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  • Models, Molecular  (60)
  • Signal Transduction  (22)
  • Nature Publishing Group (NPG)  (81)
  • 2005-2009  (81)
  • 1940-1944
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  • 1
    Publication Date: 2008-10-17
    Description: Diatoms are photosynthetic secondary endosymbionts found throughout marine and freshwater environments, and are believed to be responsible for around one-fifth of the primary productivity on Earth. The genome sequence of the marine centric diatom Thalassiosira pseudonana was recently reported, revealing a wealth of information about diatom biology. Here we report the complete genome sequence of the pennate diatom Phaeodactylum tricornutum and compare it with that of T. pseudonana to clarify evolutionary origins, functional significance and ubiquity of these features throughout diatoms. In spite of the fact that the pennate and centric lineages have only been diverging for 90 million years, their genome structures are dramatically different and a substantial fraction of genes ( approximately 40%) are not shared by these representatives of the two lineages. Analysis of molecular divergence compared with yeasts and metazoans reveals rapid rates of gene diversification in diatoms. Contributing factors include selective gene family expansions, differential losses and gains of genes and introns, and differential mobilization of transposable elements. Most significantly, we document the presence of hundreds of genes from bacteria. More than 300 of these gene transfers are found in both diatoms, attesting to their ancient origins, and many are likely to provide novel possibilities for metabolite management and for perception of environmental signals. These findings go a long way towards explaining the incredible diversity and success of the diatoms in contemporary oceans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bowler, Chris -- Allen, Andrew E -- Badger, Jonathan H -- Grimwood, Jane -- Jabbari, Kamel -- Kuo, Alan -- Maheswari, Uma -- Martens, Cindy -- Maumus, Florian -- Otillar, Robert P -- Rayko, Edda -- Salamov, Asaf -- Vandepoele, Klaas -- Beszteri, Bank -- Gruber, Ansgar -- Heijde, Marc -- Katinka, Michael -- Mock, Thomas -- Valentin, Klaus -- Verret, Frederic -- Berges, John A -- Brownlee, Colin -- Cadoret, Jean-Paul -- Chiovitti, Anthony -- Choi, Chang Jae -- Coesel, Sacha -- De Martino, Alessandra -- Detter, J Chris -- Durkin, Colleen -- Falciatore, Angela -- Fournet, Jerome -- Haruta, Miyoshi -- Huysman, Marie J J -- Jenkins, Bethany D -- Jiroutova, Katerina -- Jorgensen, Richard E -- Joubert, Yolaine -- Kaplan, Aaron -- Kroger, Nils -- Kroth, Peter G -- La Roche, Julie -- Lindquist, Erica -- Lommer, Markus -- Martin-Jezequel, Veronique -- Lopez, Pascal J -- Lucas, Susan -- Mangogna, Manuela -- McGinnis, Karen -- Medlin, Linda K -- Montsant, Anton -- Oudot-Le Secq, Marie-Pierre -- Napoli, Carolyn -- Obornik, Miroslav -- Parker, Micaela Schnitzler -- Petit, Jean-Louis -- Porcel, Betina M -- Poulsen, Nicole -- Robison, Matthew -- Rychlewski, Leszek -- Rynearson, Tatiana A -- Schmutz, Jeremy -- Shapiro, Harris -- Siaut, Magali -- Stanley, Michele -- Sussman, Michael R -- Taylor, Alison R -- Vardi, Assaf -- von Dassow, Peter -- Vyverman, Wim -- Willis, Anusuya -- Wyrwicz, Lucjan S -- Rokhsar, Daniel S -- Weissenbach, Jean -- Armbrust, E Virginia -- Green, Beverley R -- Van de Peer, Yves -- Grigoriev, Igor V -- England -- Nature. 2008 Nov 13;456(7219):239-44. doi: 10.1038/nature07410. Epub 2008 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS UMR8186, Department of Biology, Ecole Normale Superieure, 46 rue d'Ulm, 75005 Paris, France. cbowler@biologie.ens.fr〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18923393" target="_blank"〉PubMed〈/a〉
    Keywords: DNA, Algal/analysis ; Diatoms/*genetics ; *Evolution, Molecular ; Genes, Bacterial/genetics ; Genome/*genetics ; Molecular Sequence Data ; Protein Structure, Tertiary ; Sequence Homology, Amino Acid ; Signal Transduction
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  • 2
    Publication Date: 2009-12-17
