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Journal articles on the topic 'Flippases'

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Author: Grafiati

Published: 6 July 2024

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1

Takeda, Miyoko, Kanako Yamagami, and Kazuma Tanaka. "Role of Phosphatidylserine in Phospholipid Flippase-Mediated Vesicle Transport in Saccharomyces cerevisiae." Eukaryotic Cell 13, no. 3 (January 3, 2014): 363–75. http://dx.doi.org/10.1128/ec.00279-13.

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ABSTRACT Phospholipid flippases translocate phospholipids from the exoplasmic to the cytoplasmic leaflet of cell membranes to generate and maintain phospholipid asymmetry. The genome of budding yeast encodes four heteromeric flippases (Drs2p, Dnf1p, Dnf2p, and Dnf3p), which associate with the Cdc50 family noncatalytic subunit, and one monomeric flippase Neo1p. Flippases have been implicated in the formation of transport vesicles, but the underlying mechanisms are largely unknown. We show here that overexpression of the phosphatidylserine synthase gene CHO1 suppresses defects in the endocytic recycling pathway in flippase mutants. This suppression seems to be mediated by increased cellular phosphatidylserine. Two models can be envisioned for the suppression mechanism: (i) phosphatidylserine in the cytoplasmic leaflet recruits proteins for vesicle formation with its negative charge, and (ii) phosphatidylserine flipping to the cytoplasmic leaflet induces membrane curvature that supports vesicle formation. In a mutant depleted for flippases, a phosphatidylserine probe GFP-Lact-C2 was still localized to endosomal membranes, suggesting that the mere presence of phosphatidylserine in the cytoplasmic leaflet is not enough for vesicle formation. The CHO1 overexpression did not suppress the growth defect in a mutant depleted or mutated for all flippases, suggesting that the suppression was dependent on flippase-mediated phospholipid flipping. Endocytic recycling was not blocked in a mutant lacking phosphatidylserine or depleted in phosphatidylethanolamine, suggesting that a specific phospholipid is not required for vesicle formation. These results suggest that flippase-dependent vesicle formation is mediated by phospholipid flipping, not by flipped phospholipids.

2

Jing, Weidong, Mehmet Yabas, Angelika Bröer, Lucy Coupland, Elizabeth E. Gardiner, Anselm Enders, and Stefan Bröer. "Calpain cleaves phospholipid flippase ATP8A1 during apoptosis in platelets." Blood Advances 3, no. 3 (January 23, 2019): 219–29. http://dx.doi.org/10.1182/bloodadvances.2018023473.

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Abstract The asymmetric distribution of phospholipids in the plasma/organellar membranes is generated and maintained through phospholipid flippases in resting cells, but becomes disrupted in apoptotic cells and activated platelets, resulting in phosphatidylserine (PS) exposure on the cell surface. Stable PS exposure during apoptosis requires inactivation of flippases to prevent PS from being reinternalized. Here we show that flippase ATP8A1 is highly expressed in both murine and human platelets, but is not present in the plasma membrane. ATP8A1 is cleaved by the cysteine protease calpain during apoptosis, and the cleavage is prevented indirectly by caspase inhibition, involving blockage of calcium influx into platelets and subsequent calpain activation. In contrast, in platelets activated with thrombin and collagen and exposing PS, ATP8A1 remains intact. These data reveal a novel mechanism of flippase cleavage and suggest that flippase activity in intracellular membranes differs between platelets undergoing apoptosis and activation.

3

Slavetinsky, Christoph J., Andreas Peschel, and Christoph M. Ernst. "Alanyl-Phosphatidylglycerol and Lysyl-Phosphatidylglycerol Are Translocated by the Same MprF Flippases and Have Similar Capacities To Protect against the Antibiotic Daptomycin in Staphylococcus aureus." Antimicrobial Agents and Chemotherapy 56, no. 7 (April 9, 2012): 3492–97. http://dx.doi.org/10.1128/aac.00370-12.

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ABSTRACTThe lysinylation of negatively charged phosphatidylglycerol by MprF proteins reduces the affinity of cationic antimicrobial peptides (CAMPs) for bacterial cytoplasmic membranes and reduces the susceptibility of several Gram-positive bacterial pathogens to CAMPs. MprF ofStaphylococcus aureusencompasses a lysyl-phosphatidylglycerol (Lys-PG) synthase and a Lys-PG flippase domain. In contrast,Clostridium perfringensencodes two MprF homologs which specifically synthesize alanyl-phosphatidylglycerol (Ala-PG) or Lys-PG, while only the Lys-PG synthase is fused to a putative flippase domain. It remains unknown whether cationic Lys-PG and zwitterionic Ala-PG differ in their capacities to be translocated by MprF flippases and if both can reduce CAMP susceptibility in Gram-positive bacteria. By expressing the MprF proteins ofC. perfringensin anS. aureus mprFdeletion mutant, we found that both lipids can be efficiently produced inS. aureus. Simultaneous expression of the Lys-PG and Ala-PG synthases led to the production of both lipids and slightly increased the overall amounts of aminoacyl phospholipids. Ala-PG production by the correspondingC. perfringensenzyme did not affect susceptibility to CAMPs such as nisin and gallidermin or to the CAMP-like antibiotic daptomycin. However, coexpression of the Ala-PG synthase with flippase domains of Lys-PG synthesizing MprF proteins led to a wild-type level of daptomycin susceptibility, indicating that Ala-PG can also protect bacterial membranes against daptomycin and suggesting that Lys-PG flippases can also translocate the related lipid Ala-PG. Thus, bacterial aminoacyl phospholipid flippases exhibit more relaxed substrate specificity and Ala-PG and Lys-PG are more similar in their capacities to modulate membrane functions than anticipated.

4

MENON, A. "Flippases." Trends in Cell Biology 5, no. 9 (September 1995): 355–60. http://dx.doi.org/10.1016/s0962-8924(00)89069-8.

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5

Watkins, W. E., III III, and A. K. Menon. "Reconstitution of Phospholipid Flippase Activity from E. coli Inner Membrane: A Test of the Protein Translocon as a Candidate Flippase." Biological Chemistry 383, no. 9 (September 17, 2002): 1435–40. http://dx.doi.org/10.1515/bc.2002.162.

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AbstractPhospholipid flipping in biogenic membranes is a key feature of membrane bilayer assembly. Flipping is facilitated by proteinaceous transporters (flippases) that do not need metabolic energy to function. No flippase has yet been identified. The architecture of the E. coli protein translocon suggests that it could account for the flippase activity in the bacterial inner membrane. To test this possibility, we used E. coli cells depleted of SecYE or YidC to assay flipping in proteoliposomes reconstituted from detergent extracts of their inner membranes. We conclude that the protein translocon contributes minimally, if at all, to phospholipid flippase activity in the inner membrane.

