistry/*immunology ; Lymphocyte Antigen 96/*chemistry/*immunology ; Models, Molecular ; Protein Binding ; Protein Multimerization ; Structure-Activity Relationship ; Toll-Like Receptor 4/*chemistry/*immunology
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    Chemical biology: Caught in the activation (2009)
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    Publication Date: 2009-09-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yi -- England -- Nature. 2009 Sep 24;461(7263):484-5. doi: 10.1038/461484a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19779441" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallography, X-Ray ; Enzyme Activation/drug effects ; Humans ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Protein-Serine-Threonine Kinases/*chemistry/*metabolism
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    Structure of a tetrameric MscL in an expanded intermediate state (2009)
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    Publication Date: 2009-08-25
    Description: The ability of cells to sense and respond to mechanical force underlies diverse processes such as touch and hearing in animals, gravitropism in plants, and bacterial osmoregulation. In bacteria, mechanosensation is mediated by the mechanosensitive channels of large (MscL), small (MscS), potassium-dependent (MscK) and mini (MscM) conductances. These channels act as 'emergency relief valves' protecting bacteria from lysis upon acute osmotic down-shock. Among them, MscL has been intensively studied since the original identification and characterization 15 years ago. MscL is reversibly and directly gated by changes in membrane tension. In the open state, MscL forms a non-selective 3 nS conductance channel which gates at tensions close to the lytic limit of the bacterial membrane. An earlier crystal structure at 3.5 A resolution of a pentameric MscL from Mycobacterium tuberculosis represents a closed-state or non-conducting conformation. MscL has a complex gating behaviour; it exhibits several intermediates between the closed and open states, including one putative non-conductive expanded state and at least three sub-conducting states. Although our understanding of the closed and open states of MscL has been increasing, little is known about the structures of the intermediate states despite their importance in elucidating the complete gating process of MscL. Here we present the crystal structure of a carboxy-terminal truncation mutant (Delta95-120) of MscL from Staphylococcus aureus (SaMscL(CDelta26)) at 3.8 A resolution. Notably, SaMscL(CDelta26) forms a tetrameric channel with both transmembrane helices tilted away from the membrane normal at angles close to that inferred for the open state, probably corresponding to a non-conductive but partially expanded intermediate state.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737600/" 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/PMC2737600/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Zhenfeng -- Gandhi, Chris S -- Rees, Douglas C -- GM084211/GM/NIGMS NIH HHS/ -- R01 GM084211/GM/NIGMS NIH HHS/ -- R01 GM084211-01/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Sep 3;461(7260):120-4. doi: 10.1038/nature08277. Epub 2009 Aug 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19701184" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacterial Proteins/*chemistry/metabolism ; Crystallography, X-Ray ; Ion Channel Gating ; Ion Channels/*chemistry/metabolism ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Mycobacterium tuberculosis/chemistry/metabolism ; Pressure ; Protein Structure, Quaternary ; Staphylococcus aureus/*chemistry ; Structural Homology, Protein
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    Structural insights into mechanisms of the small RNA methyltransferase HEN1 (2009)
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    Publication Date: 2009-10-09
    Description: RNA silencing is a conserved regulatory mechanism in fungi, plants and animals that regulates gene expression and defence against viruses and transgenes. Small silencing RNAs of approximately 20-30 nucleotides and their associated effector proteins, the Argonaute family proteins, are the central components in RNA silencing. A subset of small RNAs, such as microRNAs and small interfering RNAs (siRNAs) in plants, Piwi-interacting RNAs in animals and siRNAs in Drosophila, requires an additional crucial step for their maturation; that is, 2'-O-methylation on the 3' terminal nucleotide. A conserved S-adenosyl-l-methionine-dependent RNA methyltransferase, HUA ENHANCER 1 (HEN1), and its homologues are responsible for this specific modification. Here we report the 3.1 A crystal structure of full-length HEN1 from Arabidopsis in complex with a 22-nucleotide small RNA duplex and cofactor product S-adenosyl-l-homocysteine. Highly cooperative recognition of the small RNA substrate by multiple RNA binding domains and the methyltransferase domain in HEN1 measures the length of the RNA duplex and determines the substrate specificity. Metal ion coordination by both 2' and 3' hydroxyls on the 3'-terminal nucleotide and four invariant residues in the active site of the methyltransferase domain suggests a novel Mg(2+)-dependent 2'-O-methylation mechanism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Ying -- Ji, Lijuan -- Huang, Qichen -- Vassylyev, Dmitry G -- Chen, Xuemei -- Ma, Jin-Biao -- GM074252/GM/NIGMS NIH HHS/ -- R01 GM074840/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Oct 8;461(7265):823-7. doi: 10.1038/nature08433.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812675" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Arabidopsis/*enzymology/genetics ; Arabidopsis Proteins/*chemistry/genetics/*metabolism ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Magnesium/metabolism ; Methylation ; Methyltransferases/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Protein Structure, Tertiary ; RNA/genetics/*metabolism ; RNA-Binding Proteins/chemistry/metabolism ; S-Adenosylhomocysteine/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    Biochemistry: Enzyme's black box cracked open (2009)
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    Publication Date: 2009-10-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sherman, David H -- England -- Nature. 2009 Oct 22;461(7267):1068-9. doi: 10.1038/4611068a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847256" target="_blank"〉PubMed〈/a〉
    Keywords: Aflatoxin B1/biosynthesis ; Aspergillus/*enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Cyclization ; Pantetheine/analogs & derivatives/metabolism ; Polyketide Synthases/*chemistry/*metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship
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    Structures of the tRNA export factor in the nuclear and cytosolic states (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-08-15
    Description: Transfer RNAs are among the most ubiquitous molecules in cells, central to decoding information from messenger RNAs on translating ribosomes. In eukaryotic cells, tRNAs are actively transported from their site of synthesis in the nucleus to their site of function in the cytosol. This is mediated by a dedicated nucleo-cytoplasmic transport factor of the karyopherin-beta family (Xpot, also known as Los1 in Saccharomyces cerevisiae). Here we report the 3.2 A resolution structure of Schizosaccharomyces pombe Xpot in complex with tRNA and RanGTP, and the 3.1 A structure of unbound Xpot, revealing both nuclear and cytosolic snapshots of this transport factor. Xpot undergoes a large conformational change on binding cargo, wrapping around the tRNA and, in particular, binding to the tRNA 5' and 3' ends. The binding mode explains how Xpot can recognize all mature tRNAs in the cell and yet distinguish them from those that have not been properly processed, thus coupling tRNA export to quality control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cook, Atlanta G -- Fukuhara, Noemi -- Jinek, Martin -- Conti, Elena -- England -- Nature. 2009 Sep 3;461(7260):60-5. doi: 10.1038/nature08394.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Cell Biology, MPI for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19680239" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Nucleus/*metabolism ; Crystallography, X-Ray ; Cytosol/*metabolism ; GTPase-Activating Proteins/chemistry/metabolism ; Models, Molecular ; Nuclear Pore Complex Proteins/*chemistry/*metabolism ; Protein Binding ; Protein Conformation ; *RNA Transport ; RNA, Fungal/chemistry/genetics/metabolism ; RNA, Transfer/chemistry/genetics/*metabolism ; RNA, Transfer, Phe/chemistry/genetics/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/metabolism ; Schizosaccharomyces pombe Proteins/*chemistry/*metabolism ; Substrate Specificity ; ran GTP-Binding Protein/chemistry/metabolism
