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  • Journal article
    Shahid T, Soroka J, Kong EH, Malivert L, McIlwraith MJ, Pape T, West SC, Zhang Xet al., 2014,

    Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor

    , Nature Structural and Molecular Biology, Vol: 21, Pages: 962-968, ISSN: 1545-9985

    Mutations in BRCA2 increase susceptibility to breast, ovarian and prostate cancers. The product of human BRCA2, BRCA2 protein, has a key role in the repair of DNA double-strand breaks and interstrand cross-links by RAD51-mediated homologous recombination. Here, we present a biochemical and structural characterization of full-length (3,418 amino acid) BRCA2, alone and in complex with RAD51. We show that BRCA2 facilitates nucleation of RAD51 filaments at multiple sites on single-stranded DNA. Three-dimensional EM reconstructions revealed that BRCA2 exists as a dimer and that two oppositely oriented sets of RAD51 molecules bind the dimer. Single-stranded DNA binds along the long axis of BRCA2, such that only one set of RAD51 monomers can form a productive complex with DNA and establish filament formation. Our data define the molecular mechanism by which this tumor suppressor facilitates RAD51-mediated homologous-recombinational repair.

  • Journal article
    Krynicka V, Tichy M, Krafl J, Yu J, Kana R, Boehm M, Nixon PJ, Komenda Jet al., 2014,

    Two essential FtsH proteases control the level of the Fur repressor during iron deficiency in the cyanobacterium <i>Synechocystis</i> sp PCC 6803

    , MOLECULAR MICROBIOLOGY, Vol: 94, Pages: 609-624, ISSN: 0950-382X
  • Journal article
    Leung HTA, Kukic P, Camilloni C, Bemporad F, De Simone A, Aprile FA, Kumita JR, Vendruscolo Met al., 2014,

    NMR characterization of the conformational fluctuations of the human lymphocyte function-associated antigen-1 I-domain

    , PROTEIN SCIENCE, Vol: 23, Pages: 1596-1606, ISSN: 0961-8368
  • Journal article
    Fajardo A, Hernando-Amado S, Oliver A, Ball G, Filloux A, Martinez JLet al., 2014,

    Characterization of a novel Zn<SUP>2+</SUP>-dependent intrinsic imipenemase from <i>Pseudomonas aeruginosa</i>

    , JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 69, Pages: 2972-2978, ISSN: 0305-7453
  • Journal article
    Pallett MA, Berger CN, Pearson JS, Hartland EL, Frankel Get al., 2014,

    The Type III Secretion Effector NleF of Enteropathogenic <i>Escherichia coli</i> Activates NF-κB Early during Infection

    , INFECTION AND IMMUNITY, Vol: 82, Pages: 4878-4888, ISSN: 0019-9567
  • Journal article
    Clements A, Stoneham CA, Furniss RCD, Frankel Get al., 2014,

    Enterohaemorrhagic <i>Escherichia coli</i> inhibits recycling endosome function and trafficking of surface receptors

    , CELLULAR MICROBIOLOGY, Vol: 16, Pages: 1693-1705, ISSN: 1462-5814
  • Journal article
    Bryan SJ, Burroughs NJ, Shevela D, Yu J, Rupprecht E, Liu L-N, Mastroianni G, Xue Q, Llorente-Garcia I, Leake MC, Eichacker LA, Schneider D, Nixon PJ, Mullineaux CWet al., 2014,

    Localisation and interactions of the Vipp1 protein in cyanobacteria

    , Molecular Microbiology, Vol: 94, Pages: 1179-1195, ISSN: 1365-2958

    The Vipp1 protein is essential in cyanobacteria andchloroplasts for the maintenance of photosyntheticfunction and thylakoid membrane architecture. Toinvestigate its mode of action we generated strainsof the cyanobacteria Synechocystis sp. PCC6803and Synechococcus sp. PCC7942 in which Vipp1was tagged with green fluorescent protein at theC-terminus and expressed from the native chromosomallocus. There was little perturbation of function. Live-cell fluorescence imaging shows dramatic relocalisationof Vipp1 under high light. Under low light,Vipp1 is predominantly dispersed in the cytoplasmwith occasional concentrations at the outer peripheryof the thylakoid membranes. High light induces Vipp1coalescence into localised puncta within minutes, withnet relocation of Vipp1 to the vicinity of the cytoplasmicmembrane and the thylakoid membranes. Pulldownsand mass spectrometry identify an extensivecollection of proteins that are directly or indirectlyassociated with Vipp1 only after high-light exposure.These include not only photosynthetic and stressrelatedproteins but also RNA-processing, translationand protein assembly factors. This suggests that theVipp1 puncta could be involved in protein assembly.One possibility is that Vipp1 is involved in the formationof stress-induced localised protein assemblycentres, enabling enhanced protein synthesis anddelivery to membranes under stress conditions.

