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Pore forming toxins

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https://www.readbyqxmd.com/read/28323617/cryoem-structures-of-membrane-pore-and-prepore-complex-reveal-cytolytic-mechanism-of-pneumolysin
#1
Katharina van Pee, Alexander Neuhaus, Edoardo D'Imprima, Deryck J Mills, Werner Kühlbrandt, Özkan Yildiz
Many pathogenic bacteria produce pore-forming toxins to attack and kill human cells. We have determined the 4.5 Å structure of the ~2.2 MDa pore complex of pneumolysin, the main virulence factor of Streptococcus pneumoniae, by cryoEM. The pneumolysin pore is a 400 Å ring of 42 membrane-inserted monomers. Domain D3 of the soluble toxin refolds into two ~85 Å β-hairpins that traverse the lipid bilayer and assemble into a 168-strand β-barrel. The pore complex is stabilized by salt bridges between β-hairpins of adjacent subunits and an internal α-barrel...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28322888/review-manuscript-pneumolysin-as-a-potential-therapeutic-target-in-severe-pneumococcal-disease
#2
REVIEW
Ronald Anderson, Charles Feldman
Acute pulmonary and cardiac injury remain significant causes of morbidity and mortality in those afflicted with severe pneumococcal disease, with the risk for early mortality often persisting several years beyond clinical recovery. Although remaining to be firmly established in the clinical setting, a considerable body of evidence, mostly derived from murine models of experimental infection, has implicated the pneumococcal, cholesterol-binding, pore-forming toxin, pneumolysin (Ply), in the pathogenesis of lung and myocardial dysfunction...
March 16, 2017: Journal of Infection
https://www.readbyqxmd.com/read/28304231/f199e-substitution-reduced-toxicity-of-clostridium-perfringens-epsilon-toxin-by-depriving-the-receptor-binding-capability
#3
Jingjing Kang, Jie Gao, Wenwu Yao, Lin Kang, Shan Gao, Hao Yang, Bin Ji, Ping Li, Jing Liu, Jiahao Yao, Wenwen Xin, Baohua Zhao, Jinglin Wang
Epsilon toxin (ETX), a potent toxin, is produced by types B and D strains of Clostridium perfringens, which could cause severe diseases in humans and domestic animals. Mutant rETX(F199E) was previously demonstrated to be a good vaccine candidate. However, the mechanism concerned remains unknown. To clarify how F199E substitution reduced ETX toxicity, we performed a series of experiments. The results showed that the cell-binding and pore-forming ability of rETX(F199E) was almost abolished. We speculated that F199E substitution reduced toxicity by depriving the receptor binding capability of ETX, which contributed to the hypothesis that domain I of ETX is responsible for cell binding...
March 17, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28223456/a-natural-chimeric-pseudomonas-bacteriocin-with-novel-pore-forming-activity-parasitizes-the-ferrichrome-transporter
#4
Maarten G K Ghequire, Lieselore Kemland, Ernesto Anoz-Carbonell, Susan K Buchanan, René De Mot
Modular bacteriocins represent a major group of secreted protein toxins with a narrow spectrum of activity, involved in interference competition between Gram-negative bacteria. These antibacterial proteins include a domain for binding to the target cell and a toxin module at the carboxy terminus. Self-inhibition of producers is provided by coexpression of linked immunity genes that transiently inhibit the toxin's activity through formation of bacteriocin-immunity complexes or by insertion in the inner membrane, depending on the type of toxin module...
February 21, 2017: MBio
https://www.readbyqxmd.com/read/28196960/repair-of-a-bacterial-small-%C3%AE-barrel-toxin-pore-depends-on-channel-width
#5
Gisela von Hoven, Amable J Rivas, Claudia Neukirch, Martina Meyenburg, Qianqian Qin, Sapun Parekh, Nadja Hellmann, Matthias Husmann
Membrane repair emerges as an innate defense protecting target cells against bacterial pore-forming toxins. Here, we report the first paradigm of Ca(2+)-dependent repair following attack by a small β-pore-forming toxin, namely, plasmid-encoded phobalysin of Photobacterium damselae subsp. damselae In striking contrast, Vibrio cholerae cytolysin, the closest ortholog of phobalysin, subverted repair. Mutational analysis uncovered a role of channel width in toxicity and repair. Thus, the replacement of serine at phobalysin´s presumed channel narrow point with the bulkier tryptophan, the corresponding residue in Vibrio cholerae cytolysin (W318), modulated Ca(2+) influx, lysosomal exocytosis, and membrane repair...
