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https://www.readbyqxmd.com/read/28894177/a-viral-protein-antibiotic-inhibits-lipid-ii-flippase-activity
#1
Karthik R Chamakura, Lok-To Sham, Rebecca M Davis, Lorna Min, Hongbaek Cho, Natividad Ruiz, Thomas G Bernhardt, Ry Young
For bacteriophage infections, the cell walls of bacteria, consisting of a single highly polymeric molecule of peptidoglycan (PG), pose a major problem for the release of progeny virions. Phage lysis proteins that overcome this barrier can point the way to new antibacterial strategies (1) , especially small lytic single-stranded DNA (the microviruses) and RNA phages (the leviviruses) that effect host lysis using a single non-enzymatic protein (2) . Previously, the A2 protein of levivirus Qβ and the E protein of the microvirus ϕX174 were shown to be 'protein antibiotics' that inhibit the MurA and MraY steps of the PG synthesis pathway (2-4) ...
September 11, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28874751/disease-mutations-reveal-residues-critical-to-the-interaction-of-p4-atpases-with-lipid-substrates
#2
Rasmus H Gantzel, Louise S Mogensen, Stine A Mikkelsen, Bente Vilsen, Robert S Molday, Anna L Vestergaard, Jens P Andersen
Phospholipid flippases (P4-ATPases) translocate specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. While there is good evidence that the overall molecular structure of flippases is similar to that of P-type ATPase ion-pumps, the transport pathway for the "giant" lipid substrate has not been determined. ATP8A2 is a flippase with selectivity toward phosphatidylserine (PS), possessing a net negatively charged head group, whereas ATP8B1 exhibits selectivity toward the electrically neutral phosphatidylcholine (PC)...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28870843/phosphatidylserine-a-cancer-cell-targeting-biomarker
#3
REVIEW
Bhupender Sharma, Shamsher S Kanwar
Cancer is a leading cause of mortality and morbidity globally. Many prominent cancer-associated molecules have been identified over the recent years which include EGFR, CD44, TGFbRII, HER2, miR-497, NMP22, BTA, Fibrin/FDP etc. These biomarkers are often used for screening, detection, diagnosis, prognosis, prediction and monitoring of cancer development. Phosphatidylserine (PS) is an essential component in all human cells which is present on the inner leaflet of the cell membrane. The oxidative stress causes exposure of PS on the surface of the vascular endothelium in the cancer cells (lung, breast, pancreatic, bladder, skin, brain metastasis, rectal adenocarcinoma etc...
September 1, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28869968/structural-basis-of-msba-mediated-lipopolysaccharide-transport
#4
Wei Mi, Yanyan Li, Sung Hwan Yoon, Robert K Ernst, Thomas Walz, Maofu Liao
Lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria is critical for the assembly of their cell envelopes. LPS synthesized in the cytoplasmic leaflet of the inner membrane is flipped to the periplasmic leaflet by MsbA, an ATP-binding cassette transporter. Despite substantial efforts, the structural mechanisms underlying MsbA-driven LPS flipping remain elusive. Here we use single-particle cryo-electron microscopy to elucidate the structures of lipid-nanodisc-embedded MsbA in three functional states...
September 14, 2017: Nature
https://www.readbyqxmd.com/read/28845973/human-microbiome-inspired-antibiotics-with-improved-%C3%AE-lactam-synergy-against-mdr-staphylococcus-aureus
#5
John Chu, Xavier Vila Farres, Daigo Inoyama, Ricardo Gallardo-Macias, Mark Jaskowski, Shruthi Satish, Joel Stephen Freundlich, Sean F Brady
The flippase MurJ is responsible for transporting the cell wall intermediate lipid II from the cytoplasm to the outside of the cell. While essential for the survival of bacteria it remains an underexploited target for antibacterial therapy. The humimycin antibiotics are lipid II flippase (MurJ) inhibitors that were synthesized based on bioinformatic predictions derived from secondary metabolite gene clusters found in the human microbiome. Here we describe an SAR campaign around humimycin A that produced humimycin 17S...
