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  • 201.
    Wigerius, Michael
    Södertörn University, School of Life Sciences, Chemistry. Södertörn University, School of Life Sciences, Molecular biology.
    Roles of mammalian Scribble in polarity signaling, virus offense and cell-fate determination2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mammalian Scribble is a target for proteins encoded by human papilloma virus, retro- and flaviviruses. Tick-borne encephalitis virus (TBEV) is a flavivirus that have evolved distinct strategies to escape antiviral responses. Information of how flaviviruses intrude on cell integrity comes from understanding of the roles that host-factors play when they interfere with viruses. The first part of this thesis describes a novel interaction between the TBEVNS5 protein and Scribble. The importance of the interaction was demonstrated by RNAi-mediated depletion of Scribble, which prevented suppression of JAK-STAT signaling by NS5. Together, these results define Scribble as a novel target for NS5.

    TBEV is known to cause central nervous system disease TBE in humans that can lead to cognitive dysfunction. A unifying theme in CNS related diseases are defects in neuronal extensions. We therefore addressed the effects of TBEV expression in PC12 cell differentiation, which is characterized by extensive neurite growth. Our data show that TBEVNS5 suppresses neurite outgrowth through the Rho GTPase Rac1. These findings provide evidence that Rac1 is an indirect target of NS5 in neurite inhibition. Scribble was recently implicated in spine morphogenesis. Thus, we tested the role of Scribble in neurite elongation. Depletion of Scribble in PC12 cells, reduced neurite density but increased length of those remaining. Moreover, Scribble bound components in the Ras/ERK cascade in a growth factor dependent manner. Together, these results demonstrate that Scribble controls neurite elongation by scaffolding MAPK components. Moreover, as loss of dendritic spines, actin-rich protrusions on neurons, is a feature in cognitive dysfunction we speculate that cognitive dysfunction in TBE might involve disturbed Scribble expression by NS5.

    We also investigated the binding between NS1 of Influenza A virus and Scribble. The PDZ domains of Scribble are usually selective for specific C-terminal motifs in proteins. Because NS1 has a canonical PDZ motif we tested if binding to Scribble depends on this motif. We found that Scribble binds NS1; the association is dependent on the NS1 C-terminus that is recognized by PDZ3-4 of Scribble. Together, these results suggest that Scribble is a target for the H5N1 NS1 protein 

  • 202.
    Wiren, Marianna
    et al.
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Silverstein, Rebecca A
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Sinha, Indranil
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Walfridsson, Julian
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Lee, Hang-mao
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Laurenson, P
    University of California, San Diego, USA.
    Pillus, L
    University of California, San Diego, USA.
    Robyr, D
    University of California, Los Angeles, USA.
    Grunstein, M
    University of California, Los Angeles, USA.
    Ekwall, Karl
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast2005In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 24, no 16, p. 2906-2918Article in journal (Refereed)
    Abstract [en]

    We have conducted a genomewide investigation into the enzymatic specificity, expression profiles, and binding locations of four histone deacetylases (HDACs), representing the three different phylogenetic classes in fission yeast ( Schizosaccharomyces pombe). By directly comparing nucleosome density, histone acetylation patterns and HDAC binding in both intergenic and coding regions with gene expression profiles, we found that Sir2 ( class III) and Hos2 ( class I) have a role in preventing histone loss; Clr6 ( class I) is the principal enzyme in promoter-localized repression. Hos2 has an unexpected role in promoting high expression of growth-related genes by deacetylating H4K16Ac in their open reading frames. Clr3 ( class II) acts cooperatively with Sir2 throughout the genome, including the silent regions: rDNA, centromeres, mat2/3 and telomeres. The most significant acetylation sites are H3K14Ac for Clr3 and H3K9Ac for Sir2 at their genomic targets. Clr3 also affects subtelomeric regions which contain clustered stress- and meiosis-induced genes. Thus, this combined genomic approach has uncovered different roles for fission yeast HDACs at the silent regions in repression and activation of gene expression.

