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Separating Dipolar and Chemical Exchange Magnetization Transfer Processes in1H‐CEST

Angewandte Chemie 2016年第22期129卷

作者： Tairan Yuwen Ashok Sekhar Lewis E. Kay Departments of Molecular Genetics Biochemistry and Chemistry University of Toronto Toronto Ontario M5S 1A8 Canada Hospital for Sick Children Program in Molecular Structure and Function 555 University Avenue Toronto Ontario M5G 1X8 Canada

An amide 1 H‐Chemical Exchange Saturation Transfer (CEST) experiment is presented for studies of conformational exchange in proteins. The approach, exploiting spin‐state‐selective magnetization transfer, completely suppresses undesired NOE‐based dips in CEST profiles so that chemical exchange processes can be studied. The methodology is demonstrated with applications involving proteins that interconvert on the millisecond timescale between major and invisible minor states, and accurate amide 1 H chemical shifts of the minor conformer are obtained in each case. The spin‐state‐selective magnetization transfer approach offers unique possibilities for quantitative studies of protein exchange through 1 H‐CEST.

关键词： Amidprotonen Konformationsdynamiken Kreuzrelaxation Proteine Protonen-CEST

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Enhancing the Sensitivity of CPMG Relaxation Dispersion to Conformational Exchange Processes by Multiple‐Quantum Spectroscopy

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Angewandte Chemie 2016年第38期128卷

作者： Tairan Yuwen Pramodh Vallurupalli Lewis E. Kay Departments of Molecular Genetics Biochemistry and Chemistry University of Toronto Toronto Ontario M5S 1A8 Canada TIFR Centre for Interdisciplinary Sciences 21 Brundavan Colony Narsingi Hyderabad 500075 India Hospital for Sick Children Program in Molecular Structure and Function 555 University Avenue Toronto Ontario M5G 1X8 Canada

A triple‐quantum 1 H Carr–Purcell–Meiboom–Gill NMR relaxation dispersion experiment is presented that uses methyl group probes as reporters of conformational exchange in highly deuterated, methyl‐protonated proteins. Significantly larger dispersion profiles, by as much as a factor of nine, can be obtained relative to single‐quantum approaches, thus offering very significant advantages in applications involving interconverting conformers with only small changes in structure or in studies of rare states that are at very low populations. Applications to a number of protein systems are presented where the utility of the method, including its improved sensitivity to chemical exchange processes, is established.

关键词： Isotopenmarkierung Konformationsdynamik NMR-Spektroskopie Proteine

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Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses (vol 6, 25080, 2016)

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SCIENTIFIC REPORTS 2016年第1期6卷 25080-25080页

作者： Galant, Natalie J. Bugyei-Twum, Antoinette Rakhit, Rishi Walsh, Patrick Sharpe, Simon Arslan, Pharhad Eli Westermark, Per Higaki, Jeffrey N. Torres, Ronald Tapia, Jose Chakrabartty, Avijit Princess Margaret Cancer Centre University Health Network Departments of Medical Biophysics and Biochemistry University of Toronto TMDT 4-305 101 College Street Toronto Ontario Canada M5G 1L7 Princess Margaret Cancer Centre University Health Network Departments of Medical Biophysics and Biochemistry University of Toronto TMDT 4-305 101 College Street Toronto Ontario Canada M5G 1L7 Department of Chemical and Systems Biology Stanford University CA 94305 USA Molecular Structure and Function Program the Hospital for Sick Children Department of Biochemistry University of Toronto 1 King’s College Circle Toronto Ontario Canada M5S 1A8 Molecular Structure and Function Program the Hospital for Sick Children Department of Biochemistry University of Toronto 1 King’s College Circle Toronto Ontario Canada M5S 1A8 Princess Margaret Cancer Centre University Health Network Departments of Medical Biophysics and Biochemistry University of Toronto TMDT 4-305 101 College Street Toronto Ontario Canada M5G 1L7 Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden Departments of Biochemistry and Histopathology Prothena Biosciences Inc. South San Francisco CA 94080. Departments of Biochemistry and Histopathology Prothena Biosciences Inc. South San Francisco CA 94080. Departments of Biochemistry and Histopathology Prothena Biosciences Inc. South San Francisco CA 94080. Princess Margaret Cancer Centre University Health Network Departments of Medical Biophysics and Biochemistry University of Toronto TMDT 4-305 101 College Street Toronto Ontario Canada M5G 1L7

Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis^® and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89-97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.