August 28, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28839191/loss-of-tmem30a-leads-to-photoreceptor-degeneration
#6
Lin Zhang, Yeming Yang, Shujin Li, Shanshan Zhang, Xiong Zhu, Zhengfu Tai, Mu Yang, Yuqing Liu, Xinzheng Guo, Bo Chen, Zhilin Jiang, Fang Lu, Xianjun Zhu
Phosphatidylserine (PS) is asymmetrically distributed between the outer and inner leaflets of the plasma membrane in eukaryotic cells. PS asymmetry on the plasma membrane depends on the activities of P4-ATPases, and disruption of PS distribution can lead to various disease conditions. Folding and transporting of P4-ATPases to their cellular destination requires the β subunit TMEM30A proteins. However, the in vivo functions of Tmem30a remain unknown. To this end, we generated retinal-specific Tmem30a-knockout mice to investigate its roles in vivo for the first time...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28745020/distinct-roles-of-the-7-transmembrane-receptor-protein-rta3-in-regulating-the-asymmetric-distribution-of-phosphatidylcholine-across-the-plasma-membrane-and-biofilm-formation-in-candida-albicans
#7
Archita Srivastava, Shabnam Sircaik, Farha Husain, Edwina Thomas, Shivani Ror, Sumit Rastogi, Darakshan Alim, Priyanka Bapat, David R Andes, Clarissa J Nobile, Sneh L Panwar
Fungal pathogens like Candida albicans exhibit several survival mechanisms to evade attack by antifungals and colonize host tissues. Rta3, a member of the Rta1-like family of lipid-translocating exporters has a 7-transmembrane domain (7TMD) topology, similar to the G-protein-coupled receptors (GPCR) and is unique to the fungal kingdom. Our findings point towards a role for the plasma membrane localized Rta3 in providing tolerance to miltefosine, an analog of alkylphosphocholine, by maintaining mitochondrial energetics...
July 25, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28698380/mmpl3-is-the-flippase-for-mycolic-acids-in-mycobacteria
#8
Zhujun Xu, Vladimir A Meshcheryakov, Giovanna Poce, Shu-Sin Chng
The defining feature of the mycobacterial outer membrane (OM) is the presence of mycolic acids (MAs), which, in part, render the bilayer extremely hydrophobic and impermeable to external insults, including many antibiotics. Although the biosynthetic pathway of MAs is well studied, the mechanism(s) by which these lipids are transported across the cell envelope is(are) much less known. Mycobacterial membrane protein Large 3 (MmpL3), an essential inner membrane (IM) protein, is implicated in MA transport, but its exact function has not been elucidated...
July 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28696276/progress-in-our-understanding-of-wzx-flippase-for-translocation-of-bacterial-membrane-lipid-linked-oligosaccharide
#9
Yaoqin Hong, Michael A Liu, Peter R Reeves
Translocation of lipid-linked oligosaccharides is a common theme across prokaryotes and eukaryotes. For bacteria, such activity is used in cell wall construction, polysaccharide synthesis and the relatively recently discovered protein glycosylation. To the best of our knowledge, the Gram-negative inner-membrane flippase Wzx was the first protein identified as being involved in oligosaccharide translocation, and yet we still have only a limited understanding of this protein after three decades of research. At present, Wzx is known to be a multi-transmembrane protein with enormous sequence diversity that flips oligosaccharide substrates with varying degrees of preference...
July 10, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28561736/a-cell-cycle-independent-conditional-gene-inactivation-strategy-for-differentially-tagging-wild-type-and-mutant-cells
#10
Sonal Nagarkar-Jaiswal, Sathiya N Manivannan, Zhongyuan Zuo, Hugo J Bellen
Here, we describe a novel method based on intronic MiMIC insertions described in Nagarkar-Jaiswal et al. (2015) to perform conditional gene inactivation in Drosophila. Mosaic analysis in Drosophila cannot be easily performed in post-mitotic cells. We therefore, therefore, developed Flip-Flop, a flippase-dependent in vivo cassette-inversion method that marks wild-type cells with the endogenous EGFP-tagged protein, whereas mutant cells are marked with mCherry upon inversion. We document the ease and usefulness of this strategy in differential tagging of wild-type and mutant cells in mosaics...