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    Enhancing CD8 T-cell memory by modulating fatty acid metabolism (2009)
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    Publication Date: 2009-06-06
    Description: CD8 T cells, which have a crucial role in immunity to infection and cancer, are maintained in constant numbers, but on antigen stimulation undergo a developmental program characterized by distinct phases encompassing the expansion and then contraction of antigen-specific effector (T(E)) populations, followed by the persistence of long-lived memory (T(M)) cells. Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to T(M) cells remain undefined. Here we show that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates CD8 T(M)-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 T(E)-cell responses, but have a profound defect in their ability to generate T(M) cells that is characterized by the disappearance of antigen-specific cells in the weeks after primary immunization. Microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lacking TRAF6 display defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and CD8 T(M)-cell generation in the absence of TRAF6. This treatment also increased CD8 T(M) cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803086/" 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/PMC2803086/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearce, Erika L -- Walsh, Matthew C -- Cejas, Pedro J -- Harms, Gretchen M -- Shen, Hao -- Wang, Li-San -- Jones, Russell G -- Choi, Yongwon -- R01 AI064909/AI/NIAID NIH HHS/ -- R01 AI064909-04/AI/NIAID NIH HHS/ -- T32 CA009140/CA/NCI NIH HHS/ -- England -- Nature. 2009 Jul 2;460(7251):103-7. doi: 10.1038/nature08097. Epub 2009 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19494812" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics ; Animals ; CD8-Positive T-Lymphocytes/cytology/drug effects/*immunology/*metabolism ; Fatty Acids/*metabolism ; Hypoglycemic Agents/pharmacology ; Immunologic Memory/*immunology ; Listeria monocytogenes/immunology ; Listeriosis/immunology/metabolism/microbiology ; Metformin/pharmacology ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-cbl/deficiency/genetics ; TNF Receptor-Associated Factor 6/*deficiency/genetics/*metabolism
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    A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range (2009)
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    Publication Date: 2009-03-03
    Description: Brachydactyly type A1 (BDA1) was the first recorded disorder of the autosomal dominant Mendelian trait in humans, characterized by shortened or absent middle phalanges in digits. It is associated with heterozygous missense mutations in indian hedgehog (IHH). Hedgehog proteins are important morphogens for a wide range of developmental processes. The capacity and range of signalling is thought to be regulated by its interaction with the receptor PTCH1 and antagonist HIP1. Here we show that a BDA1 mutation (E95K) in Ihh impairs the interaction of IHH with PTCH1 and HIP1. This is consistent with a recent paper showing that BDA1 mutations cluster in a calcium-binding site essential for the interaction with its receptor and cell-surface partners. Furthermore, we show that in a mouse model that recapitulates the E95K mutation, there is a change in the potency and range of signalling. The mice have digit abnormalities consistent with the human disorder.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Bo -- Hu, Jianxin -- Stricker, Sigmar -- Cheung, Martin -- Ma, Gang -- Law, Kit Fong -- Witte, Florian -- Briscoe, James -- Mundlos, Stefan -- He, Lin -- Cheah, Kathryn S E -- Chan, Danny -- MC_U117560541/Medical Research Council/United Kingdom -- England -- Nature. 2009 Apr 30;458(7242):1196-200. doi: 10.1038/nature07862. Epub 2009 Mar 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, the University of Hong Kong, Hong Kong, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19252479" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chickens ; DNA-Binding Proteins/genetics/metabolism ; Disease Models, Animal ; Female ; Hedgehog Proteins/*genetics/*metabolism ; Humans ; Limb Deformities, Congenital/*genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mutation/*genetics ; Protein Binding ; Receptors, Cell Surface/genetics/metabolism ; *Signal Transduction
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    Crystal structure of the sodium-potassium pump at 2.4 A resolution (2009)
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    Publication Date: 2009-05-22
    Description: Sodium-potassium ATPase is an ATP-powered ion pump that establishes concentration gradients for Na(+) and K(+) ions across the plasma membrane in all animal cells by pumping Na(+) from the cytoplasm and K(+) from the extracellular medium. Such gradients are used in many essential processes, notably for generating action potentials. Na(+), K(+)-ATPase is a member of the P-type ATPases, which include sarcoplasmic reticulum Ca(2+)-ATPase and gastric H(+), K(+)-ATPase, among others, and is the target of cardiac glycosides. Here we describe a crystal structure of this important ion pump, from shark rectal glands, consisting of alpha- and beta-subunits and a regulatory FXYD protein, all of which are highly homologous to human ones. The ATPase was fixed in a state analogous to E2.2K(+).P(i), in which the ATPase has a high affinity for K(+) and still binds P(i), as in the first crystal structure of pig kidney enzyme at 3.5 A resolution. Clearly visualized now at 2.4 A resolution are coordination of K(+) and associated water molecules in the transmembrane binding sites and a phosphate analogue (MgF(4)(2-)) in the phosphorylation site. The crystal structure shows that the beta-subunit has a critical role in K(+) binding (although its involvement has previously been suggested) and explains, at least partially, why the homologous Ca(2+)-ATPase counter-transports H(+) rather than K(+), despite the coordinating residues being almost identical.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shinoda, Takehiro -- Ogawa, Haruo -- Cornelius, Flemming -- Toyoshima, Chikashi -- England -- Nature. 2009 May 21;459(7245):446-50. doi: 10.1038/nature07939.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19458722" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calcium-Transporting ATPases/chemistry/metabolism ; Crystallography, X-Ray ; Fluorides/metabolism ; Humans ; Magnesium Compounds/metabolism ; Membrane Proteins/chemistry/metabolism ; Models, Molecular ; Phosphoproteins/chemistry/metabolism ; Phosphorylation ; Potassium/metabolism ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Salt Gland/enzymology ; Sharks ; Sodium-Potassium-Exchanging ATPase/*chemistry/metabolism ; Swine
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    A luminal epithelial stem cell that is a cell of origin for prostate cancer (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-09-11
    Description: In epithelial tissues, the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer has been poorly understood. Here we show that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3-1, marks a stem cell population that functions during prostate regeneration. Genetic lineage-marking demonstrates that rare luminal cells that express Nkx3-1 in the absence of testicular androgens (castration-resistant Nkx3-1-expressing cells, CARNs) are bipotential and can self-renew in vivo, and single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3-1 mutant mice in serial prostate regeneration suggest that Nkx3-1 is required for stem cell maintenance. Furthermore, targeted deletion of the Pten tumour suppressor gene in CARNs results in rapid carcinoma formation after androgen-mediated regeneration. These observations indicate that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2800362/" 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/PMC2800362/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xi -- Kruithof-de Julio, Marianna -- Economides, Kyriakos D -- Walker, David -- Yu, Hailong -- Halili, M Vivienne -- Hu, Ya-Ping -- Price, Sandy M -- Abate-Shen, Cory -- Shen, Michael M -- P01 CA154293/CA/NCI NIH HHS/ -- R01 DK076602/DK/NIDDK NIH HHS/ -- R01 DK076602-05/DK/NIDDK NIH HHS/ -- U01 CA084294/CA/NCI NIH HHS/ -- U01 CA084294-10/CA/NCI NIH HHS/ -- England -- Nature. 2009 Sep 24;461(7263):495-500. doi: 10.1038/nature08361. Epub 2009 Sep 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19741607" target="_blank"〉PubMed〈/a〉
