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  • Journal article
    Mueller A, Beeby M, McDowall AW, Chow J, Jensen GJ, Clemons WMet al., 2014,

    Ultrastructure and complex polar architecture of the human pathogen Campylobacter jejuni

    , MicrobiologyOpen, Vol: 3, Pages: 702-710, ISSN: 2045-8827

    Campylobacter jejuni is one of the most successful food-borne humanpathogens. Here we use electron cryotomography to explore the ultrastructureof C. jejuni cells in logarithmically growing cultures. This provides the first lookat this pathogen in a near-native state at macromolecular resolution (~5 nm).We find a surprisingly complex polar architecture that includes ribosomeexclusion zones, polyphosphate storage granules, extensive collar-shapedchemoreceptor arrays, and elaborate flagellar motors.

  • Journal article
    Puncochova K, Heng JYY, Beranek J, Stepanek Fet al., 2014,

    Investigation of drug-polymer interaction in solid dispersions by vapour sorption methods

    , INTERNATIONAL JOURNAL OF PHARMACEUTICS, Vol: 469, Pages: 159-167, ISSN: 0378-5173
  • Journal article
    Smyth E, Solomon A, Vydyanath A, Luther PK, Pitchford S, Tetley TD, Emerson Met al., 2014,

    Induction and enhancement of platelet aggregation in vitro and in vivo by model polystyrene nanoparticles

    , Nanotoxicology, Vol: 9, Pages: 356-364, ISSN: 1743-5404

    Abstract Nanoparticles (NPs) may come into contact with circulating blood elements including platelets following inhalation and translocation from the airways to the bloodstream or during proposed medical applications. Studies with model polystyrene latex nanoparticles (PLNPs) have shown that NPs are able to induce platelet aggregation in vitro suggesting a poorly defined potential mechanism of increased cardiovascular risk upon NP exposure. We aimed to provide insight into the mechanisms by which NPs may increase cardiovascular risk by determining the impact of a range of concentrations of PLNPs on platelet activation in vitro and in vivo and identifying the signaling events driving NP-induced aggregation. Model PLNPs of varying nano-size (50 and 100 nm) and surface chemistry [unmodified (uPLNP), amine-modified (aPLNP) and carboxyl-modified (cPLNP)] were therefore examined using in vitro platelet aggregometry and an established mouse model of platelet thromboembolism. Most PLNPs tested induced GPIIb/IIIa-mediated platelet aggregation with potencies that varied with both surface chemistry and nano-size. Aggregation was associated with signaling events, such as granule secretion and release of secondary agonists, indicative of conventional agonist-mediated aggregation. Platelet aggregation was associated with the physical interaction of PLNPs with the platelet membrane or internalization. 50 nm aPLNPs acted through a distinct mechanism involving the physical bridging of adjacent non-activated platelets leading to enhanced agonist-induced aggregation in vitro and in vivo. Our study suggests that should they translocate the pulmonary epithelium, or be introduced into the blood, NPs may increase the risk of platelet-driven events by inducing or enhancing platelet aggregation via mechanisms that are determined by their distinct combination of nano-size and surface chemistry.

  • Journal article
    Torre I, Jeddi M, Amat-Roldan I, Hunter S, Sadayappan S, Robbins J, Moss RL, Luther PKet al., 2014,

    Ultrastructural and electron tomography analyses of cardiac muscle: normal muscle compared to presence and absence of myosin binding protein C-phosphorylation

    , CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
  • Journal article
    Amat-Roldan I, Torre I, Luther PK, 2014,

    Molecular model confirms experimental differences on polarization second harmonic signal from cardiac myosin isoforms

    , CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
  • Journal article
    Smith RR, Williams DR, Burnett DJ, Heng JYYet al., 2014,

    A new method to determine dispersive surface energy site distributions by inverse gas chromatography

    , Langmuir: the ACS journal of surfaces and colloids, Vol: 30, Pages: 8029-8035, ISSN: 0743-7463