    Description: The majority of excitatory synapses in the mammalian CNS (central nervous system) are formed on dendritic spines, and spine morphology and distribution are critical for synaptic transmission, synaptic integration and plasticity. Here, we show that a secreted semaphorin, Sema3F, is a negative regulator of spine development and synaptic structure. Mice with null mutations in genes encoding Sema3F, and its holoreceptor components neuropilin-2 (Npn-2, also known as Nrp2) and plexin A3 (PlexA3, also known as Plxna3), exhibit increased dentate gyrus (DG) granule cell (GC) and cortical layer V pyramidal neuron spine number and size, and also aberrant spine distribution. Moreover, Sema3F promotes loss of spines and excitatory synapses in dissociated neurons in vitro, and in Npn-2(-/-) brain slices cortical layer V and DG GCs exhibit increased mEPSC (miniature excitatory postsynaptic current) frequency. In contrast, a distinct Sema3A-Npn-1/PlexA4 signalling cascade controls basal dendritic arborization in layer V cortical neurons, but does not influence spine morphogenesis or distribution. These disparate effects of secreted semaphorins are reflected in the restricted dendritic localization of Npn-2 to apical dendrites and of Npn-1 (also known as Nrp1) to all dendrites of cortical pyramidal neurons. Therefore, Sema3F signalling controls spine distribution along select dendritic processes, and distinct secreted semaphorin signalling events orchestrate CNS connectivity through the differential control of spine morphogenesis, synapse formation, and the elaboration of dendritic morphology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842559/" 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/PMC2842559/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tran, Tracy S -- Rubio, Maria E -- Clem, Roger L -- Johnson, Dontais -- Case, Lauren -- Tessier-Lavigne, Marc -- Huganir, Richard L -- Ginty, David D -- Kolodkin, Alex L -- F32 NS051003/NS/NINDS NIH HHS/ -- P50 MH06883/MH/NIMH NIH HHS/ -- R01 DC-006881/DC/NIDCD NIH HHS/ -- R01 MH059199/MH/NIMH NIH HHS/ -- R01 MH059199-07/MH/NIMH NIH HHS/ -- R01 MH059199-08/MH/NIMH NIH HHS/ -- R01 MH059199-09/MH/NIMH NIH HHS/ -- R01 MH059199-10/MH/NIMH NIH HHS/ -- R01 MH59199/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 24;462(7276):1065-9. doi: 10.1038/nature08628. Epub 2009 Dec 13.〈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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010807" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Central Nervous System/cytology/drug effects/*growth & ; development/*metabolism/ultrastructure ; Female ; Gene Expression Regulation, Developmental ; Male ; Mice ; Mice, Knockout ; Neuropilin-1/metabolism ; Neuropilin-2/metabolism ; Pyramidal Cells/*cytology/drug effects/*growth & development/ultrastructure ; Recombinant Proteins/pharmacology ; Semaphorins/genetics/*metabolism/pharmacology ; Signal Transduction ; Synapses/drug effects/*physiology/ultrastructure
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  • 3
    Publication Date: 2008-08-23
    Description: As arguably the simplest free-living animals, placozoans may represent a primitive metazoan form, yet their biology is poorly understood. Here we report the sequencing and analysis of the approximately 98 million base pair nuclear genome of the placozoan Trichoplax adhaerens. Whole-genome phylogenetic analysis suggests that placozoans belong to a 'eumetazoan' clade that includes cnidarians and bilaterians, with sponges as the earliest diverging animals. The compact genome shows conserved gene content, gene structure and synteny in relation to the human and other complex eumetazoan genomes. Despite the apparent cellular and organismal simplicity of Trichoplax, its genome encodes a rich array of transcription factor and signalling pathway genes that are typically associated with diverse cell types and developmental processes in eumetazoans, motivating further searches for cryptic cellular complexity and/or as yet unobserved life history stages.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Srivastava, Mansi -- Begovic, Emina -- Chapman, Jarrod -- Putnam, Nicholas H -- Hellsten, Uffe -- Kawashima, Takeshi -- Kuo, Alan -- Mitros, Therese -- Salamov, Asaf -- Carpenter, Meredith L -- Signorovitch, Ana Y -- Moreno, Maria A -- Kamm, Kai -- Grimwood, Jane -- Schmutz, Jeremy -- Shapiro, Harris -- Grigoriev, Igor V -- Buss, Leo W -- Schierwater, Bernd -- Dellaporta, Stephen L -- Rokhsar, Daniel S -- England -- Nature. 