    Keywords: Androgens/deficiency/metabolism ; Animals ; Castration ; Cell Differentiation ; Cell Division ; *Cell Lineage ; Cell Transformation, Neoplastic ; Epithelial Cells/metabolism/*pathology/transplantation ; Gene Expression Regulation ; Homeodomain Proteins/genetics/metabolism ; Kidney ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neoplastic Stem Cells/metabolism/*pathology/transplantation ; PTEN Phosphohydrolase/deficiency/genetics ; Prostatic Neoplasms/genetics/metabolism/*pathology ; Regeneration ; Transcription Factors/genetics/metabolism
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    Biochemistry: Anchors away (2009)
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    Publication Date: 2009-04-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Costi, Maria Paola -- Ferrari, Stefania -- England -- Nature. 2009 Apr 16;458(7240):840-1. doi: 10.1038/458840a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19370021" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Deoxyuracil Nucleotides/chemistry/metabolism ; Flavin-Adenine Dinucleotide/analogs & derivatives/chemistry/metabolism ; Flavins/chemistry/*metabolism ; Helicobacter pylori/enzymology/genetics ; Humans ; Thermotoga maritima/*enzymology/genetics/*metabolism ; Thymidine Monophosphate/*biosynthesis ; Thymidylate Synthase/antagonists & inhibitors/*genetics/*metabolism ; Uracil/metabolism
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    Protein structures: Structures of desire (2009)
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    Publication Date: 2009-05-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhattacharya, Ananyo -- England -- Nature. 2009 May 7;459(7243):24-7. doi: 10.1038/459024a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19424134" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteria/chemistry ; Crystallography, X-Ray ; Eukaryotic Cells/chemistry ; Humans ; *Models, Molecular ; Nuclear Pore/chemistry ; Proteins/*chemistry ; Receptor, Epidermal Growth Factor/chemistry ; Ribosomes/chemistry ; Spliceosomes/chemistry
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    Structure of the formate transporter FocA reveals a pentameric aquaporin-like channel (2009)
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    Publication Date: 2009-11-27
    Description: FocA is a representative member of the formate-nitrite transporter family, which transports short-chain acids in bacteria, archaea, fungi, algae and parasites. The structure and transport mechanism of the formate-nitrite transporter family remain unknown. Here we report the crystal structure of Escherichia coli FocA at 2.25 A resolution. FocA forms a symmetric pentamer, with each protomer consisting of six transmembrane segments. Despite a lack of sequence homology, the overall structure of the FocA protomer closely resembles that of aquaporin and strongly argues that FocA is a channel, rather than a transporter. Structural analysis identifies potentially important channel residues, defines the channel path and reveals two constriction sites. Unlike aquaporin, FocA is impermeable to water but allows the passage of formate. A structural and biochemical investigation provides mechanistic insights into the channel activity of FocA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Yi -- Huang, Yongjian -- Wang, Jiawei -- Cheng, Chao -- Huang, Weijiao -- Lu, Peilong -- Xu, Ya-Nan -- Wang, Pengye -- Yan, Nieng -- Shi, Yigong -- England -- Nature. 2009 Nov 26;462(7272):467-72. doi: 10.1038/nature08610.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Protein Science Laboratory, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940917" target="_blank"〉PubMed〈/a〉
    Keywords: Aquaporins/*chemistry/metabolism ; Crystallography, X-Ray ; Escherichia coli/chemistry/genetics/metabolism ; Escherichia coli Proteins/*chemistry/genetics/metabolism ; Formates/metabolism ; Liposomes/chemistry/metabolism ; Membrane Transport Proteins/*chemistry/genetics/metabolism ; Models, Molecular ; Molecular Mimicry ; Mutation ; Permeability ; Protein Structure, Quaternary ; Structure-Activity Relationship ; Water/analysis/metabolism
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    Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes (2009)
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    Publication Date: 2009-10-09
    Description: The slicer activity of the RNA-induced silencing complex resides within its Argonaute (Ago) component, in which the PIWI domain provides the catalytic residues governing guide-strand mediated site-specific cleavage of target RNA. Here we report on structures of ternary complexes of Thermus thermophilus Ago catalytic mutants with 5'-phosphorylated 21-nucleotide guide DNA and complementary target RNAs of 12, 15 and 19 nucleotides in length, which define the molecular basis for Mg(2+)-facilitated site-specific cleavage of the target. We observe pivot-like domain movements within the Ago scaffold on proceeding from nucleation to propagation steps of guide-target duplex formation, with duplex zippering beyond one turn of the helix requiring the release of the 3'-end of the guide from the PAZ pocket. Cleavage assays on targets of various lengths supported this model, and sugar-phosphate-backbone-modified target strands showed the importance of structural and catalytic divalent metal ions observed in the crystal structures.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880917/" 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/PMC2880917/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Yanli -- Juranek, Stefan -- Li, Haitao -- Sheng, Gang -- Wardle, Greg S -- Tuschl, Thomas -- Patel, Dinshaw J -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 AI068776/AI/NIAID NIH HHS/ -- R01 AI068776-04/AI/NIAID NIH HHS/ -- R01 AI068776-05/AI/NIAID NIH HHS/ -- R01 GM068476/GM/NIGMS NIH HHS/ -- R01 GM068476-05/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Oct 8;461(7265):754-61. doi: 10.1038/nature08434.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial-Sloan Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812667" target="_blank"〉PubMed〈/a〉
    Keywords: Base Pairing ; Biocatalysis ; Catalytic Domain/genetics ; Cations, Divalent/metabolism ; Crystallography, X-Ray ; DNA/chemistry/genetics/metabolism ; *Gene Silencing ; Magnesium/metabolism ; Models, Molecular ; Phosphorylation ; RNA/chemistry/genetics/*metabolism ; RNA-Induced Silencing Complex/*chemistry/genetics/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Thermus thermophilus/*enzymology/genetics
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    EBI2 mediates B cell segregation between the outer and centre follicle (2009)
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    Publication Date: 2009-07-15
