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Search Results: 1 - 10 of 162846 matches for " James B. Ames "
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Structural diversity of neuronal calcium sensor proteins and insights for activation of retinal guanylyl cyclase by GCAP1
Sunghyuk Lim,Alexander M. Dizhoor,James B. Ames
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00019
Abstract: Neuronal calcium sensor (NCS) proteins, a sub-branch of the calmodulin superfamily, are expressed in the brain and retina where they transduce calcium signals and are genetically linked to degenerative diseases. The amino acid sequences of NCS proteins are highly conserved but their physiological functions are quite different. Retinal recoverin controls Ca2+-dependent inactivation of light-excited rhodopsin during phototransduction, guanylyl cyclase activating proteins 1 and 2 (GCAP1 and GCAP2) promote Ca2+-dependent activation of retinal guanylyl cyclases, and neuronal frequenin (NCS-1) modulates synaptic activity and neuronal secretion. Here we review the molecular structures of myristoylated forms of NCS-1, recoverin, and GCAP1 that all look very different, suggesting that the attached myristoyl group helps to refold these highly homologous proteins into different three-dimensional folds. Ca2+-binding to both recoverin and NCS-1 cause large protein conformational changes that ejects the covalently attached myristoyl group into the solvent exterior and promotes membrane targeting (Ca2+-myristoyl switch). The GCAP proteins undergo much smaller Ca2+-induced conformational changes and do not possess a Ca2+-myristoyl switch. Recent structures of GCAP1 in both its activator and Ca2+-bound inhibitory states will be discussed to understand structural determinants that control their Ca2+-dependent activation of retinal guanylyl cyclases.
Olfactory Proteins Mediating Chemical Communication in the Navel Orangeworm Moth, Amyelois transitella
Walter S. Leal, Yuko Ishida, Julien Pelletier, Wei Xu, Josep Rayo, Xianzhong Xu, James B. Ames
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007235
Abstract: Background The navel orangeworm, Amyelois transitella Walker (Lepidoptera: Pyralidae), is the most serious insect pest of almonds and pistachios in California for which environmentally friendly alternative methods of control — like pheromone-based approaches — are highly desirable. Some constituents of the sex pheromone are unstable and could be replaced with parapheromones, which may be designed on the basis of molecular interaction of pheromones and pheromone-detecting olfactory proteins. Methodology By analyzing extracts from olfactory and non-olfactory tissues, we identified putative olfactory proteins, obtained their N-terminal amino acid sequences by Edman degradation, and used degenerate primers to clone the corresponding cDNAs by SMART RACE. Additionally, we used degenerate primers based on conserved sequences of known proteins to fish out other candidate olfactory genes. We expressed the gene encoding a newly identified pheromone-binding protein, which was analyzed by circular dichroism, fluorescence, and nuclear magnetic resonance, and used in a binding assay to assess affinity to pheromone components. Conclusion We have cloned nine cDNAs encoding olfactory proteins from the navel orangeworm, including two pheromone-binding proteins, two general odorant-binding proteins, one chemosensory protein, one glutathione S-transferase, one antennal binding protein X, one sensory neuron membrane protein, and one odorant receptor. Of these, AtraPBP1 is highly enriched in male antennae. Fluorescence, CD and NMR studies suggest a dramatic pH-dependent conformational change, with high affinity to pheromone constituents at neutral pH and no binding at low pH.
Structural Basis for Sequence Specific DNA Binding and Protein Dimerization of HOXA13
Yonghong Zhang, Christine A. Larsen, H. Scott Stadler, James B. Ames
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023069
Abstract: The homeobox gene (HOXA13) codes for a transcription factor protein that binds to AT-rich DNA sequences and controls expression of genes during embryonic morphogenesis. Here we present the NMR structure of HOXA13 homeodomain (A13DBD) bound to an 11-mer DNA duplex. A13DBD forms a dimer that binds to DNA with a dissociation constant of 7.5 nM. The A13DBD/DNA complex has a molar mass of 35 kDa consistent with two molecules of DNA bound at both ends of the A13DBD dimer. A13DBD contains an N-terminal arm (residues 324 – 329) that binds in the DNA minor groove, and a C-terminal helix (residues 362 – 382) that contacts the ATAA nucleotide sequence in the major groove. The N370 side-chain forms hydrogen bonds with the purine base of A5* (base paired with T5). Side-chain methyl groups of V373 form hydrophobic contacts with the pyrimidine methyl groups of T5, T6* and T7*, responsible for recognition of TAA in the DNA core. I366 makes similar methyl contacts with T3* and T4*. Mutants (I366A, N370A and V373G) all have decreased DNA binding and transcriptional activity. Exposed protein residues (R337, K343, and F344) make intermolecular contacts at the protein dimer interface. The mutation F344A weakens protein dimerization and lowers transcriptional activity by 76%. We conclude that the non-conserved residue, V373 is critical for structurally recognizing TAA in the major groove, and that HOXA13 dimerization is required to activate transcription of target genes.