  • Journal article
    Lee C, Kang HJ, Hjelm A, Qureshi AA, Nji E, Choudhury H, Beis K, de Gier J-W, Drew Det al., 2014,

    MemStar: A one-shot <i>Escherichia coli</i>-based approach for high-level bacterial membrane protein production

    , FEBS LETTERS, Vol: 588, Pages: 3761-3769, ISSN: 0014-5793
  • Journal article
    Burroughs NJ, Boehm M, Eckert C, Mastroianni G, Spence EM, Yu J, Nixon PJ, Appel J, Mullineaux CW, Bryan SJet al., 2014,

    Solar powered biohydrogen production requires specific localization of the hydrogenase.

    , Energy Environ Sci, Vol: 7, Pages: 3791-3800, ISSN: 1754-5692

    Cyanobacteria contain a bidirectional [NiFe] hydrogenase which transiently produces hydrogen upon exposure of anoxic cells to light, potentially acting as a "valve" releasing excess electrons from the electron transport chain. However, its interaction with the photosynthetic electron transport chain remains unclear. By GFP-tagging the HoxF diaphorase subunit we show that the hydrogenase is thylakoid associated, comprising a population dispersed uniformly through the thylakoids and a subpopulation localized to discrete puncta in the distal thylakoid. Thylakoid localisation of both the HoxH and HoxY hydrogenase subunits is confirmed by immunogold electron microscopy. The diaphorase HoxE subunit is essential for recruitment to the dispersed thylakoid population, potentially anchoring the hydrogenase to the membrane, but aggregation to puncta occurs through a distinct HoxE-independent mechanism. Membrane association does not require NDH-1. Localization is dynamic on a scale of minutes, with anoxia and high light inducing a significant redistribution between these populations in favour of puncta. Since HoxE is essential for access to its electron donor, electron supply to the hydrogenase depends on a physiologically controlled localization, potentially offering a new avenue to enhance photosynthetic hydrogen production by exploiting localization/aggregation signals.

  • Journal article
    Campeotto I, Percy MG, MacDonald JT, Foerster A, Freemont PS, Gruendling Aet al., 2014,

    Structural and Mechanistic Insight into the Listeria monocytogenes Two-enzyme Lipoteichoic Acid Synthesis System

    , Journal of Biological Chemistry, Vol: 289, Pages: 28054-28069, ISSN: 0021-9258

    Lipoteichoic acid (LTA) is an important cell wall componentrequired for proper cell growth in many Gram-positive bacteria.In Listeria monocytogenes, two enzymes are required for the synthesisof this polyglycerolphosphate polymer. The LTA primaseLtaPLm initiates LTA synthesis by transferring the first glycerolphosphate(GroP) subunit onto the glycolipid anchor and theLTA synthase LtaSLm extends the polymer by the repeated additionof GroP subunits to the tip of the growing chain. Here, wepresent the crystal structures of the enzymatic domains ofLtaPLm and LtaSLm. Although the enzymes share the same fold,substantial differences in the cavity of the catalytic site andsurface charge distribution contribute to enzyme specialization.The eLtaSLm structure was also determined in complexwith GroP revealing a second GroP binding site. Mutationalanalysis confirmed an essential function for this binding siteand allowed us to propose a model for the binding of thegrowing chain.