2008 Aug 21;454(7207):955-60. doi: 10.1038/nature07191.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Integrative Genomics and Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. msrivast@berkeley.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18719581" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Adhesion ; Conserved Sequence ; Extracellular Matrix/genetics ; Gene Expression Regulation, Developmental ; Genome/*genetics ; Germ Cells ; Humans ; Invertebrates/anatomy & histology/classification/*genetics/*physiology ; Phylogeny ; Reproduction/genetics ; Sequence Analysis, DNA ; Sex ; Signal Transduction ; Synteny ; Transcription Factors/genetics
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  • 4
    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
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  • 5
    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
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  • 6
    Publication Date: 2008-11-18
    Description: Pentraxins are a family of ancient innate immune mediators conserved throughout evolution. The classical pentraxins include serum amyloid P component (SAP) and C-reactive protein, which are two of the acute-phase proteins synthesized in response to infection. Both recognize microbial pathogens and activate the classical complement pathway through C1q (refs 3 and 4). More recently, members of the pentraxin family were found to interact with cell-surface Fcgamma receptors (FcgammaR) and activate leukocyte-mediated phagocytosis. Here we describe the structural mechanism for pentraxin's binding to FcgammaR and its functional activation of FcgammaR-mediated phagocytosis and cytokine secretion. The complex structure between human SAP and FcgammaRIIa reveals a diagonally bound receptor on each SAP pentamer with both D1 and D2 domains of the receptor contacting the ridge helices from two SAP subunits. The 1:1 stoichiometry between SAP and FcgammaRIIa infers the requirement for multivalent pathogen binding for receptor aggregation. Mutational and binding studies show that pentraxins are diverse in their binding specificity for FcgammaR isoforms but conserved in their recognition structure. The shared binding site for SAP and IgG results in competition for FcgammaR binding and the inhibition of immune-complex-mediated phagocytosis by soluble pentraxins. These results establish antibody-like functions for pentraxins in the FcgammaR pathway, suggest an evolutionary overlap between the innate and adaptive immune systems, and have new therapeutic implications for autoimmune diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688732/" 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/PMC2688732/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Jinghua -- Marnell, Lorraine L -- Marjon, Kristopher D -- Mold, Carolyn -- Du Clos, Terry W -- Sun, Peter D -- R01 AI28358/AI/NIAID NIH HHS/ -- T32 AI007538/AI/NIAID NIH HHS/ -- Z01 AI000853-09/Intramural NIH HHS/ -- England -- Nature. 2008 Dec 18;456(7224):989-92. doi: 10.1038/nature07468. Epub 2008 Nov 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19011614" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Binding, Competitive ; C-Reactive Protein/chemistry/*immunology/*metabolism ; Crystallography, X-Ray ; Cytokines/immunology/secretion ; Humans ; Immunity, Innate/*immunology ; Immunoglobulin G/immunology/metabolism ; Macrophages/cytology/immunology ; Models, Molecular ; Phagocytosis ; Protein Conformation ; Receptors, IgG/chemistry/*immunology/*metabolism ; Serum Amyloid P-Component/chemistry/*immunology/*metabolism
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  • 7
    Publication Date: 2008-02-26