    A computational model to predict the relative energy site contributions of a heterogeneous material from data collected by finite dilution–inverse gas chromatography (FD-IGC) is presented in this work. The methodology employed a multisolvent system site filling model utilizing Boltzmann statistics, expanding on previous efforts to calculate “experienced energies” at varying coverage, yielding a retention volume distribution allowing calculation of a surface free energy distribution. Surface free energy distributions were experimentally measured for racemic ibuprofen and β-mannitol powders, the energies of each were found in the ranges 43–52 and 40–55 mJ/m2, respectively, over a surface coverage range of 0–8%. The computed contributions to surface energy values were found to match closely with data collected on macroscopic crystals by alternative techniques (±<1.5 mJ/m2).

  • Journal article
    Goers L, Freemont P, Polizzi KM, 2014,

    Co-culture systems and technologies: taking synthetic biology to the next level

    , JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 11, ISSN: 1742-5689
  • Journal article
    Khurshid S, Saridakis E, Govada L, Chayen NEet al., 2014,

    Porous nucleating agents for protein crystallization

    , Nature Protocols, Vol: 9, Pages: 1621-1633, ISSN: 1750-2799

    Solving the structure of proteins is pivotal to achieving success in rational drug design and in other biotechnological endeavors. The most powerful method for determining the structure of proteins is X-ray crystallography, which relies on the availability of high-quality crystals. However, obtaining such crystals is a major hurdle. Nucleation is the crucial prerequisite step, which requires overcoming an energy barrier. The presence in a protein solution of a nucleant, a solid or a semiliquid substance that facilitates overcoming that barrier allows crystals to grow under ideal conditions, paving the way for the formation of high-quality crystals. The use of nucleants provides a unique means for optimizing the diffraction quality of crystals, as well as for discovering new crystallization conditions. We present a protocol for controlling the nucleation of protein crystals that is applicable to a wide variety of nucleation-inducing substances. Setting up crystallization trials using these nucleating agents takes an additional few seconds compared with conventional setup, and it can accelerate crystallization, which typically takes several days to months.

  • Journal article
    Song-Zhao GX, Srinivasan N, Pott J, Baban D, Frankel G, Maloy KJet al., 2014,

    Nlrp3 activation in the intestinal epithelium protects against a mucosal pathogen

    , MUCOSAL IMMUNOLOGY, Vol: 7, Pages: 763-774, ISSN: 1933-0219
  • Journal article
    Domingues L, Holden DW, Mota LJ, 2014,

    The Salmonella Effector SteA Contributes to the Control of Membrane Dynamics of Salmonella-Containing Vacuoles

    , INFECTION AND IMMUNITY, Vol: 82, Pages: 2923-2934, ISSN: 0019-9567
  • 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 In Vivo Interactomes Reveals Binding of the Legionella pneumophila Effector PieE to Multiple Rab GTPases

    , MBIO, Vol: 5, ISSN: 2150-7511
  • Conference paper
    Beeby M, 2014,

    Evolution of Novel Components of the Bacterial Flagellar Motor

    , 28th Annual Symposium of the Protein-Society, Publisher: WILEY-BLACKWELL, Pages: 61-61, ISSN: 0961-8368
  • Journal article
    Lin J, Oh S-H, Jones R, Garnett JA, Salgado PS, Rusnakova S, Matthews SJ, Hoyer LL, Cota Eet al., 2014,

    The peptide-binding cavity Is essential for Als3-mediated adhesion of Candida albicans to human cells

    , Journal of Biological Chemistry, Vol: 289, Pages: 18401-18412, ISSN: 1083-351X

    Background: Of the eight cell surface glycoproteins in the C. albicans Als family, Als3 makes the largest contribution to adhesion to human cells.Results: Mutation of the Als3 peptide-binding cavity (PBC) results in loss of Als3 adhesive function.Conclusion: The PBC is required for Als3 adhesive function.Significance: Interfering with PBC function is a viable strategy for inhibiting C. albicans adhesion.