February 14, 2017: MBio
https://www.readbyqxmd.com/read/28193196/rapid-eradication-of-colon-carcinoma-by-clostridium-perfringens-enterotoxin-suicidal-gene-therapy
#6
Jessica Pahle, Lutz Menzel, Nicole Niesler, Dennis Kobelt, Jutta Aumann, Maria Rivera, Wolfgang Walther
BACKGROUND: Bacterial toxins have evolved to an effective therapeutic option for cancer therapy. The Clostridium perfringens enterotoxin (CPE) is a pore-forming toxin with selective cytotoxicity. The transmembrane tight junction proteins claudin-3 and -4 are known high affinity CPE receptors. Their expression is highly upregulated in human cancers, including breast, ovarian and colon carcinoma. CPE binding to claudins triggers membrane pore complex formation, which leads to rapid cell death...
February 13, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28186501/intrinsic-repair-protects-cells-from-pore-forming-toxins-by-microvesicle-shedding
#7
Matthew Romero, Michelle Keyel, Guilan Shi, Pushpak Bhattacharjee, Robyn Roth, John E Heuser, Peter A Keyel
Pore-forming toxins (PFTs) are used by both the immune system and by pathogens to disrupt cell membranes. Cells attempt to repair this disruption in various ways, but the exact mechanism(s) that cells use are not fully understood, nor agreed upon. Current models for membrane repair include (1) patch formation (e.g., fusion of internal vesicles with plasma membrane defects), (2) endocytosis of the pores, and (3) shedding of the pores by blebbing from the cell membrane. In this study, we sought to determine the specific mechanism(s) that cells use to resist three different cholesterol-dependent PFTs: Streptolysin O, Perfringolysin O, and Intermedilysin...
February 10, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28176876/engineering-a-ph-responsive-pore-forming-protein
#8
Matic Kisovec, Saša Rezelj, Primož Knap, Miša Mojca Cajnko, Simon Caserman, Ajda Flašker, Nada Žnidaršič, Matej Repič, Janez Mavri, Yi Ruan, Simon Scheuring, Marjetka Podobnik, Gregor Anderluh
Listeriolysin O (LLO) is a cytolysin capable of forming pores in cholesterol-rich lipid membranes of host cells. It is conveniently suited for engineering a pH-governed responsiveness, due to a pH sensor identified in its structure that was shown before to affect its stability. Here we introduced a new level of control of its hemolytic activity by making a variant with hemolytic activity that was pH-dependent. Based on detailed structural analysis coupled with molecular dynamics and mutational analysis, we found that the bulky side chain of Tyr406 allosterically affects the pH sensor...
February 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28173991/damage-of-eukaryotic-cells-by-the-pore-forming-toxin-sticholysin-ii-consequences-of-the-potassium-efflux
#9
Sheila Cabezas, Sylvia Ho, Uris Ros, María E Lanio, Carlos Alvarez, F Gisou van der Goot
Pore-forming toxins (PFTs) form holes in membranes causing one of the most catastrophic damages to a target cell. Target organisms have evolved a regulated response against PFTs damage including cell membrane repair. This ability of cells strongly depends on the toxin concentration and the properties of the pores. It has been hypothesized that there is an inverse correlation between the size of the pores and the time required to repair the membrane, which has been for long a non-intuitive concept and far to be completely understood...
February 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28137589/participation-of-perforin-in-mediating-dopaminergic-neuron-loss-in-mptp-induced-parkinson-s-disease-in-mice
#10
Su-Ping Peng, Ye Zhang, Sjef Copray, Melitta Schachner, Yan-Qin Shen
Both resident innate and peripheral immune aberrations have been demonstrated to influence Parkinson's disease (PD) progression. However, it is still enigmatic how and which immune components are lethal to the dopaminergic neuron in PD. We now show that levels of perforin, a pore-forming protein expressed in cytotoxic immune cells, was significantly increased in the serum of wild-type mice 4 weeks after injection of MPTP, a toxin used to induce PD-like symptoms. We demonstrate that perforin-deficiency attenuated the acute striatal dopamine reduction by 33%, ablated microglia activation 3 days post MPTP-injection; and retarded dopaminergic neuron death 4 weeks post MPTP-injection...