6

Devaux, Philippe F. "Phospholipid flippases." FEBS Letters 234, no. 1 (July 4, 1988): 8–12. http://dx.doi.org/10.1016/0014-5793(88)81291-2.

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7

Daleke, David L. "Phospholipid Flippases." Journal of Biological Chemistry 282, no. 2 (November 27, 2006): 821–25. http://dx.doi.org/10.1074/jbc.r600035200.

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8

Basante-Bedoya, Miguel A., Stéphanie Bogliolo, Rocio Garcia-Rodas, Oscar Zaragoza, Robert A. Arkowitz, and Martine Bassilana. "Two distinct lipid transporters together regulate invasive filamentous growth in the human fungal pathogen Candida albicans." PLOS Genetics 18, no. 12 (December 14, 2022): e1010549. http://dx.doi.org/10.1371/journal.pgen.1010549.

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Flippases transport lipids across the membrane bilayer to generate and maintain asymmetry. The human fungal pathogen Candida albicans has 5 flippases, including Drs2, which is critical for filamentous growth and phosphatidylserine (PS) distribution. Furthermore, a drs2 deletion mutant is hypersensitive to the antifungal drug fluconazole and copper ions. We show here that such a flippase mutant also has an altered distribution of phosphatidylinositol 4-phosphate [PI(4)P] and ergosterol. Analyses of additional lipid transporters, i.e. the flippases Dnf1-3, and all the oxysterol binding protein (Osh) family lipid transfer proteins, i.e. Osh2-4 and Osh7, indicate that they are not critical for filamentous growth. However, deletion of Osh4 alone, which exchanges PI(4)P for sterol, in a drs2 mutant can bypass the requirement for this flippase in invasive filamentous growth. In addition, deletion of the lipid phosphatase Sac1, which dephosphorylates PI(4)P, in a drs2 mutant results in a synthetic growth defect, suggesting that Drs2 and Sac1 function in parallel pathways. Together, our results indicate that a balance between the activities of two putative lipid transporters regulates invasive filamentous growth, via PI(4)P. In contrast, deletion of OSH4 in drs2 does not restore growth on fluconazole, nor on papuamide A, a toxin that binds PS in the outer leaflet of the plasma membrane, suggesting that Drs2 has additional role(s) in plasma membrane organization, independent of Osh4. As we show that C. albicans Drs2 localizes to different structures, including the Spitzenkörper, we investigated if a specific localization of Drs2 is critical for different functions, using a synthetic physical interaction approach to restrict/stabilize Drs2 at the Spitzenkörper. Our results suggest that the localization of Drs2 at the plasma membrane is critical for C. albicans growth on fluconazole and papuamide A, but not for invasive filamentous growth.

9

Rajasekharan, Archita, Vincent Gerard Francis, and Sathyanarayana N. Gummadi. "Biochemical evidence for energy-independent flippase activity in bovine epididymal sperm membranes: an insight into membrane biogenesis." REPRODUCTION 146, no. 3 (September 2013): 209–20. http://dx.doi.org/10.1530/rep-13-0121.

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During the maturation process spermatozoa undergo a series of changes in their lateral and horizontal lipid profiles. However, lipid metabolism in spermatozoa is not clearly understood for two reasons: i) the mature spermatozoa are devoid of endoplasmic reticulum, which is the major site of phospholipid (PL) synthesis in somatic cells, and ii) studies have been superficial due to the difficulty in culturing spermatozoa. We hypothesize that spermatozoa contain biogenic membrane flippases since immense changes in lipids occur during spermatogenic differentiation. To test this, we isolated spermatozoa from bovine epididymides and reconstituted the detergent extract of sperm membranes into proteoliposomes.In vitroassays showed that proteoliposomes reconstituted with sperm membrane proteins exhibit ATP-independent flip–flop movement of phosphatidylcholine (PC), phosphatidylserine, and phosphatidylglycerol. Half-life time of PC flipping was found to be ∼3.2±1 min for whole sperm membrane, which otherwise would have taken ∼11–12 h in the absence of protein. Further biochemical studies confirm the flip–flop movement to be protein-mediated, based on its sensitivity to protease and protein-modifying reagents. To further determine the cellular localization of flippases, we isolated mitochondria of spermatozoa and checked for ATP-independent flippase activity. Interestingly, mitochondrial membranes showed flip–flop movement but were specific for PC with half-life time of ∼5±2 min. Our results also suggest that spermatozoa have different populations of flippases and that their localization within the cellular compartments depends on the type of PL synthesis.

10

Lenoir, Guillaume, and Joost C. M. Holthuis. "The elusive flippases." Current Biology 14, no. 21 (November 2004): R912—R913. http://dx.doi.org/10.1016/j.cub.2004.10.008.

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11

Braegger, Christian, Namir Al-Ansari, and Benjamin L. Shneider. "Flipping Over Flippases." Journal of Pediatric Gastroenterology and Nutrition 33, no. 1 (July 2001): 102–3. http://dx.doi.org/10.1097/00005176-200107000-00022.

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12

Braegger, Christian, Namir Al‐Ansari, and Benjamin L. Shneider. "Flipping Over Flippases." Journal of Pediatric Gastroenterology and Nutrition 33, no. 1 (July 2001): 102–3. http://dx.doi.org/10.1002/j.1536-4801.2001.tb07414.x.

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13

Khakhina, Svetlana, Soraya S. Johnson, Raman Manoharlal, Sarah B. Russo, Corinne Blugeon, Sophie Lemoine, Anna B. Sunshine, et al. "Control of Plasma Membrane Permeability by ABC Transporters." Eukaryotic Cell 14, no. 5 (February 27, 2015): 442–53. http://dx.doi.org/10.1128/ec.00021-15.