  • 203. Wu, X.
    et al.
    Jörnvall, H.
    Berndt, Kurt D.
    Södertörn University, School of Chemistry, Biology, Geography and Environmental Science. Karolinska Institutet.
    Oppermann, U.
    Codon optimization reveals critical factors for high level expression of two rare codon genes in Escherichia coli: RNA stability and secondary structure but not tRNA abundance2004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 313, no 1, p. 89-96Article in journal (Refereed)
    Abstract [en]

    Expression patterns in Escherichia coli of two small archaeal proteins with a natural content of about 30% rare codons were analyzed. The proteins, a histone-like protein from Sulfolobus shibatae (Ssh10), and a glutaredoxin-like protein from Methanobacterium thermoautotrophicum (mtGrx), were produced with expression plasmids encoding wild-type genes, codon-optimized synthetic, and GST-fusion genes. These constructs were expressed in BL21 (DE3), its LysS derivative, and modified strains carrying copies for rare codon tRNAs or deletions in the RNAseE gene. Both Ssh10 and mtGrx expression levels were constitutively high in BL21(DE3) and its derivatives, with the exception of the LysS phenotype, which prevented high level expression of the Ssh10 wild-type gene. Surprisingly, a codon-optimized mtGrx gene construct displayed undetectable levels of protein production. The translational block observed with the synthetic mtGrx gene could be circumvented by using a synthetic mtGrx-glutathione S-transferase (GST) fusion construct or by in vitro translation. Taken together, the results underscore the importance of mRNA levels and RNA stability, but not necessarily tRNA abundance for efficient heterologous protein production in E. coli.

  • 204. Wu, X
    et al.
    Oppermann, M
    Berndt, Kurt D
    Karolinska Institutet.
    Bergman, T
    Jörnvall, H
    Knapp, S
    Oppermann, U
    Thermal unfolding of the archaeal DNA and RNA binding protein Ssh102008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 373, no 4, p. 482-487Article in journal (Refereed)
    Abstract [en]

    The reversible thermal unfolding of the archaeal histone-like protein Ssh10b from the extremophile Sulfolobus shibatae was studied using differential scanning calorimetry and circular dichroism spectroscopy. Analytical ultracentrifugation and gel filtration showed that Ssh10b is a stable dimer in the pH range 2.5-7.0. Thermal denaturation data fit into a two-state unfolding model, suggesting that the Ssh10 dimer unfolds as a single cooperative unit with a maximal melting temperature of 99.9 degrees C and an enthalpy change of 134 kcal/mol at pH 7.0. The heat capacity change upon unfolding determined from linear fits of the temperature dependence of DeltaH(cal) is 2.55 kcal/(mol K). The low specific heat capacity change of 13 cal/(mol K residue) leads to a considerable flattening of the protein stability curve (DeltaG (T)) and results in a maximal DeltaG of only 9.5 kcal/mol at 320 K and a DeltaG of only 6.0 kcal/mol at the optimal growth temperature of Sulfolobus.

  • 205. Wärnmark, A
    et al.
    Wikström, Anja
    KTH.
    Wright, Anthony P H
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Gustafsson, J A
    Härd, T
    The N-terminal regions of estrogen receptor alpha and beta are unstructured in vitro and show different TBP binding properties2001In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 49, p. 45939-45944Article in journal (Refereed)
    Abstract [en]

    The N-terminal regions of the estrogen receptor ve (ER alpha -N) and beta (ER beta -N) were expressed and purified to homogeneity. Using NAM and circular dichroism spectroscopy, we conclude that both ER alpha -N and ER beta -N are unstructured in solution. The TATA box-binding protein (TBP) has been shown previously to interact with ERa-N in vitro and to potentiate ER-activated transcription. We used surface plasmon resonance and circular dichroism spectroscopy to confirm and further characterize the ER-N-TBP interaction. Our results show that the intrinsically unstructured ERa-N interacts with TBP, and suggest that structural changes are induced in ERa-N upon TBP interaction. Conformational changes upon target factor interaction have not previously been demonstrated for any N-terminal region of nuclear receptors. In addition, no binding of ER beta -N to TBP was detected. This difference in TBP binding could imply differential recruitment of target proteins by ERa-N and ER beta -N. The affinity of the ER alpha -N-TBP interaction was determined to be in the micromolar range (K-D = 10(-6) to 10(-5) m). Our results support models of TBP as a target protein for the N-terminal activation domain of ER alpha. Further, our results suggest that target proteins can induce and/or stabilize ordered structure in N-terminal regions of nuclear receptors upon interaction.