    Description: B cell follicles are specialized microenvironments that support events necessary for humoral immunity. After antigen encounter, activated B cells initially seek T-cell help at the follicle-T-zone boundary and then move to interfollicular and T-zone distal (outer) regions of the follicle. Subsequently, some cells move to the follicle centre, become germinal centre B cells and undergo antibody affinity maturation. Although germinal centres within follicles were described in 1885 (ref. 12), the molecular cues mediating segregation of B cells between the outer and centre follicle have remained undefined. Here we present a role for the orphan G-protein-coupled receptor, Epstein-Barr virus induced molecule-2 (EBI2, also known as GPR183), in this process. EBI2 is expressed in mature B cells and increases in expression early after activation, before being downregulated in germinal centre B cells. EBI2 deficiency in mice led to a reduction in the early antibody response to a T-dependent antigen. EBI2-deficient B cells failed to move to the outer follicle at day 2 of activation, and instead were found in the follicle centre, whereas EBI2 overexpression was sufficient to promote B cell localization to the outer follicle. In mixed bone marrow chimaeras, EBI2-deficient B cells phenocopied germinal centre B cells in preferentially localizing to the follicle centre. When downregulation of EBI2 in wild-type B cells was antagonized, participation in the germinal centre reaction was impaired. These studies identify an important role for EBI2 in promoting B cell localization in the outer follicle, and show that differential expression of this receptor helps position B cells appropriately for mounting T-dependent antibody responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809436/" 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/PMC2809436/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pereira, Joao P -- Kelly, Lisa M -- Xu, Ying -- Cyster, Jason G -- R01 AI045073/AI/NIAID NIH HHS/ -- R01 AI045073-09/AI/NIAID NIH HHS/ -- R01 AI045073-10/AI/NIAID NIH HHS/ -- R01 AI045073-11/AI/NIAID NIH HHS/ -- R37 AI040098/AI/NIAID NIH HHS/ -- R37 AI040098-11/AI/NIAID NIH HHS/ -- R37 AI040098-12/AI/NIAID NIH HHS/ -- R37 AI040098-13/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Aug 27;460(7259):1122-6. doi: 10.1038/nature08226. Epub 2009 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Microbiology and Immunology, 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/19597478" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*cytology/*metabolism ; Chemokine CXCL13/metabolism ; Gene Expression Regulation ; Germinal Center/*cytology/*immunology ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Receptors, G-Protein-Coupled/deficiency/genetics/*metabolism
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    Regulation of adaptive behaviour during fasting by hypothalamic Foxa2 (2009)
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    Publication Date: 2009-12-04
    Description: The lateral hypothalamic area is considered the classic 'feeding centre', regulating food intake, arousal and motivated behaviour through the actions of orexin and melanin-concentrating hormone (MCH). These neuropeptides are inhibited in response to feeding-related signals and are released during fasting. However, the molecular mechanisms that regulate and integrate these signals remain poorly understood. Here we show that the forkhead box transcription factor Foxa2, a downstream target of insulin signalling, regulates the expression of orexin and MCH. During fasting, Foxa2 binds to MCH and orexin promoters and stimulates their expression. In fed and in hyperinsulinemic obese mice, insulin signalling leads to nuclear exclusion of Foxa2 and reduced expression of MCH and orexin. Constitutive activation of Foxa2 in the brain (Nes-Cre/+;Foxa2T156A(flox/flox) genotype) results in increased neuronal MCH and orexin expression and increased food consumption, metabolism and insulin sensitivity. Spontaneous physical activity of these animals in the fed state is significantly increased and is similar to that in fasted mice. Conditional activation of Foxa2 through the T156A mutation expression in the brain of obese mice also resulted in improved glucose homeostasis, decreased fat and increased lean body mass. Our results demonstrate that Foxa2 can act as a metabolic sensor in neurons of the lateral hypothalamic area to integrate metabolic signals, adaptive behaviour and physiological responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Silva, Jose P -- von Meyenn, Ferdinand -- Howell, Jessica -- Thorens, Bernard -- Wolfrum, Christian -- Stoffel, Markus -- England -- Nature. 2009 Dec 3;462(7273):646-50. doi: 10.1038/nature08589.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Rockefeller University, Laboratory of Metabolic Diseases, 1230 York Avenue, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19956259" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Psychological/*physiology ; Animals ; Behavior, Animal/*physiology ; Fasting/*physiology/*psychology ; Gene Expression Regulation/*physiology ; Hepatocyte Nuclear Factor 3-beta/*metabolism ; Hypothalamic Hormones/metabolism ; Hypothalamus/metabolism ; Insulin/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Melanins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Neuropeptides/metabolism ; Orexins ; Pituitary Hormones/metabolism ; Promoter Regions, Genetic/genetics
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    Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis (2009)
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    Publication Date: 2009-02-11
    Description: Osteoclasts are the only somatic cells with bone-resorbing capacity and, as such, they have a critical role not only in normal bone homeostasis (called 'bone remodelling') but also in the pathogenesis of bone destructive disorders such as rheumatoid arthritis and osteoporosis. A major focus of research in the field has been on gene regulation by osteoclastogenic cytokines such as receptor activator of NF-kappaB-ligand (RANKL, also known as TNFSF11) and TNF-alpha, both of which have been well documented to contribute to osteoclast terminal differentiation. A crucial process that has been less well studied is the trafficking of osteoclast precursors to and from the bone surface, where they undergo cell fusion to form the fully differentiated multinucleated cells that mediate bone resorption. Here we report that sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, induces chemotaxis and regulates the migration of osteoclast precursors not only in culture but also in vivo, contributing to the dynamic control of bone mineral homeostasis. Cells with the properties of osteoclast precursors express functional S1P(1) receptors and exhibit positive chemotaxis along an S1P gradient in vitro. Intravital two-photon imaging of bone tissues showed that a potent S1P(1) agonist, SEW2871, stimulated motility of osteoclast precursor-containing monocytoid populations in vivo. Osteoclast/monocyte (CD11b, also known as ITGAM) lineage-specific conditional S1P(1) knockout mice showed osteoporotic changes due to increased osteoclast attachment to the bone surface. Furthermore, treatment with the S1P(1) agonist FTY720 relieved ovariectomy-induced osteoporosis in mice by reducing the number of mature osteoclasts attached to the bone surface. Together, these data provide evidence that S1P controls the migratory behaviour of osteoclast precursors, dynamically regulating bone mineral homeostasis, and identifies a critical control point in osteoclastogenesis that may have potential as a therapeutic target.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785034/" 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/PMC2785034/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ishii, Masaru -- Egen, Jackson G -- Klauschen, Frederick -- Meier-Schellersheim, Martin -- Saeki, Yukihiko -- Vacher, Jean -- Proia, Richard L -- Germain, Ronald N -- ZIA AI000545-21/Intramural NIH HHS/ -- England -- Nature. 2009 Mar 26;458(7237):524-8. doi: 10.1038/nature07713. Epub 2009 Feb 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19204730" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Density/drug effects ; Bone Resorption ; Bone and Bones/anatomy & histology/*drug effects/metabolism ; Cell Line ; Cell Lineage ; Chemotaxis/*drug effects ; Female ; Fingolimod Hydrochloride ; Homeostasis/*drug effects ; Lysophospholipids/*pharmacology ; Mice ; Mice, Inbred C57BL ; Monocytes/*cytology/*drug effects/metabolism ; Osteoclasts/*cytology ; Osteoporosis/etiology/prevention & control ; Ovariectomy/adverse effects ; Propylene Glycols ; Receptors, Lysosphingolipid/genetics/metabolism ; Sphingosine/*analogs & derivatives/pharmacology
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    Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-23