  • Journal article
    Boulet-Audet M, Byrne B, Kazarian SG, 2014,

    High-throughput thermal stability analysis of a monoclonal antibody by attenuated total reflection FT-IR spectroscopic imaging

    , Analytical Chemistry, Vol: 86, Pages: 9786-9793, ISSN: 0003-2700

    The use of biotherapeutics, such as monoclonal antibodies, has markedly increased in recent years. It is thus essential that biotherapeutic production pipelines are as efficient as possible. For the production process, one of the major concerns is the propensity of a biotherapeutic antibody to aggregate. In addition to reducing bioactive material recovery, protein aggregation can have major effects on drug potency and cause highly undesirable immunological effects. It is thus essential to identify processing conditions which maximize recovery while avoiding aggregation. Heat resistance is a proxy for long-term aggregation propensity. Thermal stability assays are routinely performed using various spectroscopic and scattering detection methods. Here, we evaluated the potential of macro attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectroscopic imaging as a novel method for the high-throughput thermal stability assay of a monoclonal antibody. This chemically specific visualization method has the distinct advantage of being able to discriminate between monomeric and aggregated protein. Attenuated total reflection is particularly suitable for selectively probing the bottom of vessels, where precipitated aggregates accumulate. With focal plane array detection, we tested 12 different buffer conditions simultaneously to assess the effect of pH and ionic strength on protein thermal stability. Applying the Finke model to our imaging kinetics allowed us to determine the rate constants of nucleation and autocatalytic growth. This analysis demonstrated the greater stability of our immunoglobulin at higher pH and moderate ionic strength, revealing the key role of electrostatic interactions. The high-throughput approach presented here has significant potential for analyzing the stability of biotherapeutics as well as any other biological molecules prone to aggregation.

  • Journal article
    Collins JW, Chervaux C, Raymond B, Derrien M, Brazeilles R, Kosta A, Chambaud I, Crepin VF, Frankel Get al., 2014,

    Fermented Dairy Products Modulate <i>Citrobacter rodentium</i>-Induced Colonic Hyperplasia

    , JOURNAL OF INFECTIOUS DISEASES, Vol: 210, Pages: 1029-1041, ISSN: 0022-1899
  • Journal article
    Hingorani K, Pace R, Whitney S, Murray JW, Smith P, Cheah MH, Wydrzynski T, Hillier Wet al., 2014,

    Photo-oxidation of tyrosine in a bio-engineered bacterioferritin 'reaction centre'-A protein model for artificial photosynthesis

    , BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, Vol: 1837, Pages: 1821-1834, ISSN: 0005-2728
  • Journal article
    Michoux F, Boehm M, Bialek W, Takasaka K, Maghlaoui K, Barber J, Murray JW, Nixon PJet al., 2014,

    Crystal structure of CyanoQ from the thermophilic cyanobacterium <i>Thermosynechococcus elongatus</i> and detection in isolated photosystem II complexes

    , PHOTOSYNTHESIS RESEARCH, Vol: 122, Pages: 57-67, ISSN: 0166-8595
  • Journal article
    Devi S, Williams DR, 2014,

    Density dependent mechanical properties and structures of a freeze dried biopharmaceutical excipient - Sucrose

  • Journal article
    Douse CH, Maas SJ, Thomas JC, Garnett JA, Sun Y, Cota E, Tate EWet al., 2014,

    Crystal Structures of Stapled and Hydrogen Bond Surrogate Peptides Targeting a Fully Buried Protein-Helix Interaction

    , ACS CHEMICAL BIOLOGY, Vol: 9, Pages: 2204-2209, ISSN: 1554-8929
  • Journal article
    Moscoso JA, Jaeger T, Valentini M, Hui K, Jenal U, Filloux Aet al., 2014,

    The Diguanylate Cyclase SadC Is a Central Player in Gac/Rsm-Mediated Biofilm Formation in Pseudomonas aeruginosa

