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https://www.readbyqxmd.com/read/29123098/phospholipid-flippase-atp11c-is-endocytosed-and-downregulated-following-ca-2-mediated-protein-kinase-c-activation
#1
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
https://www.readbyqxmd.com/read/29093443/endosomal-phosphatidylserine-is-critical-for-the-yap-signalling-pathway-in-proliferating-cells
#2
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
https://www.readbyqxmd.com/read/29066805/uptake-of-glucose-conjugated-mgmt-inhibitors-in-cancer-cells-role-of-flippases-and-type-iv-p-type-atpases
#3
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
https://www.readbyqxmd.com/read/29046690/ala6-a-p4-type-atpase-is-involved-in-heat-stress-responses-in-arabidopsis-thaliana
#4
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
https://www.readbyqxmd.com/read/28972154/neutrophil-microparticle-production-and-inflammasome-activation-by-hyperglycemia-due-to-cytoskeletal-instability
#5
Stephen R Thom, Veena M Bhopale, Kevin Yu, Weiliang Huang, Maureen A Kane, David J Margolis
Microparticles are lipid bilayer-enclosed vesicles produced by cells under oxidative stress. MP production is elevated in patients with diabetes, but the underlying cellular mechanisms are poorly understood. We hypothesized that raising glucose above the physiological level of 5.5 mm would stimulate leukocytes to produce MPs and activate the nucleotide-binding domain, leucine-rich repeat pyrin domain-containing 3 (NLRP3) inflammasome. We found that when incubated in buffer with up to 20 mm glucose, human and murine neutrophils, but not monocytes, generate progressively more MPs with high interleukin (IL)-1β content...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28894177/a-viral-protein-antibiotic-inhibits-lipid-ii-flippase-activity
#6
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) ...
November 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28874751/disease-mutations-reveal-residues-critical-to-the-interaction-of-p4-atpases-with-lipid-substrates
#7
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
#8
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
#9
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
#10
John Chu, Xavier Vila-Farres, Daigo Inoyama, Ricardo Gallardo-Macias, Mark Jaskowski, Shruthi Satish, Joel S 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 on the basis of 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...
September 11, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28839191/loss-of-tmem30a-leads-to-photoreceptor-degeneration
#11
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
#12
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 such as Candida albicans exhibit several survival mechanisms to evade attack by antifungals and colonise host tissues. Rta3, a member of the Rta1-like family of lipid-translocating exporters has a 7-transmembrane domain topology, similar to the G-protein-coupled receptors and is unique to the fungal kingdom. Our findings point towards a role for the plasma membrane localised Rta3 in providing tolerance to miltefosine, an analogue 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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