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ABSTRACTATP-binding cassette transporters Pdr5 and Yor1 fromSaccharomyces cerevisiaecontrol the asymmetric distribution of phospholipids across the plasma membrane as well as serving as ATP-dependent drug efflux pumps. Mutant strains lacking these transporter proteins were found to exhibit very different resistance phenotypes to two inhibitors of sphingolipid biosynthesis that act either late (aureobasidin A [AbA]) or early (myriocin [Myr]) in the pathway leading to production of these important plasma membrane lipids. Thesepdr5Δ yor1strains were highly AbA resistant but extremely sensitive to Myr. We provide evidence that these phenotypic changes are likely due to modulation of the plasma membrane flippase complexes, Dnf1/Lem3 and Dnf2/Lem3. Flippases act to move phospholipids from the outer to the inner leaflet of the plasma membrane. Genetic analyses indicate thatlem3Δ mutant strains are highly AbA sensitive and Myr resistant. These phenotypes are fully epistatic to those seen inpdr5Δ yor1strains. Direct analysis of AbA-induced signaling demonstrated that loss of Pdr5 and Yor1 inhibited the AbA-triggered phosphorylation of the AGC kinase Ypk1 and its substrate Orm1. Microarray experiments found that apdr5Δ yor1strain induced a Pdr1-dependent induction of the entire Pdr regulon. Our data support the view that Pdr5/Yor1 negatively regulate flippase function and activity of the nuclear Pdr1 transcription factor. Together, these data argue that the interaction of the ABC transporters Pdr5 and Yor1 with the Lem3-dependent flippases regulates permeability of AbA via control of plasma membrane protein function as seen for the high-affinity tryptophan permease Tat2.

14

Dalton, Lauren E., Björn D. M. Bean, Michael Davey, and Elizabeth Conibear. "Quantitative high-content imaging identifies novel regulators of Neo1 trafficking at endosomes." Molecular Biology of the Cell 28, no. 11 (June 2017): 1539–50. http://dx.doi.org/10.1091/mbc.e16-11-0772.

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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. This analysis identified a role for Arl1 in stabilizing the Mon2/Dop1 complex and uncovered a new function for Vps13 in early endosome recycling and Neo1 localization. We further showed that the cargo-selective sorting nexin Snx3 is required for Neo1 trafficking and identified an Snx3 sorting motif in the Neo1 N-terminus. Of importance, the Snx3-dependent sorting of Neo1 was required for the correct sorting of another Snx3 cargo protein, suggesting that the incorporation of Neo1 into recycling tubules may influence their formation.

15

Tanaka, K., K. Fujimura-Kamada, and T. Yamamoto. "Functions of phospholipid flippases." Journal of Biochemistry 149, no. 2 (December 5, 2010): 131–43. http://dx.doi.org/10.1093/jb/mvq140.

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16

Yang, Zhenke, Yang Shi, Huiting Cui, Shuzhen Yang, Han Gao, and Jing Yuan. "A malaria parasite phospholipid flippase safeguards midgut traversal of ookinetes for mosquito transmission." Science Advances 7, no. 30 (July 2021): eabf6015. http://dx.doi.org/10.1126/sciadv.abf6015.

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Mosquito midgut epithelium traversal is essential for malaria parasite transmission. Phospholipid flippases are eukaryotic type 4 P-type adenosine triphosphatases (P4-ATPases), which, in association with CDC50, translocate phospholipids across the membrane lipid bilayers. In this study, we investigated the function of a putative P4-ATPase, ATP7, from the rodent malaria parasite Plasmodium yoelii. Disruption of ATP7 blocks the parasite infection of mosquitoes. ATP7 is localized on the ookinete plasma membrane. While ATP7-depleted ookinetes are capable of invading the midgut, they are eliminated within the epithelial cells by a process independent from the mosquito complement-like immunity. ATP7 colocalizes and interacts with the flippase cofactor CDC50C. Depletion of CDC50C phenocopies ATP7 deficiency. ATP7-depleted ookinetes fail to uptake phosphatidylcholine across the plasma membrane. Ookinete microinjection into the mosquito hemocoel reverses the ATP7 deficiency phenotype. Our study identifies Plasmodium flippase as a mechanism of parasite survival in the midgut epithelium that is required for mosquito transmission.

17

Roelants, Françoise M., Brooke M. Su, Joachim von Wulffen, Subramaniam Ramachandran, Elodie Sartorel, Amy E. Trott, and Jeremy Thorner. "Protein kinase Gin4 negatively regulates flippase function and controls plasma membrane asymmetry." Journal of Cell Biology 208, no. 3 (February 2, 2015): 299–311. http://dx.doi.org/10.1083/jcb.201410076.

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Plasma membrane function requires distinct leaflet lipid compositions. Two of the P-type ATPases (flippases) in yeast, Dnf1 and Dnf2, translocate aminoglycerophospholipids from the outer to the inner leaflet, stimulated via phosphorylation by cortically localized protein kinase Fpk1. By monitoring Fpk1 activity in vivo, we found that Fpk1 was hyperactive in cells lacking Gin4, a protein kinase previously implicated in septin collar assembly. Gin4 colocalized with Fpk1 at the cortical site of future bud emergence and phosphorylated Fpk1 at multiple sites, which we mapped. As judged by biochemical and phenotypic criteria, a mutant (Fpk111A), in which 11 sites were mutated to Ala, was hyperactive, causing increased inward transport of phosphatidylethanolamine. Thus, Gin4 is a negative regulator of Fpk1 and therefore an indirect negative regulator of flippase function. Moreover, we found that decreasing flippase function rescued the growth deficiency of four different cytokinesis mutants, which suggests that the primary function of Gin4 is highly localized control of membrane lipid asymmetry and is necessary for optimal cytokinesis.

18

Veit, Sarina, Sabine Laerbusch, Rosa L. López-Marqués, and Thomas Günther Pomorski. "Functional Analysis of the P-Type ATPases Apt2-4 from Cryptococcus neoformans by Heterologous Expression in Saccharomyces cerevisiae." Journal of Fungi 9, no. 2 (February 4, 2023): 202. http://dx.doi.org/10.3390/jof9020202.

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Lipid flippases of the P4-ATPase family actively transport phospholipids across cell membranes, an activity essential for key cellular processes such as vesicle budding and membrane trafficking. Members of this transporter family have also been implicated in the development of drug resistance in fungi. The encapsulated fungal pathogen Cryptococcus neoformans contains four P4-ATPases, among which Apt2-4p are poorly characterized. Using heterologous expression in the flippase-deficient S. cerevisiae strain dnf1Δdnf2Δdrs2Δ, we tested their lipid flippase activity in comparison to Apt1p using complementation tests and fluorescent lipid uptake assays. Apt2p and Apt3p required the co-expression of the C. neoformans Cdc50 protein for activity. Apt2p/Cdc50p displayed a narrow substrate specificity, limited to phosphatidylethanolamine and –choline. Despite its inability to transport fluorescent lipids, the Apt3p/Cdc50p complex still rescued the cold-sensitive phenotype of dnf1Δdnf2Δdrs2Δ, suggesting a functional role for the flippase in the secretory pathway. Apt4p, the closest homolog to Saccharomyces Neo1p, which does not require a Cdc50 protein, was unable to complement several flippase-deficient mutant phenotypes, neither in the presence nor absence of a β-subunit. These results identify C. neoformans Cdc50 as an essential subunit for Apt1-3p and provide a first insight into the molecular mechanisms underlying their physiological functions.