  • 206.
    Wärnmark, Anette
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Intsitute.
    Gustafsson, J A
    Karolinska Institute.
    Wright, Anthony P H
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Architectural principles for the structure and function of the glucocorticoid receptor tau 1 core activation domain2000In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 275, no 20, p. 15014-15018Article in journal (Refereed)
    Abstract [en]

    A 58-amino acid region mediates the core transactivation activity of the glucocorticoid receptor tau 1 activation domain. This tau 1 core domain is unstructured in aqueous buffers, but in the presence of trifluoroethanol three Alpha-helical segments are induced. Two of these putative structural modules have been tested in different combinations with regard to transactivation potential in vivo and binding capacity to the coactivators in vitro, The results show that whereas single modules are not transcriptionally active, any combination of two or three modules is sufficient, with trimodular constructs having the highest activity. However, proteins containing one, two, or three segments bind Ada2 and cAMP-response element-binding protein with similar affinity. A single segment is thus able to bind a target factor but cannot transactivate target genes significantly. The results are consistent with models in which activation domains are comprised of short activation modules that allow multiple interactions with coactivators. Our results also suggest that an increased number of modules may not result in correspondingly higher affinity but instead that the concentration of binding sites is increased, which gives rise to a higher association rate. This is consistent with a model where the association rate for activator-target factor interactions rather than the equilibrium constant is the most relevant measure of activator potency.

  • 207.
    Xia, Ling
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Björnstedt, M.
    Nordman, Tomas
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Eriksson, L. C.
    Olsson, J. M.
    Reduction of ubiquinone by lipoamide dehydrogenase: An antioxidant regenerating pathway2001In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 268, no 5, p. 1486-1490Article in journal (Refereed)
    Abstract [en]

    Lipoamide dehydrogenase belongs to a family of pyridine nucleotide disulfide oxidoreductases and is ubiquitous in aerobic organisms. This enzyme also reduces ubiquinone (the only endogenously synthesized lipid-soluble antioxidant) to ubiquinol, the form in which it functions as an antioxidant. The reduction of ubiquinone was linear with time and exhibited turnover numbers of 5 and 1.2 min-1 in the presence and absence of zinc, respectively. The reaction was stimulated by zinc and cadmium but not by the other divalent ions tested. The zinc/cadmium-dependent stimulation of the reaction increased rapidly and linearly up to a concentration of 0.1 mM and was even further increased at 0.5 mM. At pH 6, the activity was three times higher than at physiological pH. Alteration of the NADPH : NADP+ ratio revealed that the reaction is inhibited by higher concentrations of the oxidized cofactors. FAD reduced ubiquinone in a dose-dependent manner at a considerably lower rate, suggesting that the reduction of ubiquinone by lipoamide dehydrogenase involves the FAD moiety of the enzyme.

  • 208.
    Xia, Ling
    et al.
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Nordman, Tomas
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Olsson, J M
    Damdimopoulos, A
    Björkhem-Bergman, L
    Nalvarte, I
    Eriksson, L C
    Arner, E S J
    Spyrou, Giannis
    Södertörn University, Avdelning Naturvetenskap. Karolinska Instiutet.
    Björnstedt, Mikael
    Karolinska Institutet.
    The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone - A novel mechanism for defense against oxidative stress2003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 4, p. 2141-2146Article in journal (Refereed)
  • 209.
    Xue, Yongtao
    et al.
    Södertörn University, School of Chemistry, Biology, Geography and Environmental Science. Karolinska Institute.
    Haas, S A
    Max-Plank Institute for Molecular Genetics, Berlin, Germany.
    Brino, L
    Eurogentec SA, Seraing, Belgium.
    Gusnanto, A
    Karolinska Institute.
    Reimers, M
    Karolinska Institute.
    Talibi, D
    Eurogentec SA, Seraing, Belgium.
    Vingron, M
    Max-Plank Institute for Molecular Genetics, Berlin, Germany.
    Ekwall, Karl
    Södertörn University, School of Chemistry, Biology, Geography and Environmental Science. Karolinska Institute.
    Wright, Anthony P H
    Södertörn University, School of Chemistry, Biology, Geography and Environmental Science. Karolinska Institute.
    A DNA microarray for fission yeast: minimal changes in global gene expression after temperature shift2004In: Yeast, ISSN 0749-503X, E-ISSN 1097-0061, Vol. 21, no 1, p. 25-39Article in journal (Refereed)
    Abstract [en]