Structural Insights for Activation of Retinal Guanylate Cyclase by GCAP1
Sunghyuk Lim, Igor V. Peshenko, Alexander M. Dizhoor, James B. Ames
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081822
Abstract: Guanylyl cyclase activating protein 1 (GCAP1), a member of the neuronal calcium sensor (NCS) subclass of the calmodulin superfamily, confers Ca2+-sensitive activation of retinal guanylyl cyclase 1 (RetGC1) upon light activation of photoreceptor cells. Here we present NMR assignments and functional analysis to probe Ca2+-dependent structural changes in GCAP1 that control activation of RetGC. NMR assignments were obtained for both the Ca2+-saturated inhibitory state of GCAP1 versus a GCAP1 mutant (D144N/D148G, called EF4mut), which lacks Ca2+ binding in EF-hand 4 and models the Ca2+-free/Mg2+-bound activator state of GCAP1. NMR chemical shifts of backbone resonances for Ca2+-saturated wild type GCAP1 are overall similar to those of EF4mut, suggesting a similar main chain structure for assigned residues in both the Ca2+-free activator and Ca2+-bound inhibitor states. This contrasts with large Ca2+-induced chemical shift differences and hence dramatic structural changes seen for other NCS proteins including recoverin and NCS-1. The largest chemical shift differences between GCAP1 and EF4mut are seen for residues in EF4 (S141, K142, V145, N146, G147, G149, E150, L153, E154, M157, E158, Q161, L166), but mutagenesis of EF4 residues (F140A, K142D, L153R, L166R) had little effect on RetGC1 activation. A few GCAP1 residues in EF-hand 1 (K23, T27, G32) also show large chemical shift differences, and two of the mutations (K23D and G32N) each decrease the activation of RetGC, consistent with a functional conformational change in EF1. GCAP1 residues at the domain interface (V77, A78, L82) have NMR resonances that are exchange broadened, suggesting these residues may be conformationally dynamic, consistent with previous studies showing these residues are in a region essential for activating RetGC1.
Divalent Cations and Redox Conditions Regulate the Molecular Structure and Function of Visinin-Like Protein-1
Conan K. Wang, Anne Simon, Christian M. Jessen, Cristiano L. P. Oliveira, Lynsey Mack, Karl-Heinz Braunewell, James B. Ames, Jan Skov Pedersen, Andreas Hofmann
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026793
Abstract: The NCS protein Visinin-like Protein 1 (VILIP-1) transduces calcium signals in the brain and serves as an effector of the non-retinal receptor guanylyl cyclases (GCs) GC-A and GC-B, and nicotinic acetyl choline receptors (nAchR). Analysis of the quaternary structure of VILIP-1 in solution reveals the existence of monomeric and dimeric species, the relative contents of which are affected but not exclusively regulated by divalent metal ions and Redox conditions. Using small-angle X-ray scattering, we have investigated the low resolution structure of the calcium-bound VILIP-1 dimer under reducing conditions. Scattering profiles for samples with high monomeric and dimeric contents have been obtained. The dimerization interface involves residues from EF-hand regions EF3 and EF4. Using monolayer adsorption experiments, we show that myristoylated and unmyristoylated VILIP-1 can bind lipid membranes. The presence of calcium only marginally improves binding of the protein to the monolayer, suggesting that charged residues at the protein surface may play a role in the binding process. In the presence of calcium, VILIP-1 undergoes a conformational re-arrangement, exposing previously hidden surfaces for interaction with protein partners. We hypothesise a working model where dimeric VILIP-1 interacts with the membrane where it binds membrane-bound receptors in a calcium-dependent manner.
Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Anju Singh,Vikas Misra,Rajesh K Thimmulappa,Hannah Lee,Stephen Ames,Mohammad O Hoque,James G Herman,Stephen B Baylin,David Sidransky,Edward Gabrielson,Malcolm V Brock,Shyam Biswal
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030420
Abstract: Background Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs. Methods and Findings Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps. Conclusions This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.
World law
Harold J. Berman,Robert W. Woodruff,James Barr Ames
Koers : Bulletin for Christian Scholarship , 1999, DOI: 10.4102/koers.v64i2&3.509
Abstract: In the third millennium of the Christian era, which is characterised by the emergence of a world economy and eventually a world society, the concept of world law is needed to embrace not only the traditional disciplines of public international law, and comparative law, but also the common underlying legal principles applicable in world trade, world finance, transnational transfer of technology and other fields of world economic law, as well as in such emerging fields as the protection of the world's environment and the protection of universal human rights. World law combines inter-state law with the common law of humanity and the customary law of various world communities.
Mild stroke symptoms as the initial presentation of a patient with underlying subacute bacterial endocarditis
Ami Kamdar,Michael Debney,James Scott,Diane Ames
Clinics and Practice , 2012, DOI: 10.4081/cp.2012.e1
Abstract: We describe a patient with sub-acute bacterial endocarditis, whose chief presenting feature was mild expressive dysphasia.
Quasilinear hyperbolic Fuchsian systems and AVTD behavior in T2-symmetric vacuum spacetimes
Ellery Ames,Florian Beyer,James Isenberg,Philippe G. LeFloch
Physics , 2012, DOI: 10.1007/S00023-012-0228-2
Abstract: We set up the singular initial value problem for quasilinear hyperbolic Fuchsian systems of first order and establish an existence and uniqueness theory for this problem with smooth data and smooth coefficients (and with even lower regularity). We apply this theory in order to show the existence of smooth (generally not analytic) T2-symmetric solutions to the vacuum Einstein equations, which exhibit AVTD (asymptotically velocity term dominated) behavior in the neighborhood of their singularities and are polarized or half-polarized.
Quasi-linear symmetric hyperbolic Fuchsian systems in several space dimensions
Ellery Ames,Florian Beyer,James Isenberg,Philippe G. LeFloch
Mathematics , 2012,
Abstract: We establish existence and uniqueness results for the singular initial value problem associated with a class of quasilinear, symmetric hyperbolic, partial differential equations of Fuchsian type in several space dimensions. This is an extension of earlier work by the authors for the same problem in one space dimension.
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