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Meriem El Ghachi, Nicole Howe, Chia-Ying Huang, Vincent Olieric, Rangana Warshamanage, Thierry Touzé, Dietmar Weichert, Phillip J Stansfeld, Meitian Wang, Fred Kerff, Martin Caffrey
As a protective envelope surrounding the bacterial cell, the peptidoglycan sacculus is a site of vulnerability and an antibiotic target. Peptidoglycan components, assembled in the cytoplasm, are shuttled across the membrane in a cycle that uses undecaprenyl-phosphate. A product of peptidoglycan synthesis, undecaprenyl-pyrophosphate, is converted to undecaprenyl-phosphate for reuse in the cycle by the membrane integral pyrophosphatase, BacA. To understand how BacA functions, we determine its crystal structure at 2...
March 14, 2018: Nature Communications
Tetsuo Mioka, Konomi Fujimura-Kamada, Nahiro Mizugaki, Takuma Kishimoto, Takamitsu Sano, Hitoshi Nunome, David E Williams, Raymond J Andersen, Kazuma Tanaka
Phospholipid flippase (type 4 P-type ATPase) plays a major role in the generation of phospholipid asymmetry in eukaryotic cell membranes. Loss of Lem3p-Dnf1/2p flippases leads to the exposure of phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the cell surface in yeast, resulting in sensitivity to PS- or PE-binding peptides. We isolated Sfk1p, a conserved membrane protein in the TMEM150/FRAG1/DRAM family, as a multicopy suppressor of this sensitivity. Overexpression of SFK1 decreased PS/PE exposure in lem3 Δ mutant cells...
March 14, 2018: Molecular Biology of the Cell
Jani Reddy Bolla, Joshua B Sauer, Di Wu, Shahid Mehmood, Timothy M Allison, Carol V Robinson
Translocation of lipid II across the cytoplasmic membrane is essential in peptidoglycan biogenesis. Although most steps are understood, identifying the lipid II flippase has yielded conflicting results, and the lipid II binding properties of two candidate flippases-MurJ and FtsW-remain largely unknown. Here we apply native mass spectrometry to both proteins and characterize lipid II binding. We observed lower levels of lipid II binding to FtsW compared to MurJ, consistent with MurJ having a higher affinity...
March 2018: Nature Chemistry
João M Monteiro, Ana R Pereira, Nathalie T Reichmann, Bruno M Saraiva, Pedro B Fernandes, Helena Veiga, Andreia C Tavares, Margarida Santos, Maria T Ferreira, Vânia Macário, Michael S VanNieuwenhze, Sérgio R Filipe, Mariana G Pinho
Peptidoglycan is the main component of the bacterial wall and protects cells from the mechanical stress that results from high intracellular turgor. Peptidoglycan biosynthesis is very similar in all bacteria; bacterial shapes are therefore mainly determined by the spatial and temporal regulation of peptidoglycan synthesis rather than by the chemical composition of peptidoglycan. The form of rod-shaped bacteria, such as Bacillus subtilis or Escherichia coli, is generated by the action of two peptidoglycan synthesis machineries that act at the septum and at the lateral wall in processes coordinated by the cytoskeletal proteins FtsZ and MreB, respectively...
February 14, 2018: Nature
Robert Holz, Andreas E Kremer, Dieter Lütjohann, Hermann E Wasmuth, Frank Lammert, Marcin Krawczyk
Benign recurrent intrahepatic cholestasis (BRIC) is a peculiar familial disease caused by mutations of the genes encoding hepatocanalicular flippase for phosphatidylserine (ATP8B1; BRIC type 1) or the bile salt export pump (ABCB11; BRIC type 2). Here, we report on a patient with nasobiliary drainage-refractory BRIC type 2 who improved under plasma separation and anion absorption therapy. We also suggest that nasobiliary drainage might be an ineffective approach in carriers of severe loss-of-function mutations of the bile salt export pump ABCB11...
February 2018: Hepatology Communications
Zonera Hassan, Christian Schneeweis, Matthias Wirth, Christian Veltkamp, Zahra Dantes, Benedikt Feuerecker, Güralp O Ceyhan, Shirley K Knauer, Wilko Weichert, Roland M Schmid, Roland Stauber, Alexander Arlt, Oliver H Krämer, Roland Rad, Maximilian Reichert, Dieter Saur, Günter Schneider
BACKGROUND: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. METHODS: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance...
February 6, 2018: British Journal of Cancer
Christopher Bystroff
CatSper is a voltage-dependent calcium channel located in the plasma membrane of the sperm flagellum and is responsible for triggering hyperactive motility. A homology model for the transmembrane region was built in which the arrangement of the subunits around the pseudo-four-fold symmetry axis was deduced by the pairing of conserved transmembranal cysteines across mammals. Directly emergent of the predicted quaternary structure is an architecture in which tetramers polymerize through additional, highly conserved cysteines, creating one or more double-rows channels extending the length of the principal piece of the mammalian sperm tail...