  • Journal article
    Ma L-S, Hachani A, Lin J-S, Filloux A, Lai E-Met al., 2014,

    Agrobacterium tumefaciens Deploys a Superfamily of Type VI Secretion DNase Effectors as Weapons for Interbacterial Competition In Planta

    , Cell Host & Microbe, Vol: 16, Pages: 94-104, ISSN: 1934-6069

    The type VI secretion system (T6SS) is a widespread molecular weapon deployed by many Proteobacteria to target effectors/toxins into both eukaryotic and prokaryotic cells. We report that Agrobacterium tumefaciens, a soil bacterium that triggers tumorigenesis in plants, produces a family of type VI DNase effectors (Tde) that are distinct from previously known polymorphic toxins and nucleases. Tde exhibits an antibacterial DNase activity that relies on a conserved HxxD motif and can be counteracted by a cognate immunity protein, Tdi. In vitro, A. tumefaciens T6SS could kill Escherichia coli but triggered a lethal counterattack by Pseudomonas aeruginosa upon injection of the Tde toxins. However, in an in planta coinfection assay, A. tumefaciens used Tde effectors to attack both siblings cells and P. aeruginosa to ultimately gain a competitive advantage. Such acquired T6SS-dependent fitness in vivo and conservation of Tde-Tdi couples in bacteria highlights a widespread antibacterial weapon beneficial for niche colonization.

  • Journal article
    Choudhury HG, Tong Z, Mathavan I, Li Y, Iwata S, Zirah S, Rebuffat S, van Veen HW, Beis Ket al., 2014,

    Structure of an antibacterial peptide ATP-binding cassette transporter in a novel outward occluded state

    , Proceedings of the National Academy of Sciences of the United States of America, Vol: 111, Pages: 9145-9150, ISSN: 0027-8424

    Enterobacteriaceae produce antimicrobial peptides for survival under nutrient starvation. Microcin J25 (MccJ25) is an antimicrobial peptide with a unique lasso topology. It is secreted by the ATP-binding cassette (ABC) exporter McjD, which ensures self-immunity of the producing strain through efficient export of the toxic mature peptide from the cell. Here we have determined the crystal structure of McjD from Escherichia coli at 2.7-Å resolution, which is to the authors’ knowledge the first structure of an antibacterial peptide ABC transporter. Our functional and biochemical analyses demonstrate McjD-dependent immunity to MccJ25 through efflux of the peptide. McjD can directly bind MccJ25 and displays a basal ATPase activity that is stimulated by MccJ25 in both detergent solution and proteoliposomes. McjD adopts a new conformation, termed nucleotide-bound outward occluded. The new conformation defines a clear cavity; mutagenesis and ligand binding studies of the cavity have identified Phe86, Asn134, and Asn302 as important for recognition of MccJ25. Comparisons with the inward-open MsbA and outward-open Sav1866 structures show that McjD has structural similarities with both states without the intertwining of transmembrane (TM) helices. The occluded state is formed by rotation of TMs 1 and 2 toward the equivalent TMs of the opposite monomer, unlike Sav1866 where they intertwine with TMs 3–6 of the opposite monomer. Cysteine cross-linking studies on the McjD dimer in inside-out membrane vesicles of E. coli confirmed the presence of the occluded state. We therefore propose that the outward-occluded state represents a transition intermediate between the outward-open and inward-open conformation of ABC exporters.