    Description: Polyketides are a class of natural products with diverse structures and biological activities. The structural variability of aromatic products of fungal nonreducing, multidomain iterative polyketide synthases (NR-PKS group of IPKSs) results from regiospecific cyclizations of reactive poly-beta-keto intermediates. How poly-beta-keto species are synthesized and stabilized, how their chain lengths are determined, and, in particular, how specific cyclization patterns are controlled have been largely inaccessible and functionally unknown until recently. A product template (PT) domain is responsible for controlling specific aldol cyclization and aromatization of these mature polyketide precursors, but the mechanistic basis is unknown. Here we present the 1.8 A crystal structure and mutational studies of a dissected PT monodomain from PksA, the NR-PKS that initiates the biosynthesis of the potent hepatocarcinogen aflatoxin B(1) in Aspergillus parasiticus. Despite having minimal sequence similarity to known enzymes, the structure displays a distinct 'double hot dog' (DHD) fold. Co-crystal structures with palmitate or a bicyclic substrate mimic illustrate that PT can bind both linear and bicyclic polyketides. Docking and mutagenesis studies reveal residues important for substrate binding and catalysis, and identify a phosphopantetheine localization channel and a deep two-part interior binding pocket and reaction chamber. Sequence similarity and extensive conservation of active site residues in PT domains suggest that the mechanistic insights gleaned from these studies will prove general for this class of IPKSs, and lay a foundation for defining the molecular rules controlling NR-PKS cyclization specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872118/" 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/PMC2872118/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crawford, Jason M -- Korman, Tyler P -- Labonte, Jason W -- Vagstad, Anna L -- Hill, Eric A -- Kamari-Bidkorpeh, Oliver -- Tsai, Shiou-Chuan -- Townsend, Craig A -- ES001670/ES/NIEHS NIH HHS/ -- R01 GM076330/GM/NIGMS NIH HHS/ -- R01 GM076330-01A2/GM/NIGMS NIH HHS/ -- R01 GM076330-02/GM/NIGMS NIH HHS/ -- R01 GM076330-03/GM/NIGMS NIH HHS/ -- R01 GM100305/GM/NIGMS NIH HHS/ -- R37 AI014937/AI/NIAID NIH HHS/ -- R37 AI014937-31/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Oct 22;461(7267):1139-43. doi: 10.1038/nature08475.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Johns Hopkins University, Maryland 21218, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847268" target="_blank"〉PubMed〈/a〉
    Keywords: Aflatoxin B1/biosynthesis ; Anthracenes/metabolism ; Anthraquinones/metabolism ; Aspergillus/*enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Cyclization ; Models, Molecular ; Oxidation-Reduction ; Palmitic Acid/metabolism ; Polyketide Synthases/*chemistry/*metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship
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    Structural biology: Anticancer drug target pictured (2009)
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    Publication Date: 2009-01-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Waterman, Michael R -- England -- Nature. 2009 Jan 8;457(7226):159-60. doi: 10.1038/457159a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19129840" target="_blank"〉PubMed〈/a〉
    Keywords: Aromatase/*chemistry/*metabolism ; Aromatase Inhibitors/*pharmacology/therapeutic use ; Breast Neoplasms/*drug therapy/*enzymology/metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Estrogens/*biosynthesis ; Female ; Humans
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    An unexpected twist in viral capsid maturation (2009)
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    Publication Date: 2009-02-11
    Description: Lambda-like double-stranded (ds) DNA bacteriophage undergo massive conformational changes in their capsid shell during the packaging of their viral genomes. Capsid shells are complex organizations of hundreds of protein subunits that assemble into intricate quaternary complexes that ultimately are able to withstand over 50 atm of pressure during genome packaging. The extensive integration between subunits in capsids requires the formation of an intermediate complex, termed a procapsid, from which individual subunits can undergo the necessary refolding and structural rearrangements needed to transition to the more stable capsid. Although various mature capsids have been characterized at atomic resolution, no such procapsid structure is available for a dsDNA virus or bacteriophage. Here we present a procapsid X-ray structure at 3.65 A resolution, termed prohead II, of the lambda-like bacteriophage HK97, the mature capsid structure of which was previously solved to 3.44 A (ref. 2). A comparison of the two largely different capsid forms has unveiled an unprecedented expansion mechanism that describes the transition. Crystallographic and hydrogen/deuterium exchange data presented here demonstrate that the subunit tertiary structures are significantly different between the two states, with twisting and bending motions occurring in both helical and beta-sheet regions. We also identified subunit interactions at each three-fold axis of the capsid that are maintained throughout maturation. The interactions sustain capsid integrity during subunit refolding and provide a fixed hinge from which subunits undergo rotational and translational motions during maturation. Previously published calorimetric data of a closely related bacteriophage, P22, showed that capsid maturation was an exothermic process that resulted in a release of 90 kJ mol(-1) of energy. We propose that the major tertiary changes presented in this study reveal a structural basis for an exothermic maturation process probably present in many dsDNA bacteriophage and possibly viruses such as herpesvirus, which share the HK97 subunit fold.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765791/" 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/PMC2765791/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gertsman, Ilya -- Gan, Lu -- Guttman, Miklos -- Lee, Kelly -- Speir, Jeffrey A -- Duda, Robert L -- Hendrix, Roger W -- Komives, Elizabeth A -- Johnson, John E -- GM08326/GM/NIGMS NIH HHS/ -- R01 AI040101/AI/NIAID NIH HHS/ -- R01 AI040101-04/AI/NIAID NIH HHS/ -- R01 AI040101-14/AI/NIAID NIH HHS/ -- R01 AI40101/AI/NIAID NIH HHS/ -- R01 GM47795/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 2;458(7238):646-50. doi: 10.1038/nature07686. Epub 2009 Feb 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19204733" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid/*chemistry/*metabolism ; Capsid Proteins/chemistry/genetics/metabolism ; Crystallography, X-Ray ; Deuterium Exchange Measurement ; Models, Molecular ; Movement ; Protein Conformation ; Protein Folding ; Protein Multimerization ; Protein Subunits/chemistry/metabolism ; Siphoviridae/*chemistry/genetics/*growth & development ; Thermodynamics ; *Virus Assembly
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    Structural basis for androgen specificity and oestrogen synthesis in human aromatase (2009)
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    Publication Date: 2009-01-09
    Description: Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer. In a three-step process, each step requiring 1 mol of O(2), 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16alpha-hydroxytestosterone to oestrone, 17beta-oestradiol and 17beta,16alpha-oestriol, respectively. The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme's androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820300/" 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/PMC2820300/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ghosh, Debashis -- Griswold, Jennifer -- Erman, Mary -- Pangborn, Walter -- GM59450/GM/NIGMS NIH HHS/ -- GM62794/GM/NIGMS NIH HHS/ -- R01 GM062794/GM/NIGMS NIH HHS/ -- R01 GM062794-01A1/GM/NIGMS NIH HHS/ -- R01 GM062794-02/GM/NIGMS NIH HHS/ -- R01 GM062794-03/GM/NIGMS NIH HHS/ -- R01 GM062794-04/GM/NIGMS NIH HHS/ -- R01 GM086893/GM/NIGMS NIH HHS/ -- R01 GM086893-01A1/GM/NIGMS NIH HHS/ -- R21 GM059450/GM/NIGMS NIH HHS/ -- R21 GM059450-01/GM/NIGMS NIH HHS/ -- R21 GM059450-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jan 8;457(7226):219-23. doi: 10.1038/nature07614.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology, Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, New York 14203, USA. ghosh@hwi.buffalo.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19129847" target="_blank"〉PubMed〈/a〉