March 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28128281/targeted-delivery-of-an-adp-ribosylating-bacterial-toxin-into-cancer-cells
#11
N-I Zahaf, A E Lang, L Kaiser, C D Fichter, S Lassmann, A McCluskey, A Augspach, K Aktories, G Schmidt
The actin cytoskeleton is an attractive target for bacterial toxins. The ADP-ribosyltransferase TccC3 from the insect bacterial pathogen Photorhabdus luminescence modifies actin to force its aggregation. We intended to transport the catalytic part of this toxin preferentially into cancer cells using a toxin transporter (Protective antigen, PA) which was redirected to Epidermal Growth Factor Receptors (EGFR) or to human EGF receptors 2 (HER2), which are overexpressed in several cancer cells. Protective antigen of anthrax toxin forms a pore through which the two catalytic parts (lethal factor and edema factor) or other proteins can be transported into mammalian cells...
January 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28125817/participation-of-necroptosis-in-the-host-response-to-acute-bacterial-pneumonia
#12
Danielle Ahn, Alice Prince
Common pulmonary pathogens, such as Streptococcus pneumoniae and Staphylococcus aureus, as well as the host-adapted pathogens responsible for health care-associated pneumonias, such as the carbapenem-resistant Klebsiella pneumoniae and Serratia marcecsens, are able to activate cell death through the RIPK1/RIPK3/MLKL cascade that causes necroptosis. Necroptosis can influence the pathogenesis of pneumonia through several mechanisms. Activation of this pathway can result in the loss of specific types of immune cells, especially macrophages, and, in so doing, contribute to host pathology through the loss of their critical immunoregulatory functions...
January 27, 2017: Journal of Innate Immunity
https://www.readbyqxmd.com/read/28119472/pseudomonas-aeruginosa-pore-forming-exolysin-and-type-iv-pili-cooperate-to-induce-host-cell-lysis
#13
Pauline Basso, Michel Ragno, Sylvie Elsen, Emeline Reboud, Guillaume Golovkine, Stephanie Bouillot, Philippe Huber, Stephen Lory, Eric Faudry, Ina Attrée
Clinical strains of Pseudomonas aeruginosa lacking the type III secretion system genes employ a toxin, exolysin (ExlA), for host cell membrane disruption. Here, we demonstrated that ExlA export requires a predicted outer membrane protein, ExlB, showing that ExlA and ExlB define a new active two-partner secretion (TPS) system of P. aeruginosa In addition to the TPS signals, ExlA harbors several distinct domains, which include one hemagglutinin domain, five arginine-glycine-aspartic acid (RGD) motifs, and a C-terminal region lacking any identifiable sequence motifs...
January 24, 2017: MBio
https://www.readbyqxmd.com/read/28115202/secondary-structure-preferences-of-the-anthrax-toxin-protective-antigen-translocase
#14
Debasis Das, Bryan A Krantz
In order for many proteins to move across hydrophobic membrane bilayers, they must be unfolded and translocated by a membrane-embedded channel. These translocase channels interact with the substrate proteins they translocate via hydrophobic pore loops and cleft structures called clamps. The molecular basis for how clamps facilitate unfolding and translocation is poorly understood. Anthrax toxin is composed of three proteins, a translocase channel-forming subunit, called protective antigen (PA), and two substrate proteins, called lethal factor (LF) and edema factor...
March 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28106142/identification-of-lukpq-a-novel-equid-adapted-leukocidin-of-staphylococcus-aureus
#15
Gerrit Koop, Manouk Vrieling, Daniel M L Storisteanu, Laurence S C Lok, Tom Monie, Glenn van Wigcheren, Claire Raisen, Xiaoliang Ba, Nicholas Gleadall, Nazreen Hadjirin, Arjen J Timmerman, Jaap A Wagenaar, Heleen M Klunder, J Ross Fitzgerald, Ruth Zadoks, Gavin K Paterson, Carmen Torres, Andrew S Waller, Anette Loeffler, Igor Loncaric, Armando E Hoet, Karin Bergström, Luisa De Martino, Constança Pomba, Hermínia de Lencastre, Karim Ben Slama, Haythem Gharsa, Emily J Richardson, Edwin R Chilvers, Carla de Haas, Kok van Kessel, Jos A G van Strijp, Ewan M Harrison, Mark A Holmes
Bicomponent pore-forming leukocidins are a family of potent toxins secreted by Staphylococcus aureus, which target white blood cells preferentially and consist of an S- and an F-component. The S-component recognizes a receptor on the host cell, enabling high-affinity binding to the cell surface, after which the toxins form a pore that penetrates the cell lipid bilayer. Until now, six different leukocidins have been described, some of which are host and cell specific. Here, we identify and characterise a novel S...