January 19, 2018: Reproductive Biology
Katharina B Beer, Jennifer Rivas-Castillo, Kenneth Kuhn, Gholamreza Fazeli, Birgit Karmann, Jeremy F Nance, Christian Stigloher, Ann M Wehman
Cells release extracellular vesicles (EVs) that mediate intercellular communication and repair damaged membranes. Despite the pleiotropic functions of EVs in vitro, their in vivo function is debated, largely because it is unclear how to induce or inhibit their formation. In particular, the mechanisms of EV release by plasma membrane budding or ectocytosis are poorly understood. We previously showed that TAT-5 phospholipid flippase activity maintains the asymmetric localization of the lipid phosphatidylethanolamine (PE) in the plasma membrane and inhibits EV budding by ectocytosis in Caenorhabditis elegans However, no proteins that inhibit ectocytosis upstream of TAT-5 were known...
January 24, 2018: Proceedings of the National Academy of Sciences of the United States of America
Marcus W Stepp, Mark A Doll, Samantha M Carlisle, J Christopher States, David W Hein
Arylamine N-acetyltransferase 1 (NAT1) expression is reported to affect proliferation, invasiveness, and growth of cancer cells. MDA-MB-231 breast cancer cells were engineered such that NAT1 expression was elevated or suppressed, or treated with a small molecule inhibitor of NAT1. The MDA-MB-231 human breast cancer cell lines were engineered with a scrambled shRNA, a NAT1 specific shRNA or a NAT1 overexpression cassette stably integrated into a single flippase recognition target (FRT) site facilitating incorporation of these different genetic elements into the same genomic location...
January 9, 2018: Molecular Carcinogenesis
Lukasz M Solanko, David P Sullivan, Yves Y Sere, Maria Szomek, Anita Lunding, Katarzyna A Solanko, Azra Pizovic, Lyubomir D Stanchev, Thomas Günther Pomorski, Anant K Menon, Daniel Wüstner
Transbilayer lipid asymmetry is a fundamental characteristic of the eukaryotic cell plasma membrane (PM). While PM phospholipid asymmetry is well documented, the transbilayer distribution of PM sterols such as mammalian cholesterol and yeast ergosterol is not reliably known. We now report that sterols are asymmetrically distributed across the yeast PM, with the majority (~80%) located in the cytoplasmic leaflet. By exploiting the sterol-auxotrophic hem1Δ yeast strain we obtained cells in which endogenous ergosterol was quantitatively replaced with dehydroergosterol (DHE), a closely related fluorescent sterol that functionally and accurately substitutes for ergosterol in vivo...
December 28, 2017: Traffic
Katumori Segawa, Sachiko Kurata, Shigekazu Nagata
Flippases are enzymes that translocate phosphatidylserine (PtdSer) and phosphatidyl- ethanolamine (PtdEtn) from the outer to the inner leaflet in the lipid bilayer of the plasma membrane, leading to the asymmetric distribution of aminophospholipids in the membrane. One mammalian phospholipid flippase at the plasma membrane is ATP11C, a type IV P-type ATPase (P4-ATPase) that forms a hetero-complex with the transmembrane protein CDC50A. However, the structural features in CDC50A that support the function of ATP11C and other P4-ATPases have not been characterized...
December 24, 2017: Journal of Biological Chemistry
M S Jensen, S R Costa, A S Duelli, P A Andersen, L R Poulsen, L D Stanchev, P Gourdon, M Palmgren, T Günther Pomorski, R L López-Marqués
P4 ATPase flippases translocate phospholipids across biomembranes, thus contributing to the establishment of transmembrane lipid asymmetry, a feature important for multiple cellular processes. The mechanism by which such phospholipid flipping occurs remains elusive as P4 ATPases transport a giant substrate very different from that of other P-type ATPases such as Na+/K+- and Ca2+-ATPases. Based on available crystal structures of cation-transporting P-type ATPases, we generated a structural model of the broad-specificity flippase ALA10...
December 15, 2017: Scientific Reports
Małgorzata Marczak, Andrzej Mazur, Piotr Koper, Kamil Żebracki, Anna Skorupska
Rhizobia dwell and multiply in the soil and represent a unique group of bacteria able to enter into a symbiotic interaction with plants from the Fabaceae family and fix atmospheric nitrogen inside de novo created plant organs, called nodules. One of the key determinants of the successful interaction between these bacteria and plants are exopolysaccharides, which represent species-specific homo- and heteropolymers of different carbohydrate units frequently decorated by non-carbohydrate substituents. Exopolysaccharides are typically built from repeat units assembled by the Wzx/Wzy-dependent pathway, where individual subunits are synthesized in conjunction with the lipid anchor undecaprenylphosphate (und-PP), due to the activity of glycosyltransferases...