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Interaction of myelin basic protein with cytoskeletal and signaling proteins in cultured primary oligodendrocytes and N19 oligodendroglial cells

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BMC Research Notes 2014年第1期7卷 1-14页

作者： Boggs, Joan M Homchaudhuri, Lopamudra Ranagaraj, Godha Liu, Yuanfang Smith, Graham St Harauz, George Molecular Structure and Function Program Research Institute Hospital for Sick Children Toronto ON M5G 0A4 686 Bay St Canada Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada Neurosciences and Mental Health Program Research Institute Hospital for Sick Children Toronto ON Canada Department of Molecular and Cellular Biology University of Guelph Guelph ON N1G 2W1 50 Stone Road East Canada

Background: The classic myelin basic protein (MBP) isoforms are intrinsically-disordered proteins of 14-21.5 kDa in size arising from the Golli (Gene in the Oligodendrocyte Lineage) gene complex, and are responsible for formation of the multilayered myelin sheath in the central nervous system. The predominant membrane-associated isoform of MBP is not simply a structural component of compact myelin but is highly post-translationally modified and multi-functional, having interactions with numerous proteins such as Ca ²⁺-calmodulin, and with actin, tubulin, and proteins with SH3-domains, which it can tether to a lipid membrane in vitro. It co-localizes with such proteins in primary oligodendrocytes (OLGs) and in early developmental N19-OLGs transfected with fluorescently-tagged MBP. Results: To provide further evidence for MBP associations with these proteins in vivo, we show here that MBP isoforms are co-immunoprecipitated from detergent extracts of primary OLGs together with actin, tubulin, zonula occludens 1 (ZO-1), cortactin, and Fyn kinase. We also carry out live-cell imaging of N19-OLGs co-transfected with fluorescent MBP and actin, and show that when actin filaments re-assemble after recovery from cytochalasin D treatment, MBP and actin are rapidly enriched and co-localized at certain sites at the plasma membrane and in newly-formed membrane ruffles. The MBP and actin distributions change similarly with time, suggesting a specific and dynamic association. Conclusions: These results provide more direct evidence for association of the predominant 18.5-kDa MBP isoform with these proteins in primary OLGs and in live cells than previously could be inferred from co-localization observations. This study supports further a role for classic MBP isoforms in protein-protein interactions during membrane and cytoskeletal extension and remodeling in OLGs. © 2014 Boggs et al.;licensee BioMed Central Ltd.

关键词： Actin Co-immunoprecipitation Confocal microscopy Cortactin Fyn kinase Live-cell imaging Myelin basic protein Oligodendrocyte Tubulin ZO-1

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Probing Invisible, Excited Protein States by Non‐Uniformly Sampled Pseudo‐4D CEST Spectroscopy†

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Angewandte Chemie 2015年第36期127卷

作者： Dong Long Frank Delaglio Ashok Sekhar Lewis E. Kay Departments of Molecular Genetics Biochemistry & Chemistry University of Toronto Toronto Ontario M5S 1A8 (Canada) NMR Science Campbell CA 95008 (USA) Hospital for Sick Children Program in Molecular Structure and Function 555 University Avenue Toronto Ontario M5G1X8 (Canada)

Chemical exchange saturation transfer (CEST) NMR spectroscopy is a powerful tool for studies of slow timescale protein dynamics. Typical experiments are based on recording a large number of 2D data sets and quantifying peak intensities in each of the resulting planes. A weakness of the method is that peaks must be resolved in 2D spectra, limiting applications to relatively small proteins. Resolution is significantly improved in 3D spectra but recording uniformly sampled data is time‐prohibitive. Here we describe non‐uniformly sampled HNCO‐based pseudo‐4D CEST that provides excellent resolution in reasonable measurement times. Data analysis is done through fitting in the time domain, without the need of reconstructing the frequency dimensions, exploiting previously measured accurate peak positions in reference spectra. The methodology is demonstrated on several protein systems, including a nascent form of superoxide dismutase that is implicated in neurodegenerative disease.