19

Sakuragi, Takaharu, Hidetaka Kosako, and Shigekazu Nagata. "Phosphorylation-mediated activation of mouse Xkr8 scramblase for phosphatidylserine exposure." Proceedings of the National Academy of Sciences 116, no. 8 (February 4, 2019): 2907–12. http://dx.doi.org/10.1073/pnas.1820499116.

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The exposure of phosphatidylserine (PtdSer) to the cell surface is regulated by the down-regulation of flippases and the activation of scramblases. Xkr8 has been identified as a scramblase that is activated during apoptosis, but its exogenous expression in the mouse Ba/F3 pro B cell line induces constitutive PtdSer exposure. Here we found that this Xkr8-mediated PtdSer exposure occurred at 4 °C, but not at 20 °C, although its scramblase activity was observed at 20 °C. The Xkr8-mediated PtdSer exposure was inhibited by a kinase inhibitor and enhanced by phosphatase inhibitors. Phosphorylated Xkr8 was detected by Phos-tag PAGE, and a mass spectrometric and mutational analysis identified three phosphorylation sites. Their phosphomimic mutation rendered Xkr8 resistant to the kinase inhibitor for PtdSer exposure at 4 °C, but unlike phosphatase inhibitors, it did not induce constitutive PtdSer exposure at 20 °C. On the other hand, when the flippase genes were deleted, the Xkr8 induced constitutive PtdSer exposure at high temperature, indicating that the flippase activity normally counteracted Xkr8’s ability to expose PtdSer. These results indicate that PtdSer exposure can be increased by the phosphorylation-mediated activation of Xkr8 scramblase and flippase down-regulation.

20

Yazlovitskaya, Eugenia M., and Todd R. Graham. "Type IV P-Type ATPases: Recent Updates in Cancer Development, Progression, and Treatment." Cancers 15, no. 17 (August 30, 2023): 4327. http://dx.doi.org/10.3390/cancers15174327.

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Adaptations of cancer cells for survival are remarkable. One of the most significant properties of cancer cells to prevent the immune system response and resist chemotherapy is the altered lipid metabolism and resulting irregular cell membrane composition. The phospholipid distribution in the plasma membrane of normal animal cells is distinctly asymmetric. Lipid flippases are a family of enzymes regulating membrane asymmetry, and the main class of flippases are type IV P-type ATPases (P4-ATPases). Alteration in the function of flippases results in changes to membrane organization. For some lipids, such as phosphatidylserine, the changes are so drastic that they are considered cancer biomarkers. This review will analyze and discuss recent publications highlighting the role that P4-ATPases play in the development and progression of various cancer types, as well as prospects of targeting P4-ATPases for anti-cancer treatment.

21

Vehring, Stefanie, Leroy Pakkiri, Adrien Schröer, Nele Alder-Baerens, Andreas Herrmann, Anant K. Menon, and Thomas Pomorski. "Flip-Flop of Fluorescently Labeled Phospholipids in Proteoliposomes Reconstituted with Saccharomyces cerevisiae Microsomal Proteins." Eukaryotic Cell 6, no. 9 (July 6, 2007): 1625–34. http://dx.doi.org/10.1128/ec.00198-07.

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ABSTRACT A phospholipid flippase activity from the endoplasmic reticulum (ER) of the model organism Saccharomyces cerevisiae has been characterized and functionally reconstituted into proteoliposomes. Analysis of the transbilayer movement of acyl-7-nitrobenz-2-oxa-1,3-diazol-4-yl (acyl-NBD)-labeled phosphatidylcholine in yeast microsomes using a fluorescence stopped-flow back exchange assay revealed a rapid, ATP-independent flip-flop (half-time, <2 min). Proteoliposomes prepared from a Triton X-100 extract of yeast microsomal membranes were also capable of flipping NBD-labeled phospholipid analogues rapidly in an ATP-independent fashion. Flippase activity was sensitive to the protein modification reagents N-ethylmaleimide and diethylpyrocarbonate. Resolution of the Triton X-100 extract by velocity gradient centrifugation resulted in the identification of a ∼4S protein fraction enriched in flippase activity as well as of other fractions where flippase activity was depleted or undetectable. We estimate that flippase activity is due to a protein(s) representing ∼2% (wt/wt) of proteins in the Triton X-100 extract. These results indicate that specific proteins are required to facilitate ATP-independent phospholipid flip-flop in the ER and that their identification is feasible. The architecture of the ER protein translocon suggests that it could account for the flippase activity in the ER. We tested this hypothesis using microsomes prepared from a temperature-sensitive yeast mutant in which the major translocon component, Sec61p, was quantitatively depleted. We found that the protein translocon is not required for transbilayer movement of phospholipids across the ER. Our work defines yeast as a promising model system for future attempts to identify the ER phospholipid flippase and to test and purify candidate flippases.

22

Fay, Allison, and Jonathan Dworkin. "Bacillus subtilis Homologs of MviN (MurJ), the Putative Escherichia coli Lipid II Flippase, Are Not Essential for Growth." Journal of Bacteriology 191, no. 19 (August 7, 2009): 6020–28. http://dx.doi.org/10.1128/jb.00605-09.

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ABSTRACT Although peptidoglycan synthesis is one of the best-studied metabolic pathways in bacteria, the mechanism underlying the membrane translocation of lipid II, the undecaprenyl-disaccharide pentapeptide peptidoglycan precursor, remains mysterious. Recently, it was proposed that the essential Escherichia coli mviN gene encodes the lipid II flippase. Bacillus subtilis contains four proteins that are putatively homologous to MviN, including SpoVB, previously reported to be necessary for spore cortex peptidoglycan synthesis during sporulation. MviN complemented the sporulation defect of a ΔspoVB mutation, and SpoVB and another of the B. subtilis homologs, YtgP, complemented the growth defect of an E. coli strain depleted for MviN. Thus, these B. subtilis proteins are likely to be MviN homologs. However, B. subtilis strains lacking these four proteins have no defects in growth, indicating that they likely do not serve as lipid II flippases in this organism.

23

Ruiz, Natividad. "Lipid Flippases for Bacterial Peptidoglycan Biosynthesis." Lipid Insights 8s1 (January 2015): LPI.S31783. http://dx.doi.org/10.4137/lpi.s31783.