December 1, 2017: Genes
Zhongxin Guo, Xian-Bing Wang, Ying Wang, Wan-Xiang Li, Amit Gal-On, Shou-Wei Ding
Small interfering RNAs (siRNAs) are processed from virus-specific dsRNA to direct antiviral RNA interference (RNAi) in diverse eukaryotic hosts. We have recently performed a sensitized genetic screen in Arabidopsis ( Arabidopsis thaliana ) and identified two related phospholipid flippases required for antiviral RNAi and the amplification of virus-derived siRNAs by plant RNA-dependent RNA polymerase1 (RDR1) and RDR6. Here we report the identification and cloning of ANTIVIRAL RNAI - DEFECTIVE2 ( AVI2 ) from the same genetic screen...
February 2018: Plant Physiology
Sheila Ingemann Jensen, Alex Toftgaard Nielsen
Lambda Red recombineering is an easy and efficient method for generating genetic modifications in Escherichia coli. For gene deletions, lambda Red recombineering is combined with the use of selectable markers, which are removed through the action of, e.g., flippase (Flp) recombinase. This PCR-based engineering method has also been applied to a number of other bacteria. In this chapter, we describe a recently developed one plasmid-based method as well as the use of a strain with genomically integrated recombineering genes, which significantly speeds up the engineering of strains with multiple genomic alterations...
2018: Methods in Molecular Biology
Gail G Hardy, Evelyn Toh, Cécile Berne, Yves V Brun
Attachment is essential for microorganisms to establish interactions with both biotic and abiotic surfaces. Stable attachment of Caulobacter crescentus to surfaces requires an adhesive polysaccharide holdfast, but the exact composition of holdfast is unknown. The holdfast is anchored to the cell envelope by outer membrane proteins HfaA, HfaB and HfaD. Holdfast anchor gene mutations result in holdfast shedding and reduced cell adherence. Translocation of HfaA and HfaD to the cell surface requires HfaB. The Wzx homolog, HfsF, is predicted to be a bacterial polysaccharide flippase...
November 20, 2017: Journal of Bacteriology
Hiroyuki Takatsu, Masahiro Takayama, Tomoki Naito, Naoto Takada, Kazuya Tsumagari, Yasushi Ishihama, Kazuhisa Nakayama, Hye-Won Shin
We and others showed that ATP11A and ATP11C, members of the P4-ATPase family, translocate phosphatidylserine (PS) and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflets at the plasma membrane. PS exposure on the outer leaflet of the plasma membrane in activated platelets, erythrocytes, and apoptotic cells was proposed to require the inhibition of PS-flippases, as well as activation of scramblases. Although ATP11A and ATP11C are cleaved by caspases in apoptotic cells, it remains unclear how PS-flippase activity is regulated in non-apoptotic cells...
November 10, 2017: Nature Communications
Tatsuyuki Matsudaira, Kojiro Mukai, Taishin Noguchi, Junya Hasegawa, Tomohisa Hatta, Shun-Ichiro Iemura, Tohru Natsume, Norio Miyamura, Hiroshi Nishina, Jun Nakayama, Kentaro Semba, Takuya Tomita, Shigeo Murata, Hiroyuki Arai, Tomohiko Taguchi
Yes-associated protein (YAP) is a recently discovered growth-promoting transcription coactivator that has been shown to regulate the malignancy of various cancers. How YAP is regulated is not fully understood. Here, we show that one of the factors regulating YAP is phosphatidylserine (PS) in recycling endosomes (REs). We use proximity biotinylation to find proteins proximal to PS. Among these proteins are YAP and multiple proteins related to YAP signalling. Knockdown of ATP8A1 (an RE PS-flippase) or evectin-2 (an RE-resident protein) and masking of PS in the cytoplasmic leaflet of membranes, all suppress nuclear localization of YAP and YAP-dependent transcription...
November 1, 2017: Nature Communications
Karl-Heinz Tomaszowski, Nadja Hellmann, Viviane Ponath, Hiroyuki Takatsu, Hye-Won Shin, Bernd Kaina
The DNA repair protein O (6)-methylguanine-DNA-methyltransferase (MGMT) is a key determinant of cancer resistance. The MGMT inhibitors O (6)-benzylguanine (O(6)BG) and O (6)-(4-bromothenyl)guanine (O(6)BTG) failed to enhance the therapeutic response due to toxic side effects when applied in combination with alkylating chemotherapeutics, indicating a need of inhibitor targeting. We assessed MGMT targeting that relies on conjugating the inhibitors O(6)BG and O(6)BTG to ß-D-glucose, resulting in O(6)BG-Glu and O(6)BTG-Glu, respectively...
October 24, 2017: Scientific Reports
Yue Niu, Dong Qian, Baiyun Liu, Jianchao Ma, Dongshi Wan, Xinyu Wang, Wenliang He, Yun Xiang
Maintaining lipid membrane integrity is an essential aspect of plant tolerance to high temperature. P4-type ATPases are responsible for flipping and stabilizing asymmetric phospholipids in membrane systems, though their functions in stress tolerance are not entirely clear. Aminophospholipid ATPase6 (ALA6) is a member of the P4-type ATPase family, which has 12 members in Arabidopsis thaliana. Here, we show that a loss-of-function mutant of ALA6 (ala6) exhibits clear sensitivity to heat stress, including both basal and acquired thermotolerance treatments...
2017: Frontiers in Plant Science
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