    Completion of the fission yeast genome sequence has opened up possibilities for post-genomic approaches. We have constructed a DNA microarray for genome-wide gene expression analysis in fission yeast. The microarray contains DNA fragments, PCR-amplified from a genomic DNA template, that represent >99% of the 5000 or so annotated fission yeast genes, as well as a number of control sequences. The GenomePRIDE software used attempts to design similarly sized DNA fragments corresponding to gene regions within single exons, near the 3'-end of genes that lack homology to other fission yeast genes. To validate the design and utility of the array, we studied expression changes after a 2 h temperature shift from 25degreesC to 36degreesC, conditions widely used when studying temperature-sensitive mutants. Obligingly, the vast majority of genes do not change more than two-fold, supporting the widely held view that temperature-shift experiments specifically reveal phenotypes associated with temperature-sensitive mutants. However, we did identify a small group of genes that showed a reproducible change in expression. Importantly, most of these corresponded to previously characterized heat-shock genes, whose expression has been reported to change after more extreme temperature shifts than those used here.. We conclude that the DNA microarray represents a useful resource for fission yeast researchers as well as the broader yeast community, since it will facilitate comparison with the distantly related budding yeast, Saccharomyces cerevisiae. To maximize the utility of this resource, the array and its component parts are fully described in On-line Supplementary Information and are also available commercially.

  • 210.
    Xue-Franzen, Yongtao
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intitutet.
    DNA microarray approaches to understanding the regulation and evolution of gene expression networks2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    DNA microarray technology allows biological and medical research to shift from investigation of individual functions of a few related genes to the whole genome level. This creates opportunities for discovery of complex and coordinated transcriptional networks in biological systems. The aim of this thesis has been to study gene regulation and evolution using yeast responses to environmental cues as a model system. We first developed and validated a fission yeast cDNA microarray for genome-wide expression analysis (Paper I). It is the first commercially available fission yeast microarray, which presents a useful resouce for yeast researchers and provides information required to contruct the array from scratch. Next, we characterised the gene regulatory networks involved in the pheromone response (Paper II) and investigate the role of Gcn5 transcription co-regulator, a histone acetyltransferase (HAT), in re-programming gene expression during the salt stress response in fission yeast (Paper III). We further investigated evolutionary conservation and divergence of Gcn5 in gene regulation by comparing its role in the evolutionarily distantly related yeast species. The parallel study of the fission yeast and budding yeast showed that Gcn5 has a conserved physiological role in salt stress responses, but it regulates diverged sets of stress response genes potentially via distinct mechanisms (paper IV). Finally, we investigated interactions between different HATs and between HATs and HDACs (histone deacetylases). Phenotypic studies and gene expression profiling revealed that Gcn5 has overlapping functions with another HAT, Mst2, in the stress response and DNA damage repair (Paper V). We found that the HDAC Clr3 acts antagonistically to Gcn5 in transcriptional elongation and stress responses (Paper VI).

  • 211. Yang, Y
    et al.
    Griffiths, W J
    Nordling, M
    Nygren, Jonas
    Södertörn University, Avdelning Naturvetenskap. Karoliska Institute.
    Möller, L
    Bergman, Jan
    Liepinsh, E
    Otting, G
    Gustafsson, J A
    Rafter, J
    Sjövall, J
    Ring opening of benzo[a]pyrene in the germ-free rat is a novel pathway for formation of potentially genotoxic metabolites2000In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 39, no 50, p. 15585-15591Article in journal (Refereed)
    Abstract [en]