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The biosynthesis of cellular polysaccharides and glycoconjugates often involves lipid-linked intermediates that need to be translocated across membranes. Essential pathways such as N-glycosylation in eukaryotes and biogenesis of the peptidoglycan (PG) cell wall in bacteria share a common strategy where nucleotide-sugars are used to build a membrane-bound oligosaccharide precursor that is linked to a phosphorylated isoprenoid lipid. Once made, these lipid-linked intermediates must be translocated across a membrane so that they can serve as substrates in a different cellular compartment. How translocation occurs is poorly understood, although it clearly requires a transporter or flippase. Identification of these transporters is notoriously difficult, and, in particular, the identity of the flippase of lipid II, an intermediate required for PG biogenesis, has been the subject of much debate. Here, I will review the body of work that has recently fueled this controversy, centered on proposed flippase candidates FtsW, MurJ, and AmJ.

24

Daleke, David L., and Jill V. Lyles. "Identification and purification of aminophospholipid flippases." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1486, no. 1 (June 2000): 108–27. http://dx.doi.org/10.1016/s1388-1981(00)00052-4.

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25

Graham, Todd R. "Flippases and vesicle-mediated protein transport." Trends in Cell Biology 14, no. 12 (December 2004): 670–77. http://dx.doi.org/10.1016/j.tcb.2004.10.008.

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26

Pomorski, T., and A. K. Menon. "Lipid flippases and their biological functions." Cellular and Molecular Life Sciences 63, no. 24 (November 13, 2006): 2908–21. http://dx.doi.org/10.1007/s00018-006-6167-7.

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27

Poulsen, L. R., R. L. López-Marqués, and M. G. Palmgren. "Flippases: still more questions than answers." Cellular and Molecular Life Sciences 65, no. 20 (September 15, 2008): 3119–25. http://dx.doi.org/10.1007/s00018-008-8341-6.

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28

Langosch, Dieter. "Phospholipid Flip Mediated by Model Flippases." Biophysical Journal 110, no. 3 (February 2016): 174a. http://dx.doi.org/10.1016/j.bpj.2015.11.970.

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29

Langer, Marcella, Rashmi Sah, Anika Veser, Markus Gütlich, and Dieter Langosch. "Structural Properties of Model Phosphatidylcholine Flippases." Chemistry & Biology 20, no. 1 (January 2013): 63–72. http://dx.doi.org/10.1016/j.chembiol.2012.11.006.

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30

Nagata, Shigekazu. "Flippases and Scramblases at Plasma Membranes that Regulate Phosphatidylserine Exposure." Blood 126, no. 23 (December 3, 2015): SCI—31—SCI—31. http://dx.doi.org/10.1182/blood.v126.23.sci-31.sci-31.

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Abstract One of the hallmarks of apoptosis is the caspase-dependent exposure of phosphatidylserine (PtdSer) on cell surface, which is recognized by macrophages for engulfment of dead cells (1). How PtdSer is exposed to the cell surface had been elusive for a long time. We recently identified two membrane proteins (TMEM16F and Xkr8) that are involved in scrambling of phospholipids in plasma membrane (2, 3). TMEM16F carries 8 transmembrane regions, and requires Ca2+ to mediate phospholipid scrambling. It plays a role in the PtdSer-exposure in activated platelets for blood clotting, and patients of Scott Syndrome who suffer bleeding disorder carry a mutation in TMEM16F gene. Xkr8 is a protein carrying 6 transmembrane regions. Caspase 3 and 7 cleave off the C-terminal tail of Xkr8, and the cleaved Xkr8 promotes the PtdSer-exposure. In addition to the activation of scramblase, the flippase that translocates PtdSer from outer to inner leaflets was thought to be inactivated during apoptosis. In fact, we recently found that a pair of molecules, ATP11C of a P4-type ATPase and its chaperon CDC50A work as a flippase at plasma membrane (4, 5). ATP11C carries three caspase recognition sites in the middle of the molecule, and is cleaved during apoptosis. When ATP11C gene is mutated, the cells lose most of the flippase activity, but the asymmetrical distribution of PtdSer was still maintained at plasma membrane. Whereas, the cells lacking CDC50A completely lost the flippase activity and constitutively exposed PtdSer. The PtdSer-exposing living CDC50A-null cells were engulfed by thioglycollate-elicited macrophages, indicating that PtdSer exposed on the cell surface is necessary and sufficient to be recognized by macrophages for engulfment. Several molecules such as MFG-E8, Tim-4, Gas6, and Protein S specifically bind to PtdSer with high affinity, and promote the engulfment of PtdSer-exposing cells. However, how they work for the engulfment of apoptotic cells in certain macrophages has not been clear. We recently found that that resident peritoneal macrophages require both Tim4 and Protein S for engulfment, and Tim4, PtdSer-receptor, was involved in tethering of apoptotic cells, while Protein S promoted the engulfment of apoptotic cells by binding to MerTK, a tyrosine kinase receptor (6, 7). Here, I discuss how PdtSer is exposed during apoptotic cell death, and how dead cells are engulfed by macrophages. 1. Nagata S, Hanayama R, Kawane K. Autoimmunity and the clearance of dead cells. Cell. 2010;140:619-630. 2. Suzuki J, Umeda M, Sims PJ, Nagata S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature. 2010;468:834-838. 3. Suzuki J, Denning DP, Imanishi E, Horvitz HR, Nagata S. Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science. 2013;341:403-406. 4. Segawa K, Suzuki J, Nagata S. Flippases and scramblases in the plasma membrane. Cell Cycle. 2014;13:2990-2991. 5. Segawa K, Kurata S, Yanagihashi Y, Brummelkamp T, Matsuda F, Nagata S. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science. 2014;344:1164-1168. 6. Nishi C, Toda S, Segawa K, Nagata S. Tim4- and MerTK-mediated engulfment of apoptotic cells by mouse resident peritoneal macrophages. Mol Cell Biol. 2014;34:1512-1520. 7. Toda S, Segawa K, Nagata S. MerTK-mediated engulfment of pyrenocytes by central macrophages in erythroblastic islands. Blood. 2014;123:3963-3971. Disclosures No relevant conflicts of interest to declare.

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Motahari-Rad, Hanieh, Alba Subiri, Rocio Soler, Luis Ocaña, Juan Alcaide, Jorge Rodríguez-Capitan, Veronica Buil, et al. "The Effect of Sex and Obesity on the Gene Expression of Lipid Flippases in Adipose Tissue." Journal of Clinical Medicine 11, no. 13 (July 4, 2022): 3878. http://dx.doi.org/10.3390/jcm11133878.