关键词： CEST Konformationsdynamik Nicht‐uniformes Sampling Proteine Pseudo‐4D‐NMR

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26th Annual Computational Neuroscience Meeting (CNS*2017) of the Organization for Computational Neuroscience Antwerp, Belgium, July 15-20, 2017

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BMC NEUROSCIENCE 2017年第SUPPL 1期18卷 59-59页

作者： [Anonymous] Indiana University Purdue University Indianapolis Indianapolis IN 46032 USA Stark Neurosciences Research Institute Indiana University School of Medicine Indianapolis IN 46032 USA Department of Mathematics East Carolina University Greenville NC 27858 USA Jülich Supercomputing Centre Forschungszentrum Jülich 52425 Jülich Germany Future Systems Swiss National Supercomputing Centre 8092 Zurich Switzerland User Engagement and Support Swiss National Supercomputing Centre 6900 Lugano Switzerland Institut de Neurosciences des Systèmes Aix Marseille Univ 13005 Marseille France Simulation Lab Neuroscience Forschungszentrum Jülich Jülich Germany Department of Experimental Psychology Ghent University 9000 Ghent Belgium Donders Center for Cognitive Neuroimaging Radboud University 6525HR Nijmegen The Netherlands Department of Electrical Computer and Energy Engineering University of Colorado Boulder CO 80309 USA Department of Neurosurgery Johns Hopkins School of Medicine Baltimore MD 21287 USA Department of Neurology Johns Hopkins School of Medicine Baltimore MD 21287 USA Department of Otolaryngology Johns Hopkins School of Medicine Baltimore MD 21287 USA INSERM U968 Paris France Sorbonne Universités UPMC University Paris 06 UMR_S 968 Institut de la Vision Paris France CNRS UMR_7210 Paris France Department of Computer Architecture and Technology University of Granada (CITIC) Granada Spain Sorbonne Universités UPMC Univ Paris 06 INSERM CNRS Institut de la Vision Paris France Department of Adaptive Machine Systems Osaka University Osaka Japan Department of Computer Science University of Cergy-Pontoise Cergy-Pontoise France Department of Physics and Astronomy College of Charleston Charleston SC 29424 USA School of Physics Faculty of Science University of Sydney Sydney NSW 2006 Australia Center of Excellence for Integrative Brain Function Australian Research Council Sydney Australia Max Planck Institute for Human Cognitive and Brain Sciences Saxony Lei

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Beyond blob-ology

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Science 2014年第6197期345卷 617-619页

作者： Martin T. J. Smith John L. Rubinstein Molecular Structure and Function Program Hospital for Sick Children Research Institute Toronto Ontario M5G 0A4 Canada. Department of Medical Biophysics University of Toronto Toronto Ontario M5G 1L7 Canada. Department of Biochemistry University of Toronto Toronto Ontario M5S 1A8 Canada.

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25th Annual Computational Neuroscience Meeting CNS-2016, Seogwipo City, South Korea, July 2-7, 2016 Abstracts

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BMC NEUROSCIENCE 2016年第1期17卷 1-112页

作者： [Anonymous] Computational Neurobiology Laboratory The Salk Institute for Biological Studies San Diego USA UNIC CNRS Gif sur Yvette France The European Institute for Theoretical Neuroscience (EITN) Paris France ATR Computational Neuroscience Laboratories Kyoto Japan Krembil Research Institute University Health Network Toronto Canada Department of Physiology University of Toronto Toronto Canada Department of Medicine (Neurology) University of Toronto Toronto Canada Department of Physics University of New Hampshire Durham USA Department of Neurophysiology Nencki Institute of Experimental Biology Warsaw Poland Department of Theory Wigner Research Centre for Physics of the Hungarian Academy of Sciences Budapest Hungary Department of Mathematical Sciences KAIST Daejoen Republic of Korea Department of Mathematics University of Houston Houston USA Department of Biochemistry & Cell Biology and Institute of Biosciences and Bioengineering Rice University Houston USA Department of Biology and Biochemistry University of Houston Houston USA Grupo de Neurocomputación Biológica Dpto. de Ingeniería Informática Escuela Politécnica Superior Universidad Autónoma de Madrid Madrid Spain Department of Biological Sciences University of Southern California Los Angeles USA Center for Neuroscience Korea Institute of Science and Technology Seoul South Korea Department of Neurology Albert Einstein College of Medicine Bronx USA Center for Neuroscience KIST Seoul South Korea Department of Neuroscience University of Science and Technology Daejon South Korea Systems Neuroscience Group QIMR Berghofer Medical Research Institute Herston Australia Department of Psychology Yonsei University Seoul South Korea Department of Psychiatry Kyung Hee University Hospital at Gangdong Seoul South Korea Department of Psychiatry Veterans Administration Boston Healthcare System and Harvard Medical School Brockton USA Department of Electrical and Electronic Engineering The University of Melbourne Parkvil