    The metabolism of benzo[a]pyrene (BP) is known to lead to a large number of oxygenated compounds, some of which can bind covalently to DNA. We have studied the integrated metabolism of BP in vivo in germ-free rats given C-14-labeled BP. Urinary metabolites were separated into groups according to acidity using lipophilic ion exchangers. The groups were analyzed by mass spectrometry and were further fractionated by high-performance liquid chromatography. The fraction of urinary metabolites previously shown to contain N-acetylcysteine and glucuronic acid conjugates was found to contain derivatives of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid as major components. These compounds, which were identified by mass spectrometry and NMR, accounted for about 30% of the total metabolites in urine, demonstrating that, surprisingly, ring opening is a major pathway for metabolism of BP in the germ-free rat. The dicarboxylic acid may be excreted in urine as an ester glucuronide. By using the single cell gel electrophoresis or COMET assay, we were able to demonstrate that the anhydride of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid was an efficient inducer of DNA damage. Taken together, these results indicate that the novel ring opening metabolic pathway may provide alternative mechanisms for the toxicity of BP.

  • 212.
    Yildirim, Håkan H
    et al.
    Södertörn University, School of Life Sciences. Karolinska institutet.
    Li, J J
    National Research Council, Ottawa, Canada.
    Richards, J C
    National Research Council, Ottawa, Canada.
    Hood, D W
    John Radcliffe Hospital, Oxford, UK.
    Moxon, E R
    John Radcliffe Hospital, Oxford, UK.
    Schweda, Elke K H
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Complex O-acetylation in non-typeable Haemophilus influenzae lipopolysaccharide: evidence for a novel site of O-acetylation2005In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 340, no 17, p. 2598-2611Article in journal (Refereed)
    Abstract [en]

    The structure of the lipopolysaccharide (LPS) of non-typeable Haemophilus influenzae strain 723 has been elucidated using NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS) on O-deacylated LPS and core oligosaccharide material (OS), as well as ESI-MSn on permethylated dephosphorylated OS. It was found that the LPS contains the common structural element of H. influenzae, L-alpha-D-Hepp-(1 -> 2)-[PEtn -> 6]-L-alpha-D-Hepp-(1 -> 3)-[beta-D-Glcp-(1 -> 4)]-L-alpha-D-Hepp-(1 -> 5)-[PPEtn -> 4]-alpha-Kdo-(2 -> 6)-Lipid A, in which the beta-D-Glcp residue (GlcI) is substituted by phosphocholine at O-6 and the distal heptose residue (HepIII) by PEW at O-3, respectively. In a subpopulation of glycoforms O-2 of HepIII was substituted by beta-D-Galp-(1 -> 4)-beta-D-Glcp-(1 -> or beta-D-Glcp-(1 ->. Considerable heterogeneity of the LPS was due to the extent of substitution by O-acetyl groups (Ac) and ester-linked glycine of the core oligosaccharide. The location for glycine was found to be at Kdo. Prominent acetylation sites were found to be at GlcI, HepIII, and the proximal heptose (HepI) residue of the triheptosyl moiety. Moreover, GlcI was acetylated at O-3 and/or O-4 and HepI was acetylated at O-2 as evidenced by capillary electrophoresis ESI-MS" in combination with NMR analyses. This is the first study to show that an acetyl group can substitute HepI of the inner-core region of H. influenzae LPS.

  • 213. Zhang, X F
    et al.
    Meining, Winfried
    Södertörn University, Avdelning Naturvetenskap.
    Cushman, M
    Haase, I
    Fischer, M
    Bacher, A
    Ladenstein, R
    A structure-based model of the reaction catalyzed by lumazine synthase from Aquifex aeolicus2003In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 328, no 1, p. 167-182Article in journal (Refereed)
    Abstract [en]