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Molecular mechanisms behind obesity and sex-related effects in adipose tissue remain elusive. During adipocyte expansion, adipocytes undergo drastic remodelling of lipid membrane compositions. Lipid flippases catalyse phospholipid translocation from exoplasmic to the cytoplasmic leaflet of membranes. The present study aimed to analyse the effect of sex, obesity, and their interactions on the gene expression of two lipid flippases—ATP8A1 and ATP8B1—and their possible microRNA (miR) modulators in visceral adipose tissue (VAT). In total, 12 normal-weight subjects (5 premenopausal women and 7 men) and 13 morbidly obese patients (7 premenopausal women and 6 men) were submitted to surgery, and VAT samples were obtained. Gene expression levels of ATP8A1, ATP8B1, miR-548b-5p, and miR-4643 were measured in VAT. Our results showed a marked influence of obesity on VAT ATP8A1 and ATP8B1, although the effects of obesity were stronger in men for ATP8A1. Both genes positively correlated with obesity and metabolic markers. Furthermore, ATP8B1 was positively associated with miR-548b-5p and negatively associated with miR-4643. Both miRs were also affected by sex. Thus, lipid flippases are altered by obesity in VAT in a sex-specific manner. Our study provides a better understanding of the sex-specific molecular mechanisms underlying obesity, which may contribute to the development of sex-based precision medicine.

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Muhlberger, Tamara, Melisa Micaela Balach, Carlos Gastón Bisig, Verónica Silvina Santander, Noelia Edith Monesterolo, Cesar Horacio Casale, and Alexis Nazareno Campetelli. "Inhibition of flippase-like activity by tubulin regulates phosphatidylserine exposure in erythrocytes from hypertensive and diabetic patients." Journal of Biochemistry 169, no. 6 (February 12, 2021): 731–45. http://dx.doi.org/10.1093/jb/mvab016.

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Abstract Plasma membrane tubulin is an endogenous regulator of P-ATPases and the unusual accumulation of tubulin in the erythrocyte membrane results in a partial inhibition of some their activities, causing hemorheological disorders like reduced cell deformability and osmotic resistance. These disorders are of particular interest in hypertension and diabetes, where the abnormal increase in membrane tubulin may be related to the disease development. Phosphatidylserine (PS) is more exposed on the membrane of diabetic erythrocytes than in healthy cells. In most cells, PS is transported from the exoplasmic to the cytoplasmic leaflet of the membrane by lipid flippases. Here, we report that PS is more exposed in erythrocytes from both hypertensive and diabetic patients than in healthy erythrocytes, which could be attributed to the inhibition of flippase activity by tubulin. This is supported by: (i) the translocation rate of a fluorescent PS analog in hypertensive and diabetic erythrocytes was slower than in healthy cells, (ii) the pharmacological variation of membrane tubulin in erythrocytes and K562 cells was linked to changes in PS translocation and (iii) the P-ATPase-dependent PS translocation in inside-out vesicles (IOVs) from human erythrocytes was inhibited by tubulin. These results suggest that tubulin regulates flippase activity and hence, the membrane phospholipid asymmetry.

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Takar, Mehmet, Yannan Huang, and Todd R. Graham. "The PQ-loop protein Any1 segregates Drs2 and Neo1 functions required for viability and plasma membrane phospholipid asymmetry." Journal of Lipid Research 60, no. 5 (March 1, 2019): 1032–42. http://dx.doi.org/10.1194/jlr.m093526.

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Membrane asymmetry is a key organizational feature of the plasma membrane. Type IV P-type ATPases (P4-ATPases) are phospholipid flippases that establish membrane asymmetry by translocating phospholipids, such as phosphatidylserine (PS) and phospatidylethanolamine, from the exofacial leaflet to the cytosolic leaflet. Saccharomyces cerevisiae expresses five P4-ATPases: Drs2, Neo1, Dnf1, Dnf2, and Dnf3. The inactivation of Neo1 is lethal, suggesting Neo1 mediates an essential function not exerted by the other P4-ATPases. However, the disruption of ANY1, which encodes a PQ-loop membrane protein, allows the growth of neo1Δ and reveals functional redundancy between Golgi-localized Neo1 and Drs2. Here we show Drs2 PS flippase activity is required to support neo1Δ any1Δ viability. Additionally, a Dnf1 variant with enhanced PS flipping ability can replace Drs2 and Neo1 function in any1Δ cells. any1Δ also suppresses drs2Δ growth defects but not the loss of membrane asymmetry. Any1 overexpression perturbs the growth of cells but does not disrupt membrane asymmetry. Any1 coimmunoprecipitates with Neo1, an association prevented by the Any1-inactivating mutation D84G. These results indicate a critical role for PS flippase activity in Golgi membranes to sustain viability and suggests Any1 regulates Golgi membrane remodeling through protein-protein interactions rather than a previously proposed scramblase activity.

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van der Mark, Vincent, Ronald Elferink, and Coen Paulusma. "P4 ATPases: Flippases in Health and Disease." International Journal of Molecular Sciences 14, no. 4 (April 11, 2013): 7897–922. http://dx.doi.org/10.3390/ijms14047897.

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Segawa, Katsumori, Jun Suzuki, and Shigekazu Nagata. "Flippases and scramblases in the plasma membrane." Cell Cycle 13, no. 19 (October 2014): 2990–91. http://dx.doi.org/10.4161/15384101.2014.962865.

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Lee, Shoken, Tomohiko Taguchi, and Hiroyuki Arai. "Endosomal lipid flippases and their related diseases." Channels 9, no. 4 (July 4, 2015): 166–68. http://dx.doi.org/10.1080/19336950.2015.1062332.

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Devaux, Philippe F., Andreas Herrmann, Nina Ohlwein, and Michael M. Kozlov. "How lipid flippases can modulate membrane structure." Biochimica et Biophysica Acta (BBA) - Biomembranes 1778, no. 7-8 (July 2008): 1591–600. http://dx.doi.org/10.1016/j.bbamem.2008.03.007.

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Lopez-Marques, Rosa L., Lisa Theorin, Michael G. Palmgren, and Thomas Günther Pomorski. "P4-ATPases: lipid flippases in cell membranes." Pflügers Archiv - European Journal of Physiology 466, no. 7 (September 29, 2013): 1227–40. http://dx.doi.org/10.1007/s00424-013-1363-4.

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39

Meeske, Alexander J., Lok-To Sham, Harvey Kimsey, Byoung-Mo Koo, Carol A. Gross, Thomas G. Bernhardt, and David Z. Rudner. "MurJ and a novel lipid II flippase are required for cell wall biogenesis in Bacillus subtilis." Proceedings of the National Academy of Sciences 112, no. 20 (April 27, 2015): 6437–42. http://dx.doi.org/10.1073/pnas.1504967112.