January 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28088448/fast-formation-of-low-defect-density-tethered-bilayers-by-fusion-of-multilamellar-vesicles
#16
Tadas Ragaliauskas, Mindaugas Mickevicius, Bozena Rakovska, Tadas Penkauskas, David J Vanderah, Frank Heinrich, Gintaras Valincius
A facile and reproducible preparation of surface-supported lipid bilayers is essential for fundamental membrane research and biotechnological applications. We demonstrate that multilamellar vesicles fuse to molecular-anchor-grafted surfaces yielding low-defect-density, tethered bilayer membranes. Continuous bilayers are formed within 10min, while the electrically insulating bilayers with <0.1μm(-2) defect density can be accomplished within 60min. Surface plasmon resonance spectroscopy indicates that an amount of lipid material transferred from vesicles to a surface is inversely proportional to the density of an anchor, while the total amount of lipid that includes tethered and transferred lipid remains constant within 5% standard error...
January 12, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28081446/host-to-host-transmission-of-streptococcus-pneumoniae-is-driven-by-its-inflammatory-toxin-pneumolysin
#17
M Ammar Zafar, Yang Wang, Shigeto Hamaguchi, Jeffrey N Weiser
Host-to-host transmission is a critical step for infection. Here we studied transmission of the opportunistic pathogen Streptococcus pneumoniae in an infant mouse model. Transmission from nasally colonized pups required high levels of bacterial shedding in nasal secretions and was temporally correlated with, and dependent upon, the acute inflammatory response. Pneumolysin, a pore-forming cytotoxin and major virulence determinant, was both necessary and sufficient to promote inflammation, which increased shedding and allowed for intralitter transmission...
January 11, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28074026/promyelocytic-leukemia-protein-pml-controls-listeria-monocytogenes-infection
#18
David Ribet, Valérie Lallemand-Breitenbach, Omar Ferhi, Marie-Anne Nahori, Hugo Varet, Hugues de Thé, Pascale Cossart
The promyelocytic leukemia protein (PML) is the main organizer of stress-responsive subnuclear structures called PML nuclear bodies. These structures recruit multiple interactors and modulate their abundance or their posttranslational modifications, notably by the SUMO ubiquitin-like modifiers. The involvement of PML in antiviral responses is well established. In contrast, the role of PML in bacterial infection remains poorly characterized. Here, we show that PML restricts infection by the pathogenic bacterium Listeria monocytogenes but not by Salmonella enterica serovar Typhimurium...
January 10, 2017: MBio
https://www.readbyqxmd.com/read/28062388/netf-producing-clostridium-perfringens-clonality-and-plasmid-pathogenicity-loci-analysis
#19
Iman Mehdizadeh Gohari, Andrew M Kropinski, Scott J Weese, Ashley E Whitehead, Valeria R Parreira, Patrick Boerlin, John F Prescott
Clostridium perfringens is an important cause of foal necrotizing enteritis and canine acute hemorrhagic diarrhea. A major virulence determinant of the strains associated with these diseases appears to be a beta-sheet pore-forming toxin, NetF, encoded within a pathogenicity locus (NetF locus) on a large tcp-conjugative plasmid. Strains producing NetF also produce the putative toxin NetE, encoded within the same pathogenicity locus, as well as CPE enterotoxin and CPB2 on a second plasmid, and sometimes the putative toxin NetG within a pathogenicity locus (NetG locus) on another separate large conjugative plasmid...
January 3, 2017: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/28060924/the-effector-domain-region-of-the-vibrio-vulnificus-martx-toxin-confers-biphasic-epithelial-barrier-disruption-and-is-essential-for-systemic-spread-from-the-intestine
#20
Hannah E Gavin, Nike T Beubier, Karla J F Satchell
Vibrio vulnificus causes highly lethal bacterial infections in which the Multifunctional Autoprocessing Repeats-in-Toxins (MARTX) toxin product of the rtxA1 gene is a key virulence factor. MARTX toxins are secreted proteins up to 5208 amino acids in size. Conserved MARTX N- and C-terminal repeat regions work in concert to form pores in eukaryotic cell membranes, through which the toxin's central region of modular effector domains is translocated. Upon inositol hexakisphosphate-induced activation of the of the MARTX cysteine protease domain (CPD) in the eukaryotic cytosol, effector domains are released from the holotoxin by autoproteolytic activity...
January 2017: PLoS Pathogens
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