    Keywords: Androgens/*metabolism ; Aromatase/*chemistry/*metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Estrogens/*biosynthesis ; Female ; Humans ; Lipid Bilayers/metabolism ; Models, Molecular ; Placenta/enzymology ; Protein Binding ; Protein Conformation ; Substrate Specificity
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    Structure of the connexin 26 gap junction channel at 3.5 A resolution (2009)
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    Publication Date: 2009-04-03
    Description: Gap junctions consist of arrays of intercellular channels between adjacent cells that permit the exchange of ions and small molecules. Here we report the crystal structure of the gap junction channel formed by human connexin 26 (Cx26, also known as GJB2) at 3.5 A resolution, and discuss structural determinants of solute transport through the channel. The density map showed the two membrane-spanning hemichannels and the arrangement of the four transmembrane helices of the six protomers forming each hemichannel. The hemichannels feature a positively charged cytoplasmic entrance, a funnel, a negatively charged transmembrane pathway, and an extracellular cavity. The pore is narrowed at the funnel, which is formed by the six amino-terminal helices lining the wall of the channel, which thus determines the molecular size restriction at the channel entrance. The structure of the Cx26 gap junction channel also has implications for the gating of the channel by the transjunctional voltage.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maeda, Shoji -- Nakagawa, So -- Suga, Michihiro -- Yamashita, Eiki -- Oshima, Atsunori -- Fujiyoshi, Yoshinori -- Tsukihara, Tomitake -- England -- Nature. 2009 Apr 2;458(7238):597-602. doi: 10.1038/nature07869.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Protein Research, Osaka University, OLABB, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19340074" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Connexins/*chemistry/genetics ; Crystallography, X-Ray ; Gap Junctions/*chemistry ; Humans ; Ion Channel Gating ; Models, Molecular ; Protein Multimerization ; Protein Structure, Quaternary ; Spodoptera/virology
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    A role for Lin28 in primordial germ-cell development and germ-cell malignancy (2009)
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    Publication Date: 2009-07-07
    Description: The rarity and inaccessibility of the earliest primordial germ cells (PGCs) in the mouse embryo thwart efforts to investigate molecular mechanisms of germ-cell specification. stella (also called Dppa3) marks the rare founder population of the germ lineage. Here we differentiate mouse embryonic stem cells carrying a stella transgenic reporter into putative PGCs in vitro. The Stella(+) cells possess a transcriptional profile similar to embryo-derived PGCs, and like their counterparts in vivo, lose imprints in a time-dependent manner. Using inhibitory RNAs to screen candidate genes for effects on the development of Stella(+) cells in vitro, we discovered that Lin28, a negative regulator of let-7 microRNA processing, is essential for proper PGC development. Furthermore, we show that Blimp1 (also called Prdm1), a let-7 target and a master regulator of PGC specification, can rescue the effect of Lin28 deficiency during PGC development, thereby establishing a mechanism of action for Lin28 during PGC specification. Overexpression of Lin28 promotes formation of Stella(+) cells in vitro and PGCs in chimaeric embryos, and is associated with human germ-cell tumours. The differentiation of putative PGCs from embryonic stem cells in vitro recapitulates the early stages of gamete development in vivo, and provides an accessible system for discovering novel genes involved in germ-cell development and malignancy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729657/" 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/PMC2729657/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉West, Jason A -- Viswanathan, Srinivas R -- Yabuuchi, Akiko -- Cunniff, Kerianne -- Takeuchi, Ayumu -- Park, In-Hyun -- Sero, Julia E -- Zhu, Hao -- Perez-Atayde, Antonio -- Frazier, A Lindsay -- Surani, M Azim -- Daley, George Q -- DP1 OD000256/OD/NIH HHS/ -- DP1 OD000256-01/OD/NIH HHS/ -- G0300723/Medical Research Council/United Kingdom -- G0800784/Medical Research Council/United Kingdom -- T32 CA009172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Aug 13;460(7257):909-13. doi: 10.1038/nature08210. Epub 2009 Jul 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Pediatric Hematology/Oncology, Children's Hospital Boston and the Dana-Farber Cancer Institute, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19578360" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cell Line ; Embryonic Stem Cells/cytology/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Germ Cells/*cytology/*metabolism/pathology ; Humans ; Mice ; Mice, Inbred C57BL ; Neoplasms, Germ Cell and Embryonal/genetics/*metabolism/*pathology ; RNA-Binding Proteins/genetics/*metabolism ; Repressor Proteins/genetics/metabolism ; Transcription Factors/metabolism ; Transgenes
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    A mechanosensitive transcriptional mechanism that controls angiogenesis (2009)
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    Publication Date: 2009-02-27
    Description: Angiogenesis is controlled by physical interactions between cells and extracellular matrix as well as soluble angiogenic factors, such as VEGF. However, the mechanism by which mechanical signals integrate with other microenvironmental cues to regulate neovascularization remains unknown. Here we show that the Rho inhibitor, p190RhoGAP (also known as GRLF1), controls capillary network formation in vitro in human microvascular endothelial cells and retinal angiogenesis in vivo by modulating the balance of activities between two antagonistic transcription factors, TFII-I (also known as GTF2I) and GATA2, that govern gene expression of the VEGF receptor VEGFR2 (also known as KDR). Moreover, this new angiogenesis signalling pathway is sensitive to extracellular matrix elasticity as well as soluble VEGF. This is, to our knowledge, the first known functional cross-antagonism between transcription factors that controls tissue morphogenesis, and that responds to both mechanical and chemical cues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708674/" 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/PMC2708674/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mammoto, Akiko -- Connor, Kip M -- Mammoto, Tadanori -- Yung, Chong Wing -- Huh, Dongeun -- Aderman, Christopher M -- Mostoslavsky, Gustavo -- Smith, Lois E H -- Ingber, Donald E -- P01 CA045548/CA/NCI NIH HHS/ -- P01 CA045548-22/CA/NCI NIH HHS/ -- England -- Nature. 2009 Feb 26;457(7233):1103-8. doi: 10.1038/nature07765.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vascular Biology Program, Department of Pathology & Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242469" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Cell Line ; Endothelial Cells/metabolism ; Endothelium, Vascular/cytology/growth & development ; Extracellular Matrix/metabolism ; GATA2 Transcription Factor/metabolism ; Gene Knockdown Techniques ; Guanine Nucleotide Exchange Factors/deficiency/genetics/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Neovascularization, Physiologic/*genetics/physiology ; Repressor Proteins/genetics/metabolism ; Retinal Vessels/growth & development/metabolism ; Signal Transduction ; Transcription Factors/deficiency/genetics/*metabolism ; Transcription Factors, TFII/metabolism ; *Transcription, Genetic ; Up-Regulation ; Vascular Endothelial Growth Factor A/metabolism ; Vascular Endothelial Growth Factor Receptor-2/biosynthesis/genetics/metabolism
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    Adult mice generated from induced pluripotent stem cells (2009)
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    Publication Date: 2009-08-13