    6,7-Dimethyl-8-ribityllumazine is the biosynthetic precursor of riboflavin, which, as a coenzyme, plays a vital role in the electron transfer process for energy production in all cellular organisms. The enzymes involved in lumazine biosynthesis have been studied in considerable detail. However, the conclusive mechanism of the reaction catalyzed by lumazine synthase has remained unclear. Here, we report four crystal structures of the enzyme from the hyperthermophilic bacterium Aquifex aeolicus in complex with different inhibitor compounds. The structures were refined at resolutions of 1.72 Angstrom, 1.85 Angstrom, 2.05 Angstrom and 2.2 Angstrom, respectively. The inhibitors have been designed in order to mimic the substrate, the putative reaction intermediates and the final product. Structural comparisons of the native enzyme and the inhibitor complexes as well as the kinetic data of singlesite mutants of lumazine synthase from Bacillus subtilis showed that several highly conserved residues at the active site, namely Phe22, His88, Arg127, Lys135 and Glu138 are most likely involved in catalysis. A structural model of the catalytic process, which illustrates binding of substrates, enantiomer specificity, proton abstraction/donation, inorganic phosphate elimination, formation of the Schiff base and cyclization is proposed.

  • 214. Zhang, X F
    et al.
    Meining, Winfried
    Södertörn University, Avdelning Naturvetenskap.
    Fischer, M
    Bacher, A
    Ladenstein, R
    X-ray structure analysis and crystallographic refinement of lumazine synthase from the hyperthermophile Aquifex aeolicus at 1.6 angstrom resolution: Determinants of thermostability revealed from structural comparisons2001In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 306, no 5, p. 1099-1114Article in journal (Refereed)
    Abstract [en]

    An open reading frame optimized for expression of 6,7-dimethyl-8-ribityllumazine synthase of the hyperthermophilic bacterium Aquifex aeolicus in Escherichia coli was synthesized and expressed in a recombinant E. coli strain to a level of around 15%. The recombinant protein was purified by heat-treatment and gel-filtration. The protein was crystallized in the cubic space group 123 with the cell dimensions a = b = c = 180.8 Angstrom, and diffraction data were collected to 1.6 Angstrom resolution. The structure was solved by molecular replacement using lumazine synthase from Bacillus subtilis as search model. The structure of the A. aeolicus enzyme was refined to a resolution of 1.6 Angstrom. The spherical protein consists of 60 identical subunits with strict icosahedral 532 symmetry. The subunit fold is closely related to that of the B. subtilis enzyme (rmsd 0.80 Angstrom). The extremely thermostable lumazine synthase from A. aeolicus has a melting temperature of 119.9 degreesC. Compared to other icosahedral and pentameric lumazine synthases, the A. aeolicus enzyme has the largest accessible surface presented by charged residues and the smallest surface presented by hydrophobic residues. It also has the largest number of ion-pairs per subunit. Two ion-pair networks involving two, respectively three, stacking arginine residues assume a distinct role in linking adjacent subunits. The findings indicate the influence of the optimization of hydrophobic and ionic contacts in gaining thermostability.

  • 215.
    Zhu, Xuefeng
    et al.
    Karolinska Institutet.
    Wirén, Marianna
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Sinha, Indranil
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Rasmussen, Nina N
    Institute of Molecular Biology, Copenhagen, Denmark.
    Linder, Tomas
    Karolinska Institutet.
    Holmberg, Steen
    Institute of Molecular Biology, Copenhagen, Denmark.
    Ekwall, Karl
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Gustafsson, Claes M
    Karolinska Institutet.
    Genome-wide occupancy profile of mediator and the Srb8-11 module reveals interactions with coding regions2006In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 22, no 2, p. 169-178Article in journal (Refereed)
    Abstract [en]

    Mediator exists in a free form containing the Med12, Med13, CDK8, and CycC subunits (the Srb8-11 module) and a smaller form, which lacks these four subunits and associates with RNA polymerase II (Pol II), forming a holoenzyme. We use chromatin immunoprecipitation (ChIP) and DNA microarrays to investigate genome-wide localization of Mediator and the Srb8-11 module in fission yeast. Mediator and the Srb8-11 module display similar binding patterns, and interactions with promoters and upstream activating sequences correlate with increased transcription activity. Unexpectedly, Mediator also interacts with the downstream coding region of many genes. These interactions display a negative bias for positions closer to the 5' ends of open reading frames (ORFs) and appear functionally important, because downregulation of transcription in a temperature-sensitive med17 mutant strain correlates with increased Mediator occupancy in the coding region. We propose that Mediator coordinates transcription initiation with transcriptional events in the coding region of eukaryotic genes.

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