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Bacterial surface polysaccharides are synthesized from lipid-linked precursors at the inner surface of the cytoplasmic membrane before being translocated across the bilayer for envelope assembly. Transport of the cell wall precursor lipid II in Escherichia coli requires the broadly conserved and essential multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) exporter superfamily member MurJ. Here, we show that Bacillus subtilis cells lacking all 10 MOP superfamily members are viable with only minor morphological defects, arguing for the existence of an alternate lipid II flippase. To identify this factor, we screened for synthetic lethal partners of MOP family members using transposon sequencing. We discovered that an uncharacterized gene amj (alternate to MurJ; ydaH) and B. subtilis MurJ (murJBs; formerly ytgP) are a synthetic lethal pair. Cells defective for both Amj and MurJBs exhibit cell shape defects and lyse. Furthermore, expression of Amj or MurJBs in E. coli supports lipid II flipping and viability in the absence of E. coli MurJ. Amj is present in a subset of gram-negative and gram-positive bacteria and is the founding member of a novel family of flippases. Finally, we show that Amj is expressed under the control of the cell envelope stress-response transcription factor σM and cells lacking MurJBs increase amj transcription. These findings raise the possibility that antagonists of the canonical MurJ flippase trigger expression of an alternate translocase that can resist inhibition.

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Stanchev, Lyubomir Dimitrov, Juliana Rizzo, Rebecca Peschel, Lilli A. Pazurek, Lasse Bredegaard, Sarina Veit, Sabine Laerbusch, Marcio L. Rodrigues, Rosa L. López-Marqués, and Thomas Günther Pomorski. "P-Type ATPase Apt1 of the Fungal Pathogen Cryptococcus neoformans Is a Lipid Flippase of Broad Substrate Specificity." Journal of Fungi 7, no. 10 (October 8, 2021): 843. http://dx.doi.org/10.3390/jof7100843.

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Lipid flippases of the P4-ATPase family are ATP-driven transporters that translocate lipids from the exoplasmic to the cytosolic leaflet of biological membranes. In the encapsulated fungal pathogen Cryptococcus neoformans, the P4-ATPase Apt1p is an important regulator of polysaccharide secretion and pathogenesis, but its biochemical characterization is lacking. Phylogenetic analysis revealed that Apt1p belongs to the subclade of P4A-ATPases characterized by the common requirement for a β-subunit. Using heterologous expression in S. cerevisiae, we demonstrate that Apt1p forms a heterodimeric complex with the C. neoformans Cdc50 protein. This association is required for both localization and activity of the transporter complex. Lipid flippase activity of the heterodimeric complex was assessed by complementation tests and uptake assays employing fluorescent lipids and revealed a broad substrate specificity, including several phospholipids, the alkylphospholipid miltefosine, and the glycolipids glucosyl- and galactosylceramide. Our results suggest that transbilayer lipid transport in C. neoformans is finely regulated to promote fungal virulence, which reinforces the potential of Apt1p as a target for antifungal drug development.

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Lucy, Coupland, Mehmet Yabas, Deborah Cromer, Markus Winterberg, Narcissus Teoh, Kiaran Kirk, Stefan Broer, Christopher Parish, and Anselm Enders. "Anemia, Shortened Erythrocyte Lifespan and Stomatocytosis In a Flippase Mutant Mouse Strain." Blood 122, no. 21 (November 15, 2013): 2183. http://dx.doi.org/10.1182/blood.v122.21.2183.2183.

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Abstract Background Mammalian erythrocytes are anucleate biconcave discs with marked flexibility and deformability, features necessary for efficient function. The cell membrane consists of a lipid bilayer containing proteins and an asymmetric distribution of phospholipids (PL). Phosphatidylcholine and sphingomyelin are predominantly concentrated in the outer layer and phosphatidylserine (PS) and phosphatidylethanolamine are mainly confined to the inner layer of the erythrocyte membrane. Maintenance of PL asymmetry is essential for erythrocyte survival and function as increased externalization of PS results in adherence of erythrocytes to vascular endothelium, activation of plasma blood clotting factors and premature removal from the circulation. Flippases, floppases and scramblases are the enzymes responsible for the establishment and maintenance of PL distribution. A mouse deficient in the flippase ATP11C was generated through ENU mutagenesis and was found to have reduced hemoglobin in comparison to wild type (WT) littermates. This study was performed to characterize the etiology of anemia in these mice. Results ATP11C-deficient mice had significant reductions in erythrocyte numbers and hematocrit compared to WT but higher MCH and MCV. Reticulocyte numbers were comparable to WT as were serum iron parameters. Bone marrow and splenic erythropoiesis was normal in ATP11C mutant mice, however, erythrocyte lifespan was reduced by 35%. A marked increase in the frequency of PS+ erythrocytes was demonstrated in ATP11C mutant mice and was shown to increase with erythrocyte age. Bone marrow and splenic erythroblasts from ATP11C-deficient animals displayed a lower rate of PS translocation in vitro compared to WT confirming defective flippase activity. Erythrocytes and late-stage splenic erythroblasts in ATP11C mutants were significantly larger than WT based on flow cytometry. SEM revealed the majority of mutant erythrocytes displayed stomatocyte-like morphology, as confirmed on peripheral blood smears. The osmotic fragility of the ATP11C-deficient erythrocytes was comparable to WT erythrocytes as was Na+ and K+ homeostasis. Discussion These studies reveal the important role of flippases in maintaining normal erythrocyte function through the maintenance of the asymmetric distribution of PS within the membrane. Perturbation of this process, as seen in the ATP11C-deficient mice, results in (i) increased exposure of PS on the erythrocyte outer membrane, (ii) increased size of late-stage erythroblasts and erythrocytes with stomatocyte formation (iii) reduced erythrocyte lifespan and (iv) normochromic anemia. This study, therefore, reveals a new mechanism for stomatocytosis and raises the question of whether mutations in ATP11C may serve as a previously unclassified cause of anemia in humans. Disclosures: No relevant conflicts of interest to declare.

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López-Marqués, Rosa L., Pontus Gourdon, Thomas Günther Pomorski, and Michael Palmgren. "The transport mechanism of P4 ATPase lipid flippases." Biochemical Journal 477, no. 19 (October 12, 2020): 3769–90. http://dx.doi.org/10.1042/bcj20200249.