  • Journal article
    De Simone A, Mote KR, Veglia G, 2014,

    Structural Dynamics and Conformational Equilibria of SERCA Regulatory Proteins in Membranes by Solid-State NMR Restrained Simulations

    , BIOPHYSICAL JOURNAL, Vol: 106, Pages: 2566-2576, ISSN: 0006-3495
  • Journal article
    Shah UV, Olusanmi D, Narang AS, Hussain MA, Gamble JF, Tobyn MJ, Heng JYYet al., 2014,

    Effect of crystal habits on the surface energy and cohesion of crystalline powders

    , International Journal of Pharmaceutics, Vol: 472, Pages: 140-147, ISSN: 1873-3476

    The role of surface properties, influenced by particle processing, in particle–particle interactions (powder cohesion) is investigated in this study. Wetting behaviour of mefenamic acid was found to be anisotropic by sessile drop contact angle measurements on macroscopic (>1 cm) single crystals, with variations in contact angle of water from 56.3° to 92.0°. This is attributed to variations in surface chemical functionality at specific facets, and confirmed using X-ray photoelectron spectroscopy (XPS). Using a finite dilution inverse gas chromatography (FD-IGC) approach, the surface energy heterogeneity of powders was determined. The surface energy profile of different mefenamic acid crystal habits was directly related to the relative exposure of different crystal facets. Cohesion, determined by a uniaxial compression test, was also found to relate to surface energy of the powders. By employing a surface modification (silanisation) approach, the contribution from crystal shape from surface area and surface energy was decoupled. By “normalising” contribution from surface energy and surface area, needle shaped crystals were found to be ∼2.5× more cohesive compared to elongated plates or hexagonal cuboid shapes crystals.

  • Journal article
    Xu Y, Plechanovova A, Simpson P, Marchant J, Leidecker O, Kraatz S, Hay RT, Matthews SJet al., 2014,

    Structural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4

    , NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723
  • Journal article
    Lambert SM, Langley DR, Garnett JA, Angell R, Hedgethorne K, Meanwell NA, Matthews SJet al., 2014,

    The crystal structure of NS5A domain 1 from genotype 1a reveals new clues to the mechanism of action for dimeric HCV inhibitors

    , PROTEIN SCIENCE, Vol: 23, Pages: 723-734, ISSN: 0961-8368
  • Journal article
    Liu J, Yang J, Wen J, Yang Y, Wei X, Zhang X, Wang Y-Pet al., 2014,

    Mutational analysis of dimeric linkers in peri- and cytoplasmic domains of histidine kinase DctB reveals their functional roles in signal transduction

    , OPEN BIOLOGY, Vol: 4, ISSN: 2046-2441
  • Journal article
    Fusco G, De Simone A, Gopinath T, Vostrikov V, Vendruscolo M, Dobson CM, Veglia Get al., 2014,

    Direct observation of the three regions in alpha-synuclein that determine its membrane-bound behaviour

    , Nature Communications, Vol: 5, Pages: 1-8, ISSN: 2041-1723

    α-synuclein (αS) is a protein involved in neurotransmitter release in presynaptic terminals, and whose aberrant aggregation is associated with Parkinson’s disease. In dopaminergic neurons, αS exists in a tightly regulated equilibrium between water-soluble and membrane-associated forms. Here we use a combination of solid-state and solution NMR spectroscopy to characterize the conformations of αS bound to lipid membranes mimicking the composition and physical properties of synaptic vesicles. The study shows three αS regions possessing distinct structural and dynamical properties, including an N-terminal helical segment having a role of membrane anchor, an unstructured C-terminal region that is weakly associated with the membrane and a central region acting as a sensor of the lipid properties and determining the affinity of αS membrane binding. Taken together, our data define the nature of the interactions of αS with biological membranes and provide insights into their roles in the function of this protein and in the molecular processes leading to its aggregation.