    Description: Recent landmark experiments have shown that transient overexpression of a small number of transcription factors can reprogram differentiated cells into induced pluripotent stem (iPS) cells that resemble embryonic stem (ES) cells. These iPS cells hold great promise for medicine because they have the potential to generate patient-specific cell types for cell replacement therapy and produce in vitro models of disease, without requiring embryonic tissues or oocytes. Although current iPS cell lines resemble ES cells, they have not passed the most stringent test of pluripotency by generating full-term or adult mice in tetraploid complementation assays, raising questions as to whether they are sufficiently potent to generate all of the cell types in an organism. Whether this difference between iPS and ES cells reflects intrinsic limitations of direct reprogramming is not known. Here we report fertile adult mice derived entirely from iPS cells that we generated by inducible genetic reprogramming of mouse embryonic fibroblasts. Producing adult mice derived entirely from a reprogrammed fibroblast shows that all features of a differentiated cell can be restored to an embryonic level of pluripotency without exposure to unknown ooplasmic factors. Comparing these fully pluripotent iPS cell lines to less developmentally potent lines may reveal molecular markers of different pluripotent states. Furthermore, mice derived entirely from iPS cells will provide a new resource to assess the functional and genomic stability of cells and tissues derived from iPS cells, which is important to validate their utility in cell replacement therapy and research applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boland, Michael J -- Hazen, Jennifer L -- Nazor, Kristopher L -- Rodriguez, Alberto R -- Gifford, Wesley -- Martin, Greg -- Kupriyanov, Sergey -- Baldwin, Kristin K -- England -- Nature. 2009 Sep 3;461(7260):91-4. doi: 10.1038/nature08310.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19672243" target="_blank"〉PubMed〈/a〉
    Keywords: *Aging ; Animals ; Cell Dedifferentiation ; Cell Differentiation ; Cell Line ; Cell Lineage ; Embryo, Mammalian/cytology/embryology/metabolism ; Female ; Fibroblasts/cytology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Pluripotent Stem Cells/cytology/*physiology ; Pregnancy ; *Reproductive Techniques ; Survival Rate
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    Crystal structure of human spliceosomal U1 snRNP at 5.5 A resolution (2009)
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    Publication Date: 2009-03-28
    Description: Human spliceosomal U1 small nuclear ribonucleoprotein particles (snRNPs), which consist of U1 small nuclear RNA and ten proteins, recognize the 5' splice site within precursor messenger RNAs and initiate the assembly of the spliceosome for intron excision. An electron density map of the functional core of U1 snRNP at 5.5 A resolution has enabled us to build the RNA and, in conjunction with site-specific labelling of individual proteins, to place the seven Sm proteins, U1-C and U1-70K into the map. Here we present the detailed structure of a spliceosomal snRNP, revealing a hierarchical network of intricate interactions between subunits. A striking feature is the amino (N)-terminal polypeptide of U1-70K, which extends over a distance of 180 A from its RNA binding domain, wraps around the core domain consisting of the seven Sm proteins and finally contacts U1-C, which is crucial for 5'-splice-site recognition. The structure of U1 snRNP provides insights into U1 snRNP assembly and suggests a possible mechanism of 5'-splice-site recognition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673513/" 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/PMC2673513/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pomeranz Krummel, Daniel A -- Oubridge, Chris -- Leung, Adelaine K W -- Li, Jade -- Nagai, Kiyoshi -- MC_U105184330/Medical Research Council/United Kingdom -- U.1051.04.016(78933)/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2009 Mar 26;458(7237):475-80. doi: 10.1038/nature07851.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19325628" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Humans ; Models, Biological ; Models, Molecular ; Nucleic Acid Conformation ; Protein Folding ; Protein Structure, Tertiary ; RNA Splice Sites ; RNA Splicing ; RNA, Small Nuclear/chemistry ; Ribonucleoprotein, U1 Small Nuclear/*chemistry/metabolism ; Spliceosomes/*chemistry ; Zinc Fingers
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  • 95
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    X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor (2009)
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    Publication Date: 2009-12-01
    Description: Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of glutamate. Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic glutamate receptor are unknown. Here we report the crystal structure of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3.6 A resolution in complex with a competitive antagonist. The receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry. A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits. Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA (N-methyl-d-aspartate) receptors have a similar architecture, with subunits arranged in a 1-2-1-2 pattern. We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861655/" 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/PMC2861655/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sobolevsky, Alexander I -- Rosconi, Michael P -- Gouaux, Eric -- F32 NS049767-05/NS/NINDS NIH HHS/ -- R01 NS038631/NS/NINDS NIH HHS/ -- R01 NS038631-06/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 10;462(7274):745-56. doi: 10.1038/nature08624. Epub .〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19946266" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Crystallization ; Crystallography, X-Ray ; Ion Channel Gating ; Models, Molecular ; Potassium Channels/chemistry/metabolism ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Rats ; Receptors, AMPA/antagonists & inhibitors/*chemistry/*metabolism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Role of the polycomb protein EED in the propagation of repressive histone marks (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-09-22
    Description: Polycomb group proteins have an essential role in the epigenetic maintenance of repressive chromatin states. The gene-silencing activity of the Polycomb repressive complex 2 (PRC2) depends on its ability to trimethylate lysine 27 of histone H3 (H3K27) by the catalytic SET domain of the EZH2 subunit, and at least two other subunits of the complex: SUZ12 and EED. Here we show that the carboxy-terminal domain of EED specifically binds to histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks, and that this leads to the allosteric activation of the methyltransferase activity of PRC2. Mutations in EED that prevent it from recognizing repressive trimethyl-lysine marks abolish the activation of PRC2 in vitro and, in Drosophila, reduce global methylation and disrupt development. These findings suggest a model for the propagation of the H3K27me3 mark that accounts for the maintenance of repressive chromatin domains and for the transmission of a histone modification from mother to daughter cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772642/" 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/PMC3772642/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Margueron, Raphael -- Justin, Neil -- Ohno, Katsuhito -- Sharpe, Miriam L -- Son, Jinsook -- Drury, William J 3rd -- Voigt, Philipp -- Martin, Stephen R -- Taylor, William R -- De Marco, Valeria -- Pirrotta, Vincenzo -- Reinberg, Danny -- Gamblin, Steven J -- GM064844/GM/NIGMS NIH HHS/ -- GM37120/GM/NIGMS NIH HHS/ -- MC_U117584222/Medical Research Council/United Kingdom -- R01 GM064844/GM/NIGMS NIH HHS/ -- R01 GM064844-08/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Medical Research Council/United Kingdom -- England -- Nature. 2009 Oct 8;461(7265):762-7. doi: 10.1038/nature08398. Epub 2009 Sep 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Biochemistry, New York University Medical School, 522 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/19767730" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Cell Line ; Chromatin/chemistry/*genetics/metabolism ; Crystallography, X-Ray ; Drosophila Proteins/chemistry/genetics/*metabolism ; Drosophila melanogaster/*genetics/growth & development/*metabolism ; Enzyme Activation ; *Gene Silencing ; Histone-Lysine N-Methyltransferase/chemistry/metabolism ; Histones/*chemistry/*metabolism ; Lysine/analogs & derivatives/metabolism ; Methylation ; Models, Biological ; Models, Molecular ; Nuclear Proteins/metabolism ; Nucleosomes/chemistry/genetics/metabolism ; Polycomb Repressive Complex 2 ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/chemistry/genetics/*metabolism ; Substrate Specificity