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P4 ATPase lipid flippases are ATP-driven transporters that translocate specific lipids from the exoplasmic to the cytosolic leaflet of biological membranes, thus establishing a lipid gradient between the two leaflets that is essential for many cellular processes. While substrate specificity, subcellular and tissue-specific expression, and physiological functions have been assigned to a number of these transporters in several organisms, the mechanism of lipid transport has been a topic of intense debate in the field. The recent publication of a series of structural models based on X-ray crystallography and cryo-EM studies has provided the first glimpse into how P4 ATPases have adapted the transport mechanism used by the cation-pumping family members to accommodate a substrate that is at least an order of magnitude larger than cations.

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Panatala, R., H. Hennrich, and J. C. M. Holthuis. "Inner workings and biological impact of phospholipid flippases." Journal of Cell Science 128, no. 11 (April 27, 2015): 2021–32. http://dx.doi.org/10.1242/jcs.102715.

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Pomorski, T. "Tracking down lipid flippases and their biological functions." Journal of Cell Science 117, no. 6 (February 22, 2004): 805–13. http://dx.doi.org/10.1242/jcs.01055.

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Muthusamy, Baby-Periyanayaki, Paramasivam Natarajan, Xiaoming Zhou, and Todd R. Graham. "Linking phospholipid flippases to vesicle-mediated protein transport." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1791, no. 7 (July 2009): 612–19. http://dx.doi.org/10.1016/j.bbalip.2009.03.004.

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Sebastian, Tessy T., Ryan D. Baldridge, Peng Xu, and Todd R. Graham. "Phospholipid flippases: Building asymmetric membranes and transport vesicles." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1821, no. 8 (August 2012): 1068–77. http://dx.doi.org/10.1016/j.bbalip.2011.12.007.

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van Meer, Gerrit, David Halter, Hein Sprong, Pentti Somerharju, and Maarten R. Egmond. "ABC lipid transporters: Extruders, flippases, or flopless activators?" FEBS Letters 580, no. 4 (December 19, 2005): 1171–77. http://dx.doi.org/10.1016/j.febslet.2005.12.019.

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Kishimoto, Takuma, Tetsuo Mioka, Eriko Itoh, David E. Williams, Raymond J. Andersen, and Kazuma Tanaka. "Phospholipid flippases and Sfk1 are essential for the retention of ergosterol in the plasma membrane." Molecular Biology of the Cell 32, no. 15 (July 15, 2021): 1374–92. http://dx.doi.org/10.1091/mbc.e20-11-0699.

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Phospholipids are asymmetrically distributed in the plasma membrane (PM). However, our understanding of their physiological significance is still limited. Here we show that phospholipid flippases and a PM protein, Sfk1, cooperatively play an essential role in retaining ergosterol in the PM of budding yeast.

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Panda, Gayatree, Sabyasachi Dash, and Santosh Kumar Sahu. "Harnessing the Role of Bacterial Plasma Membrane Modifications for the Development of Sustainable Membranotropic Phytotherapeutics." Membranes 12, no. 10 (September 22, 2022): 914. http://dx.doi.org/10.3390/membranes12100914.

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Membrane-targeted molecules such as cationic antimicrobial peptides (CAMPs) are amongst the most advanced group of antibiotics used against drug-resistant bacteria due to their conserved and accessible targets. However, multi-drug-resistant bacteria alter their plasma membrane (PM) lipids, such as lipopolysaccharides (LPS) and phospholipids (PLs), to evade membrane-targeted antibiotics. Investigations reveal that in addition to LPS, the varying composition and spatiotemporal organization of PLs in the bacterial PM are currently being explored as novel drug targets. Additionally, PM proteins such as Mla complex, MPRF, Lpts, lipid II flippase, PL synthases, and PL flippases that maintain PM integrity are the most sought-after targets for development of new-generation drugs. However, most of their structural details and mechanism of action remains elusive. Exploration of the role of bacterial membrane lipidome and proteome in addition to their organization is the key to developing novel membrane-targeted antibiotics. In addition, membranotropic phytochemicals and their synthetic derivatives have gained attractiveness as popular herbal alternatives against bacterial multi-drug resistance. This review provides the current understanding on the role of bacterial PM components on multidrug resistance and their targeting with membranotropic phytochemicals.

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Arashiki, Nobuto, Yuichi Takakuwa, Hiromi Ogura, Taiju Utsugisawa, Satoru Miyano, Seishi Ogawa, Seiji Kojima, Shouichi Ohga, Narla Mohandas, and Hitoshi Kanno. "ATP11C Encodes a Major Flippase in Human Erythrocyte and Its Genetic Defect Causes Congenital Non-Spherocytic Hemolytic Anemia." Blood 126, no. 23 (December 3, 2015): 2131. http://dx.doi.org/10.1182/blood.v126.23.2131.2131.

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Abstract Flippases are members of the P-IV ATPase family of proteins, and contribute to localization of phosphatidylserine (PS) in inner leaflet by its ATP-dependent active transport from outer to inner leaflet of lipid bilayer of erythrocyte membranes. It is critical that erythrocytes maintain PS in the inner monolayer to ensure their 120-day survival in circulation since externalization of PS will be recognized as an eat-me signal, resulting in phagocytosis by splenic macrophages. In the present study, we identified that ATP11C gene encodes a major flippase in human erythrocytes. A 13 years-old boy was referred to our hospital for consultation for work up of an undiagnosed congenital hemolytic anemia. Since extensive biochemical and molecular analysis failed to identify hemoglobin, erythrocyte membranes and enzyme abnormalities for the pathogenesis of hemolysis, we performed the whole exome analysis by massively parallel sequencing. We identified that the proband is hemizyogous, and the mother is heterozygous for a missense mutation of ATP11C, c.1253C>A, corresponding to a single amino acid substitution, p.Thr418Asn. Flipping activity as measured by PS internalization was decreased to 10% in the red cells of the proband compared to a normal control, clearly demonstrating that ATP11C encodes a major flippase in the human erythrocyte membranes. The PS-positive erythrocytes were not significantly increased in the whole blood but only in the most dense senescent cells, suggesting that PS exposure did not occur until very late stages of lifespan. We showed that PS exposure mediated by Ca2+-stimulated phospholipid scrambling was not different between red cells of the proband and control. Taken together, our findings imply that suppressed scrambling activity rather than flippase activity is the major contributor to maintainance of PS in inner leaflet of normal red cells during their 120-day lifespan, and that PS exposure to cell surface as an 'eat-me' signal depends primarily on scramblase activity at the end of lifespan. Importantly, our study has enables us to identify the major flippase of human erythrocyte membrane. Disclosures No relevant conflicts of interest to declare.