A1 functional advantages of cell-type heterogeneity in neural circuits Tatyana O. Sharpee A2 Mesoscopic modeling of propagating waves in visual cortex Alain Destexhe A3 Dynamics and biomarkers of mental disorders Mitsuo Kawato F1 Precise recruitment of spiking output at theta frequencies requires dendritic h-channels in multi-compartment models of oriens-lacunosum/moleculare hippocampal interneurons Vladislav Sekulić, Frances K. Skinner F2 Kernel methods in reconstruction of current sources from extracellular potentials for single cells and the whole brains Daniel K. Wójcik, Chaitanya Chintaluri, Dorottya Cserpán, Zoltán Somogyvári F3 The synchronized periods depend on intracellular transcriptional repression mechanisms in circadian clocks. Jae Kyoung Kim, Zachary P. Kilpatrick, Matthew R. Bennett, Kresimir Josić O1 Assessing irregularity and coordination of spiking-bursting rhythms in central pattern generators Irene Elices, David Arroyo, Rafael Levi, Francisco B. Rodriguez, Pablo Varona O2 Regulation of top-down processing by cortically-projecting parvalbumin positive neurons in basal forebrain Eunjin Hwang, Bowon Kim, Hio-Been Han, Tae Kim, James T. McKenna, Ritchie E. Brown, Robert W. McCarley, Jee Hyun Choi O3 Modeling auditory stream segregation, build-up and bistability James Rankin, Pamela Osborn Popp, John Rinzel O4 Strong competition between tonotopic neural ensembles explains pitch-related dynamics of auditory cortex evoked fields Alejandro Tabas, André Rupp, Emili Balaguer-Ballester O5 A simple model of retinal response to multi-electrode stimulation Matias I. Maturana, David B. Grayden, Shaun L. Cloherty, Tatiana Kameneva, Michael R. Ibbotson, Hamish Meffin O6 Noise correlations in V4 area correlate with behavioral performance in visual discrimination task Veronika Koren, Timm Lochmann, Valentin Dragoi, Klaus Obermayer O7 Input-location dependent gain modulation in cerebellar nucleus neurons Maria Psarrou, Maria Schilstra, Neil Davey, Benjamin Torben-Ni

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Manifestations of Charge Induced Instability in Droplets Effected by Charged Macromolecules

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Physical Review Letters 2012年第14期109卷 148301-148301页

作者： Styliani Consta Anatoly Malevanets Molecular Structure and Function Program Hospital for Sick Children Toronto Ontario Canada M5G 1X8

Ion-release processes from droplets that contain excess charge are of central importance in determining the charge-state distributions of macromolecules in electrospray ionization methods. We develop an analytical theory to describe the mechanism of contiguous extrusion of a charged macromolecule from a droplet. We find that the universal parameter determining the system behavior is the ratio of solvation energy per unit length to the square of the ion charge density per unit length. Systems with the same value of the ratio will follow the same path in the course of droplet evaporation. The analytical model is compared with molecular simulations of charged polyethylene glycol macroion in aqueous droplets, and the results are in excellent agreement.

关键词： MACROMOLECULES IONS SOLVATION PARAMETER estimation ELECTROSPRAY ionization mass spectrometry POLYETHYLENE glycol

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Probing Slow Chemical Exchange at Carbonyl Sites in Proteins by Chemical Exchange Saturation Transfer NMR Spectroscopy†

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Angewandte Chemie 2013年第15期125卷

作者： Pramodh Vallurupalli Lewis E. Kay Departments of Molecular Genetics Biochemistry and Chemistry The University of Toronto Toronto Ontario M5S1A8 (Canada) Program in Molecular Structure and Function Hospital for Sick Children 555 University Avenue Toronto Ontario M5G1X8 (Canada)

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