    , Journal of Bacteriology, Vol: 196, Pages: 4081-4088, ISSN: 1098-5530

    Pseudomonas aeruginosa is a Gram-negative opportunistic human pathogen and a threat for immunocompromised and cysticfibrosis patients. It is responsible for acute and chronic infections and can switch between these lifestyles upon taking an informeddecision involving complex regulatory networks. The RetS/LadS/Gac/Rsm network and the cyclic-di-GMP (c-di-GMP)signaling pathways are both central to this phenomenon redirecting the P. aeruginosa population toward a biofilm mode ofgrowth, which is associated with chronic infections. While these two pathways were traditionally studied independently fromeach other, we recently showed that cellular levels of c-di-GMP are increased in the hyperbiofilm retS mutant. Here, we have formallyestablished the link between the two networks by showing that the SadC diguanylate cyclase is central to the Gac/Rsmassociatedphenotypes, notably, biofilm formation. Importantly, SadC is involved in the signaling that converges onto the RsmAtranslational repressor either via RetS/LadS or via HptB/HsbR. Although the level of expression of the sadC gene does not seemto be impacted by the regulatory cascade, the production of the SadC protein is tightly repressed by RsmA. This adds to thegrowing complexity of the signaling network associated with c-di-GMP in P. aeruginosa. While this organism possesses morethan 40 c-di-GMP-related enzymes, it remains unclear how signaling specificity is maintained within the c-di-GMP network. Thefinding that SadC but no other diguanylate cyclase is related to the formation of biofilm governed by the Gac/Rsm pathway furthercontributes to understanding of this insulation mechanism.

  • Journal article
    Michie KA, Boysen A, Low HH, Moller-Jensen J, Loewe Jet al., 2014,

    LeoA, B and C from enterotoxigenic escherichia coli (ETEC) are bacterial dynamins

    , PLoS One, Vol: 9, Pages: 1-10, ISSN: 1932-6203

    Escherichia coli (ETEC) strain H10407 contains a GTPase virulence factor, LeoA, which is encoded on a pathogenicity island and has been shown to enhance toxin release, potentially through vesicle secretion. By sequence comparisons and X-ray structure determination we now identify LeoA as a bacterial dynamin-like protein (DLP). Proteins of the dynamin family remodel membranes and were once thought to be restricted to eukaryotes. In ETEC H10407 LeoA localises to the periplasm where it forms a punctate localisation pattern. Bioinformatic analyses of leoA and the two upstream genes leoB and leoC suggest that LeoA works in concert with a second dynamin-like protein, made up of LeoB and LeoC. Disruption of the leoAB genes leads to a reduction in secretion of periplasmic Tat-GFP and outer membrane OmpA. Our data suggest a role for LeoABC dynamin-like proteins in potentiating virulence through membrane vesicle associated toxin secretion.

  • Journal article
    Matsuo E, Leon E, Matthews SJ, Roy Pet al., 2014,

    Structure based modification of Bluetongue virus helicase protein VP6 to produce a viable VP6-truncated BTV

  • Journal article
    Cole K, Buffler A, Cilliers JJ, Govender I, Heng JYY, Liu C, Parker DJ, Shah UV, van Heerden M, Fan Xet al., 2014,

    A surface coating method to modify tracers for positron emission particle tracking (PEPT) measurements of froth flotation

    , Powder Technology, Vol: 263, Pages: 26-30, ISSN: 0032-5910

    Positron emission particle tracking (PEPT) is a technique by which particle behaviour can be measured in a system of flow. The quality of the measurement is related to the spatial and temporal precision of the PET scanner and the characteristics of the tracer, which must replicate physical and chemical properties of the system bulk. Tracer particles can be made from ion exchange resins which have a high capacity for the commonly used positron emitting radionuclides 18F or 68Ga. However, these resins have a polymer composition and are naturally hydrophilic, which limits their application in systems involving mineral particles. This work presents a method to modify ion exchange resins with a coating to change the physical properties of the tracer. Two types of tracer were fabricated in this way, with hydrophobic and hydrophilic surfaces, to investigate the behaviour of valuable and gangue minerals in froth flotation with PEPT. The PEPT data were used to determine the spatial occupancies of each tracer, showing that the hydrophobic tracer has the highest occupancy in the froth region and the hydrophilic tracer is rarely entrained.

  • Conference paper
    Mota J, Holden DW, Domingues L, 2014,

    The <i>Salmonella</i> effector SteA contributes to the control of membrane dynamics of <i>Salmonella</i>-containing vacuoles

    , FEBS EMBO 2014 Conference, Publisher: WILEY-BLACKWELL, Pages: 766-767, ISSN: 1742-464X
  • Journal article
    Hirt MN, Boeddinghaus J, Mitchell A, Schaaf S, Boernchen C, Mueller C, Schulz H, Hubner N, Stenzig J, Stoehr A, Neuber C, Eder A, Luther PK, Hansen A, Eschenhagen Tet al., 2014,

    Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation

    , JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 74, Pages: 151-161, ISSN: 0022-2828
  • Journal article
    Collins JW, Keeney KM, Crepin VE, Rathinam VAK, Fitzgerald KA, Finlay BB, Frankel Get al., 2014,

    <i>Citrobacter rodentium</i>: infection, inflammation and the microbiota

    , NATURE REVIEWS MICROBIOLOGY, Vol: 12, Pages: 612-623, ISSN: 1740-1526
  • Journal article
    Berry AA, Yang Y, Pakharukova N, Garnett JA, Lee W-C, Cota E, Marchant J, Roy S, Tuittila M, Liu B, Inman KG, Ruiz-Perez F, Mandomando I, Nataro JP, Zavialov AV, Matthews Set al., 2014,

    Structural Insight into Host Recognition by Aggregative Adherence Fimbriae of Enteroaggregative <i>Escherichia coli</i>

    , PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366
  • Journal article
    Mousnier A, Schroeder GN, Stoneham CA, So EC, Garnett JA, Yu L, Matthews SJ, Choudhary JS, Hartland EL, Frankel Get al., 2014,

    A New Method To Determine <i>In Vivo</i> Interactomes Reveals Binding of the <i>Legionella pneumophila</i> Effector PieE to Multiple Rab GTPases

    , MBIO, Vol: 5, ISSN: 2150-7511
  • Journal article
    Gründling A, 2014,

    Milestones in nucleotide signaling research: Nucleotide signals are found in bacteria as well as eukaryotes, and may act intra- or extracellularly

    , Microbe, Vol: 9, Pages: 315-320, ISSN: 1558-7452
  • Journal article
    Chung L, Bailey D, Leen EN, Emmott EP, Chaudhry Y, Roberts LO, Curry S, Locker N, Goodfellow IGet al., 2014,

    Norovirus Translation Requires an Interaction between the C Terminus of the Genome-linked Viral Protein VPg and Eukaryotic Translation Initiation Factor 4G

    , Journal of Biological Chemistry, Vol: 289, Pages: 21738-21750, ISSN: 0021-9258
  • Journal article
    Casini A, Christodoulou G, Freemont PS, Baldwin GS, Ellis T, MacDonald JTet al., 2014,

    R2oDNA Designer: Computational Design of Biologically Neutral Synthetic DNA Sequences

    , ACS SYNTHETIC BIOLOGY, Vol: 3, Pages: 525-528, ISSN: 2161-5063
  • Journal article
    Baek KT, Grundling A, Mogensen RG, Thogersen L, Petersen A, Paulander W, Frees Det al., 2014,

    β-Lactam Resistance in Methicillin-Resistant <i>Staphylococcus aureus</i> USA300 Is Increased by Inactivation of the ClpXP Protease

    , ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 58, Pages: 4593-4603, ISSN: 0066-4804
  • Journal article
    Stevens MP, Frankel GM, 2014,

    The Locus of Enterocyte Effacement and Associated Virulence Factors of Enterohemorrhagic Escherichia coli.

    , Microbiol Spectr, Vol: 2

    A subset of Shiga toxin-producing Escherichia coli strains, termed enterohemorrhagic E. coli (EHEC), is defined in part by the ability to produce attaching and effacing (A/E) lesions on intestinal epithelia. Such lesions are characterized by intimate bacterial attachment to the apical surface of enterocytes, cytoskeletal rearrangements beneath adherent bacteria, and destruction of proximal microvilli. A/E lesion formation requires the locus of enterocyte effacement (LEE), which encodes a Type III secretion system that injects bacterial proteins into host cells. The translocated proteins, termed effectors, subvert a plethora of cellular pathways to the benefit of the pathogen, for example, by recruiting cytoskeletal proteins, disrupting epithelial barrier integrity, and interfering with the induction of inflammation, phagocytosis, and apoptosis. The LEE and selected effectors play pivotal roles in intestinal persistence and virulence of EHEC, and it is becoming clear that effectors may act in redundant, synergistic, and antagonistic ways during infection. Vaccines that target the function of the Type III secretion system limit colonization of reservoir hosts by EHEC and may thus aid control of zoonotic infections. Here we review the features and functions of the LEE-encoded Type III secretion system and associated effectors of E. coli O157:H7 and other Shiga toxin-producing E. coli strains.

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