May 31, 2017: ELife
https://www.readbyqxmd.com/read/28490499/development-of-an-optimized-synthetic-notch-receptor-as-an-in-vivo-cell-cell-contact-sensor
#11
Li He, Jiuhong Huang, Norbert Perrimon
Detection and manipulation of direct cell-cell contact in complex tissues is a fundamental and challenging problem in many biological studies. Here, we report an optimized Notch-based synthetic receptor (synNQ) useful to study direct cell-cell interactions in Drosophila With the synNQ system, cells expressing a synthetic receptor, which contains Notch activation machinery and a downstream transcriptional activator, QF, are activated by a synthetic GFP ligand expressed by contacting neighbor cells. To avoid cis-inhibition, mutually exclusive expression of the synthetic ligand and receptor is achieved using the "flippase-out" system...
May 23, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28439275/arabidopsis-ala1-and-ala2-mediate-rnai-based-antiviral-immunity
#12
Biyun Zhu, Hua Gao, Gang Xu, Dewei Wu, Susheng Song, Hongshan Jiang, Shuifang Zhu, Tiancong Qi, Daoxin Xie
RNA intereferencing (RNAi) pathway regulates antiviral immunity and mediates plant growth and development. Despite considerable research efforts, a few components in RNAi pathway have been revealed, including ARGONAUTEs (AGOs), DICER-LIKEs (DCLs), RNA-dependent RNA polymerase 1 and 6 (RDR1/6), and ALTERED MERISTEM PROGRAM 1 (AMP1). In this study, we performed a forward genetic screening for enhancers of rdr6 via inoculation of CMV2aTΔ2b, a 2b-deficient Cucumber Mosaic Virus that is unable to suppress RNAi-mediated antiviral immunity...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28434950/an-arabidopsis-lipid-flippase-is-required-for-timely-recruitment-of-defenses-to-the-host-pathogen-interface-at-the-plant-cell-surface
#13
William Underwood, Andrew Ryan, Shauna C Somerville
Deposition of cell wall-reinforcing papillae is an integral component of the plant immune response. The Arabidopsis PENETRATION 3 (PEN3) ATP binding cassette (ABC) transporter plays a role in defense against numerous pathogens and is recruited to sites of pathogen detection where it accumulates within papillae. However, the trafficking pathways and regulatory mechanisms contributing to recruitment of PEN3 and other defenses to the host-pathogen interface are poorly understood. Here, we report a confocal microscopy-based screen to identify mutants with altered localization of PEN3-GFP after inoculation with powdery mildew fungi...
June 5, 2017: Molecular Plant
https://www.readbyqxmd.com/read/28432259/probing-native-metal-ion-association-sites-through-quenching-of-fluorophores-in-the-nucleotide-binding-domains-of-the-abc-transporter-msba
#14
Daiki Tatsumi, Kei Nanatani, Yuto Koike, Kiyoto Kamagata, Satoshi Takahashi, Ayumu Konno, Tadaomi Furuta, Minoru Sakurai, Nobuyuki Uozumi
ATP-binding cassette (ABC) transporters are ubiquitously present in prokaryotic and eukaryotic cells. Binding of ATP to the nucleotide-binding domains (NBDs) elicits major conformational changes of the transporters resulting in the transport of the substrate across the membrane. The availability of a crystal structure of the NBDs enabled us to elucidate the local structure and small-scale dynamics in the NBDs. Here, we labeled the ABC transporter MsbA, a homodimeric flippase from Escherichia coli, with a fluorescent probe, Alexa532, within the NBDs...
May 30, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28422165/structural-basis-of-inhibition-of-lipid-linked-oligosaccharide-flippase-pglk-by-a-conformational-nanobody
#15
Camilo Perez, Martin Köhler, Daniel Janser, Els Pardon, Jan Steyaert, Renato Zenobi, Kaspar P Locher
PglK is an ABC transporter that flips a lipid-linked oligosaccharide (LLO) that serves as a donor in protein N-glycosylation. Previous structures revealed two inward-facing conformations, both with very large separations of the nucleotide binding domains (NBDs), and a closed, ADP-bound state that featured an occluded cavity. To investigate additional states, we developed conformation-sensitive, single-domain camelid nanobodies (Nb) and studied their effect on PglK activity. Biochemical, structural, and mass spectrometric analyses revealed that one inhibitory Nb binds as a single copy to homodimeric PglK...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28404745/quantitative-high-content-imaging-identifies-novel-regulators-of-neo1-trafficking-at-endosomes
#16
Lauren E Dalton, Björn D M Bean, Michael Davey, Elizabeth Conibear
P4-ATPases are a family of putative phospholipid flippases that regulate lipid membrane asymmetry, which is important for vesicle formation. Two yeast flippases, Drs2 and Neo1, have nonredundant functions in the recycling of the synaptobrevin-like v-SNARE Snc1 from early endosomes. Drs2 activity is needed to form vesicles and regulate its own trafficking, suggesting that flippase activity and localization are linked. However, the role of Neo1 in endosomal recycling is not well characterized. To identify novel regulators of Neo1 trafficking and activity at endosomes, we first identified mutants with impaired recycling of a Snc1-based reporter and subsequently used high-content microscopy to classify these mutants based on the localization of Neo1 or its binding partners, Mon2 and Dop1...