  • Journal article
    Xu H, Abe T, Liu JKH, Zalivina I, Hohenester E, Leitinger Bet al., 2014,

    Normal Activation of Discoidin Domain Receptor 1 Mutants with Disulfide Cross-links, Insertions, or Deletions in the Extracellular Juxtamembrane Region

    , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289, Pages: 13565-13574
  • Journal article
    Hachani A, Allsopp LP, Oduko Y, Filloux Aet al., 2014,

    The VgrG Proteins Are "à la Carte" Delivery Systems for Bacterial Type VI Effectors

    , Journal of Biological Chemistry, Vol: 289, Pages: 17872-17884, ISSN: 1083-351X

    The bacterial type VI secretion system (T6SS) is a supra-molecular complex akin to bacteriophage tails, with VgrG proteins acting as a puncturing device. The Pseudomonas aeruginosa H1-T6SS has been extensively characterized. It is involved in bacterial killing and in the delivery of three toxins, Tse1–3. Here, we demonstrate the independent contribution of the three H1-T6SS co-regulated vgrG genes, vgrG1abc, to bacterial killing. A putative toxin is encoded in the vicinity of each vgrG gene, supporting the concept of specific VgrG/toxin couples. In this respect, VgrG1c is involved in the delivery of an Rhs protein, RhsP1. The RhsP1 C terminus carries a toxic activity, from which the producing bacterium is protected by a cognate immunity. Similarly, VgrG1a-dependent toxicity is associated with the PA0093 gene encoding a two-domain protein with a putative toxin domain (Toxin_61) at the C terminus. Finally, VgrG1b-dependent killing is detectable upon complementation of a triple vgrG1abc mutant. The VgrG1b-dependent killing is mediated by PA0099, which presents the characteristics of the superfamily nuclease 2 toxin members. Overall, these data develop the concept that VgrGs are indispensable components for the specific delivery of effectors. Several additional vgrG genes are encoded on the P. aeruginosa genome and are not linked genetically to other T6SS genes. A closer inspection of these clusters reveals that they also encode putative toxins. Overall, these associations further support the notion of an original form of secretion system, in which VgrG acts as the carrier.

  • Journal article
    Lansky S, Alalouf O, Solomon V, Alhassid A, Govada L, Chayen NE, Belrhali H, Shoham Y, Shoham Get al., 2014,

    Crystallization and preliminary crystallographic analysis of Axe2, an acetylxylan esterase from Geobacillus stearothermophilus. (vol 69, pg 430, 2013)

    , ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, Vol: 70, Pages: 685-685
  • Journal article
    Burgoyne T, Lewis A, Dewar A, Luther P, Hogg C, Shoemark A, Dixon Met al., 2014,

    Characterizing the ultrastructure of primary ciliary dyskinesia transposition defect using electron tomography

    , CYTOSKELETON, Vol: 71, Pages: 294-301, ISSN: 1949-3584
  • Journal article
    Shinopoulos KE, Yu J, Nixon PJ, Brudvig GWet al., 2014,

    Using site-directed mutagenesis to probe the role of the D2 carotenoid in the secondary electron-transfer pathway of photosystem II

    , Photosynthesis Research, Vol: 120, Pages: 141-152, ISSN: 1573-5079

    Secondary electron transfer in photosystem II(PSII), which occurs when water oxidation is inhibited,involves redox-active carotenoids (Car), as well as chlorophylls(Chl), and cytochrome b559 (Cyt b559), and is believedto play a role in photoprotection. CarD2 may be the initialpoint of secondary electron transfer because it is the closestcofactor to both P680, the initial oxidant, and to Cyt b559, theterminal secondary electron donor within PSII. In order tocharacterize the role of CarD2 and to determine the effects ofperturbing CarD2 on both the electron-transfer events and onthe identity of the redox-active cofactors, it is necessary tovary the properties of CarD2 selectively without affecting theten other Car per PSII. To this end, site-directed mutationsaround the binding pocket of CarD2 (D2-G47W, D2-G47F,and D2-T50F) have been generated in Synechocystissp. PCC6803. Characterization by near-IR and EPR spectroscopyprovides the first experimental evidence that CarD2 is one ofthe redox-active carotenoids in PSII. There is a specificperturbation of the Car•? near-IR spectrum in all threemutated PSII samples, allowing the assignment of thespectral signature of CarD2•?; CarD2•? exhibits a near-IR peak at 980 nm and is the predominant secondary donor oxidized ina charge separation at low temperature in ferricyanide-treatedwild-type PSII. The yield of secondary donor radicals issubstantially decreased in PSII complexes isolated from eachmutant. In addition, the kinetics of radical formation arealtered in the mutated PSII samples. These results are consistentwith oxidation of CarD2 being the initial step in secondaryelectron transfer. Furthermore, normal light levelsduring mutant cell growth perturb the shape of the Chl•?near-IR absorption peak and generate a dark-stable radicalobservable in the EPR spectra, indicating a higher susceptibilityto photodamage further linking the secondary electron-transferpathway to photoprotection.