    Description: The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743172/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743172/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gonzalez-Maeso, Javier -- Ang, Rosalind L -- Yuen, Tony -- Chan, Pokman -- Weisstaub, Noelia V -- Lopez-Gimenez, Juan F -- Zhou, Mingming -- Okawa, Yuuya -- Callado, Luis F -- Milligan, Graeme -- Gingrich, Jay A -- Filizola, Marta -- Meana, J Javier -- Sealfon, Stuart C -- G9811527/Medical Research Council/United Kingdom -- P01 DA012923/DA/NIDA NIH HHS/ -- P01 DA012923-06A10004/DA/NIDA NIH HHS/ -- T32 DA007135/DA/NIDA NIH HHS/ -- T32 DA007135-25S1/DA/NIDA NIH HHS/ -- T32 GM062754/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Mar 6;452(7183):93-7. doi: 10.1038/nature06612. Epub 2008 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. javier.maeso@mssm.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18297054" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/cytology/metabolism ; Cell Line ; Cells, Cultured ; Down-Regulation ; Hallucinogens/metabolism/pharmacology ; Humans ; Mice ; Models, Molecular ; Multiprotein Complexes/chemistry/genetics/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Psychotic Disorders/drug therapy/genetics/*metabolism ; Receptor, Serotonin, 5-HT2A/analysis/deficiency/genetics/*metabolism ; Receptors, Metabotropic Glutamate/analysis/antagonists & ; inhibitors/genetics/*metabolism ; Schizophrenia/metabolism ; Signal Transduction/drug effects ; Up-Regulation
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  • 8
    Publication Date: 2008-02-01
    Description: The M2 protein from influenza A virus is a pH-activated proton channel that mediates acidification of the interior of viral particles entrapped in endosomes. M2 is the target of the anti-influenza drugs amantadine and rimantadine; recently, resistance to these drugs in humans, birds and pigs has reached more than 90% (ref. 1). Here we describe the crystal structure of the transmembrane-spanning region of the homotetrameric protein in the presence and absence of the channel-blocking drug amantadine. pH-dependent structural changes occur near a set of conserved His and Trp residues that are involved in proton gating. The drug-binding site is lined by residues that are mutated in amantadine-resistant viruses. Binding of amantadine physically occludes the pore, and might also perturb the pK(a) of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889492/" 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/PMC3889492/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stouffer, Amanda L -- Acharya, Rudresh -- Salom, David -- Levine, Anna S -- Di Costanzo, Luigi -- Soto, Cinque S -- Tereshko, Valentina -- Nanda, Vikas -- Stayrook, Steven -- DeGrado, William F -- R37 GM054616/GM/NIGMS NIH HHS/ -- T32 GM008275/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Jan 31;451(7178):596-9. doi: 10.1038/nature06528.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18235504" target="_blank"〉PubMed〈/a〉
    Keywords: Amantadine/chemistry/metabolism/pharmacology ; Crystallography, X-Ray ; Drug Resistance, Viral/genetics ; Histidine/metabolism ; Hydrogen-Ion Concentration ; Influenza A virus/*chemistry/genetics/metabolism ; Ion Channel Gating/drug effects ; Models, Molecular ; Protein Structure, Quaternary ; Protons ; Structure-Activity Relationship ; Tryptophan/metabolism ; Viral Matrix Proteins/*antagonists & inhibitors/*chemistry/genetics/metabolism
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  • 9
    Publication Date: 2008-11-11
    Description: Angiogenesis does not only depend on endothelial cell invasion and proliferation: it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) through their cognate receptors on endothelial cells and vascular smooth muscle cells (VSMCs), respectively. PDGF induces neovascularization by priming VSMCs/pericytes to release pro-angiogenic mediators. Although VEGF directly stimulates endothelial cell proliferation and migration, its role in pericyte biology is less clear. Here we define a role for VEGF as an inhibitor of neovascularization on the basis of its capacity to disrupt VSMC function. Specifically, under conditions of PDGF-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGF-R2 suppresses PDGF-Rbeta signalling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-Rbeta and VEGF-R2. Inhibition of VEGF-R2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. Finally, genetic deletion of tumour cell VEGF disrupts PDGF-Rbeta/VEGF-R2 complex formation and increases tumour vessel maturation. These findings underscore the importance of VSMCs/pericytes in neovascularization and reveal a dichotomous