June 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28357373/cryptococcus-flips-its-lid-membrane-phospholipid-asymmetry-modulates-antifungal-drug-resistance-and-virulence
#17
COMMENT
Erika Shor, Yina Wang, David S Perlin, Chaoyang Xue
Human fungal infections are increasing in prevalence and acquisition of antifungal drug resistance, while our antifungal drug armamentarium remains very limited, constituting a significant public health problem. Despite the fact that prominent antifungal drugs target the fungal cell membrane, very little is known about how fungal membrane biology regulates drug-target interactions. Asymmetrical phospholipid distribution is an essential property of biological membranes, which is maintained by a group of transporters that dynamically translocate specific phospholipid groups across the membrane bilayer...
August 1, 2016: Microbial Cell
https://www.readbyqxmd.com/read/28324143/rapid-customised-operon-assembly-by-yeast-recombinational-cloning
#18
Michael A Liu, Johanna J Kenyon, Jason Lee, Peter R Reeves
We have developed a system called the Operon Assembly Protocol (OAP), which takes advantage of the homologous recombination DNA repair pathway in Saccharomyces cerevisiae to assemble full-length operons from a series of overlapping PCR products into a specially engineered yeast-Escherichia coli shuttle vector. This flexible, streamlined system can be used to assemble several operon clones simultaneously, and each clone can be expressed in the same E. coli tester strain to facilitate direct functional comparisons...
March 21, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28302728/high-phosphatidylinositol-4-phosphate-pi4p-dependent-atpase-activity-for-the-drs2p-cdc50p-flippase-after-removal-of-its-n-and-c-terminal-extensions
#19
Hassina Azouaoui, Cédric Montigny, Thibaud Dieudonné, Philippe Champeil, Aurore Jacquot, José Luis Vázquez-Ibar, Pierre Le Maréchal, Jakob Ulstrup, Miriam-Rose Ash, Joseph A Lyons, Poul Nissen, Guillaume Lenoir
P4-ATPases, also known as phospholipid flippases, are responsible for creating and maintaining transbilayer lipid asymmetry in eukaryotic cell membranes. Here, we use limited proteolysis to investigate the role of the N and C termini in ATP hydrolysis and auto-inhibition of the yeast flippase Drs2p-Cdc50p. We show that limited proteolysis of the detergent-solubilized and purified yeast flippase may result in more than 1 order of magnitude increase of its ATPase activity, which remains dependent on phosphatidylinositol 4-phosphate (PI4P), a regulator of this lipid flippase, and specific to a phosphatidylserine substrate...
May 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28288918/increased-carbon-dioxide-levels-stimulate-neutrophils-to-produce-microparticles-and-activate-the-nucleotide-binding-domain-like-receptor-3-inflammasome
#20
Stephen R Thom, Veena M Bhopale, JingPing Hu, Ming Yang
We hypothesized that elevations of carbon dioxide (CO2) commonly found in modern buildings will stimulate leukocytes to produce microparticles (MPs) and activate the nucleotide-binding domain-like receptor 3 (NLRP3) inflammasome due to mitochondrial oxidative stress. Human and murine neutrophils generate MPs with high interleukin-1β (IL-1β) content when incubated ex vivo in buffer equilibrated with 0.1-0.4% additional CO2. Enhanced MPs production requires mitochondrial reactive oxygen species production, which is mediated by activities of pyruvate carboxylase and phosphoenolpyruvate carboxykinase...
March 10, 2017: Free Radical Biology & Medicine
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