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    XIAP discriminates between type I and type II FAS-induced apoptosis (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-07-25
    Description: FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of 'effector caspases' by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956120/" 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/PMC2956120/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jost, Philipp J -- Grabow, Stephanie -- Gray, Daniel -- McKenzie, Mark D -- Nachbur, Ueli -- Huang, David C S -- Bouillet, Philippe -- Thomas, Helen E -- Borner, Christoph -- Silke, John -- Strasser, Andreas -- Kaufmann, Thomas -- CA 43540/CA/NCI NIH HHS/ -- CA 80188/CA/NCI NIH HHS/ -- R01 CA043540/CA/NCI NIH HHS/ -- R01 CA043540-09/CA/NCI NIH HHS/ -- R01 CA043540-22/CA/NCI NIH HHS/ -- R01 CA080188-01/CA/NCI NIH HHS/ -- R01 CA080188-08/CA/NCI NIH HHS/ -- England -- Nature. 2009 Aug 20;460(7258):1035-9. doi: 10.1038/nature08229. Epub 2009 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Walter and Eliza Hall Institute of Medical Research, Melbourne University, Parkville, Victoria 3050, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19626005" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD95/antagonists & inhibitors/immunology/*metabolism ; *Apoptosis ; BH3 Interacting Domain Death Agonist Protein/deficiency/genetics ; Biomimetic Materials/pharmacology ; Caspase Inhibitors ; Enzyme Activation ; Fas Ligand Protein/metabolism ; Female ; Hepatitis/metabolism/pathology ; Hepatocytes/cytology/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Signal Transduction ; Thymus Gland/cytology/drug effects ; X-Linked Inhibitor of Apoptosis Protein/antagonists & ; inhibitors/deficiency/genetics/*metabolism
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    Structural biology: Tracing Argonaute binding (2009)
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    Publication Date: 2009-10-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bouasker, Samir -- Simard, Martin J -- England -- Nature. 2009 Oct 8;461(7265):743-4. doi: 10.1038/461743a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812664" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Catalytic Domain/genetics ; Crystallography, X-Ray ; DNA/metabolism ; *Gene Silencing ; Magnesium/metabolism ; RNA/*metabolism ; RNA-Induced Silencing Complex/*chemistry/*metabolism ; Thermus thermophilus/*enzymology
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  • 99
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    Encounter and extrusion of an intrahelical lesion by a DNA repair enzyme (2009)
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    Publication Date: 2009-12-17
    Description: How living systems detect the presence of genotoxic damage embedded in a million-fold excess of undamaged DNA is an unresolved question in biology. Here we have captured and structurally elucidated a base-excision DNA repair enzyme, MutM, at the stage of initial encounter with a damaged nucleobase, 8-oxoguanine (oxoG), nested within a DNA duplex. Three structures of intrahelical oxoG-encounter complexes are compared with sequence-matched structures containing a normal G base in place of an oxoG lesion. Although the protein-DNA interfaces in the matched complexes differ by only two atoms-those that distinguish oxoG from G-their pronounced structural differences indicate that MutM can detect a lesion in DNA even at the earliest stages of encounter. All-atom computer simulations show the pathway by which encounter of the enzyme with the lesion causes extrusion from the DNA duplex, and they elucidate the critical free energy difference between oxoG and G along the extrusion pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951314/" 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/PMC2951314/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qi, Yan -- Spong, Marie C -- Nam, Kwangho -- Banerjee, Anirban -- Jiralerspong, Sao -- Karplus, Martin -- Verdine, Gregory L -- CA100742/CA/NCI NIH HHS/ -- GM030804/GM/NIGMS NIH HHS/ -- GM044853/GM/NIGMS NIH HHS/ -- GM047467/GM/NIGMS NIH HHS/ -- P01 GM047467/GM/NIGMS NIH HHS/ -- P01 GM047467-100006/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 CA100742/CA/NCI NIH HHS/ -- R01 CA100742-06A1/CA/NCI NIH HHS/ -- R01 GM044853/GM/NIGMS NIH HHS/ -- R01 GM044853-18/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 10;462(7274):762-6. doi: 10.1038/nature08561.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate Program in Biophysics, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010681" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Computer Simulation ; Crystallography, X-Ray ; *DNA Damage ; *DNA Repair ; DNA-Formamidopyrimidine Glycosylase/genetics/*metabolism ; Genome, Bacterial/genetics ; Geobacillus stearothermophilus/*enzymology/genetics ; Guanine/*analogs & derivatives/metabolism ; Models, Biological ; Models, Molecular ; Molecular Dynamics Simulation ; Mutation/genetics ; Thermodynamics
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    Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-30
    Description: A growing body of evidence indicates that resolution of acute inflammation is an active process. Resolvins are a new family of lipid mediators enzymatically generated within resolution networks that possess unique and specific functions to orchestrate catabasis, the phase in which disease declines. Resolvin D2 (RvD2) was originally identified in resolving exudates, yet its individual contribution in resolution remained to be elucidated. Here, we establish RvD2's potent stereoselective actions in reducing excessive neutrophil trafficking to inflammatory loci. RvD2 decreased leukocyte-endothelial interactions in vivo by endothelial-dependent nitric oxide production, and by direct modulation of leukocyte adhesion receptor expression. In mice with microbial sepsis initiated by caecal ligation and puncture, RvD2 sharply decreased both local and systemic bacterial burden, excessive cytokine production and neutrophil recruitment, while increasing peritoneal mononuclear cells and macrophage phagocytosis. These multi-level pro-resolving actions of RvD2 translate to increased survival from sepsis induced by caecal ligation and puncture and surgery. Together, these results identify RvD2 as a potent endogenous regulator of excessive inflammatory responses that acts via multiple cellular targets to stimulate resolution and preserve immune vigilance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779525/" 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/PMC2779525/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spite, Matthew -- Norling, Lucy V -- Summers, Lisa -- Yang, Rong -- Cooper, Dianne -- Petasis, Nicos A -- Flower, Roderick J -- Perretti, Mauro -- Serhan, Charles N -- 085903/Z/08/Wellcome Trust/United Kingdom -- 086867/Z/08/Z/Wellcome Trust/United Kingdom -- 18103/Arthritis Research UK/United Kingdom -- 18445/Arthritis Research UK/United Kingdom -- F32 HL087526/HL/NHLBI NIH HHS/ -- F32 HL087526-02/HL/NHLBI NIH HHS/ -- GM-38765/GM/NIGMS NIH HHS/ -- HL087526/HL/NHLBI NIH HHS/ -- P50 DE016191/DE/NIDCR NIH HHS/ -- P50 DE016191-05/DE/NIDCR NIH HHS/ -- P50-DE016191/DE/NIDCR NIH HHS/ -- R37 GM038765/GM/NIGMS NIH HHS/ -- R37 GM038765-23/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Oct 29;461(7268):1287-91. doi: 10.1038/nature08541.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19865173" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Docosahexaenoic Acids/chemical synthesis/chemistry/*metabolism ; Endothelial Cells/metabolism ; Escherichia coli/growth & development/isolation & purification ; Humans ; Inflammation/immunology/metabolism/microbiology ; Leukocytes/*immunology/*metabolism ; Macrophages/immunology/microbiology ; Male ; Mice ; Mice, Inbred C57BL ; Nitric Oxide/metabolism ; Peritoneal Cavity/cytology/microbiology ; Peritonitis/immunology/metabolism/microbiology ; Phagocytosis ; Reactive Oxygen Species/metabolism ; Sepsis/*immunology/metabolism/*microbiology
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