role for VEGF and VEGF-R2 signalling as both a promoter of endothelial cell function and a negative regulator of VSMCs and vessel maturation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605188/" 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/PMC2605188/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Greenberg, Joshua I -- Shields, David J -- Barillas, Samuel G -- Acevedo, Lisette M -- Murphy, Eric -- Huang, Jianhua -- Scheppke, Lea -- Stockmann, Christian -- Johnson, Randall S -- Angle, Niren -- Cheresh, David A -- GM 68524/GM/NIGMS NIH HHS/ -- P01 CA078045/CA/NCI NIH HHS/ -- P01 CA078045-050004/CA/NCI NIH HHS/ -- P01 CA078045-100004/CA/NCI NIH HHS/ -- P01 CA078045-109001/CA/NCI NIH HHS/ -- R01 CA095262/CA/NCI NIH HHS/ -- R01 CA095262-06/CA/NCI NIH HHS/ -- R01 CA118165/CA/NCI NIH HHS/ -- R01 HL078912/HL/NHLBI NIH HHS/ -- R01 HL078912-04/HL/NHLBI NIH HHS/ -- R21 CA129660/CA/NCI NIH HHS/ -- R21 CA129660-02/CA/NCI NIH HHS/ -- R37 CA050286/CA/NCI NIH HHS/ -- R37 CA050286-19/CA/NCI NIH HHS/ -- R37 CA050286-20/CA/NCI NIH HHS/ -- R37-CA082515/CA/NCI NIH HHS/ -- R37-CA50286/CA/NCI NIH HHS/ -- England -- Nature. 2008 Dec 11;456(7223):809-13. doi: 10.1038/nature07424. Epub 2008 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, School of Medicine, Moore's UCSD Cancer Center, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18997771" target="_blank"〉PubMed〈/a〉
    Keywords: Angiogenesis Inhibitors/pharmacology ; Animals ; Blood Vessels/*metabolism ; Cell Line ; Cells, Cultured ; Fibrosarcoma/blood supply ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neovascularization, Physiologic/drug effects/*physiology ; Pericytes/drug effects/*metabolism ; Platelet-Derived Growth Factor/*metabolism/pharmacology ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Signal Transduction ; Vascular Endothelial Growth Factor A/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2008-02-01
    Description: Understanding cellular response to environmental stress has broad implications for human disease. AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and -consuming pathways, and protects the heart against ischaemic injury and apoptosis. A role for circulating hormones such as adiponectin and leptin in the activation of AMPK has received recent attention. Whether local autocrine and paracrine factors within target organs such as the heart modulate AMPK is unknown. Here we show that macrophage migration inhibitory factor (MIF), an upstream regulator of inflammation, is released in the ischaemic heart, where it stimulates AMPK activation through CD74, promotes glucose uptake and protects the heart during ischaemia-reperfusion injury. Germline deletion of the Mif gene impairs ischaemic AMPK signalling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischaemia, functionally linking inflammation and metabolism in the heart. We anticipate that genetic variation in MIF expression may impact on the response of the human heart to ischaemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, Edward J -- Li, Ji -- Leng, Lin -- McDonald, Courtney -- Atsumi, Toshiya -- Bucala, Richard -- Young, Lawrence H -- England -- Nature. 2008 Jan 31;451(7178):578-82. doi: 10.1038/nature06504.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Medicine Section of the Department of Internal Medicine, 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/18235500" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases ; Animals ; Anoxia/enzymology/genetics/metabolism ; Antigens, Differentiation, B-Lymphocyte/genetics/metabolism ; Coronary Artery Disease/genetics ; Enzyme Activation ; Genetic Predisposition to Disease ; Genotype ; Glucose/metabolism ; Histocompatibility Antigens Class II/genetics/metabolism ; Humans ; Macrophage Migration-Inhibitory Factors/deficiency/genetics/*metabolism/secretion ; Mice ; Multienzyme Complexes/*metabolism ; Myocardial Ischemia/enzymology/genetics/*metabolism ; Myocardial Reperfusion Injury/physiopathology/prevention & control ; Myocardium/enzymology/metabolism ; Polymorphism, Genetic/genetics ; Promoter Regions, Genetic/genetics ; Protein-Serine-Threonine Kinases/*metabolism ; Rats ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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