  • Journal article
    Mathavan I, Zirah S, Mehmood S, Choudhury HG, Goulard C, Li Y, Robinson CV, Rebuffat S, Beis Ket al., 2014,

    Structural basis for hijacking siderophore receptors by antimicrobial lasso peptides

    , Nature Chemical Biology, Vol: 10, Pages: 340-342, ISSN: 1552-4450

    The lasso peptide microcin J25 is known to hijack the siderophore receptor FhuA for initiating internalization. Here, we provide what is to our knowledge the first structural evidence on the recognition mechanism, and our biochemical data show that another closely related lasso peptide cannot interact with FhuA. Our work provides an explanation on the narrow activity spectrum of lasso peptides and opens the path to the development of new antibacterials.

  • Journal article
    Ewens CA, Panico S, Kloppsteck P, McKeown C, Ebong I-O, Robinson C, Zhang X, Freemont PSet al., 2014,

    The p97-FAF1 Protein Complex Reveals a Common Mode of p97 Adaptor Binding

    , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289, Pages: 12077-12084
  • Journal article
    Horejs C-M, Serio A, Purvis A, Gormley AJ, Bertazzo S, Poliniewicz A, Wang AJ, DiMaggio P, Hohenester E, Stevens MMet al., 2014,

    Biologically-active laminin-111 fragment that modulates the epithelial-to-mesenchymal transition in embryonic stem cells

    , Proceedings of the National Academy of Sciences of the United States of America, Vol: 111, Pages: 5908-5913, ISSN: 0027-8424

    The dynamic interplay between the extracellular matrix and embryonic stem cells (ESCs) constitutes one of the key steps in understanding stem cell differentiation in vitro. Here we report a biologically-active laminin-111 fragment generated by matrix metalloproteinase 2 (MMP2) processing, which is highly up-regulated during differentiation. We show that the β1-chain–derived fragment interacts via α3β1-integrins, thereby triggering the down-regulation of MMP2 in mouse and human ESCs. Additionally, the expression of MMP9 and E-cadherin is up-regulated in mouse ESCs—key players in the epithelial-to-mesenchymal transition. We also demonstrate that the fragment acts through the α3β1-integrin/extracellular matrix metalloproteinase inducer complex. This study reveals a previously unidentified role of laminin-111 in early stem cell differentiation that goes far beyond basement membrane assembly and a mechanism by which an MMP2-cleaved laminin fragment regulates the expression of E-cadherin, MMP2, and MMP9.

  • Journal article
    Curry S, 2014,

    Open access - reasons to be cheerful: a reply to Agrawal

    , Trends in Plant Science, Vol: 19, Pages: 196-197

    Anurag Agrawal's recent letter on open access publishing raises an important topic that many researchers may have found difficult to engage with, not least because its myriad complexities are frequently enveloped in strong cross-currents of opinion. Agrawal is concerned that some scientists might still be rather uncritical of the accelerating open-access bandwagon and rightly highlights some of the possible pitfalls. However, although it is important to be aware of the risks of open access, Agrawal was more pessimistic in his assessment than is warranted by the evidence and, in my view, paid insufficient attention to the possible benefits.

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