Unraveling the Mysteries of Phospholipid Scrambling

Summary

Plasma membrane phospholipid asymmetry is maintained by an aminophospholipid translocase that transports phosphatidylserine (PS) and phosphatidylethanolamine (PE) from outer to inner membrane leaflet. Cell activation or injury leads to redistribution of all major lipid classes within the plasma membrane, resulting in surface exposure of PS and PE. Cell surface-exposed PS can serve as receptor sites for coagulation enzyme complexes, and contributes to cell clearance by the reticuloendothelial system. The mechanism(s) by which this PL ”scrambling” occurs is poorly understood. A protein called phospholipid scramblase (PLSCR1) has been cloned that exhibits Ca²⁺-activated PL scrambling activity in vitro. PLSCR1 belongs to a new family of proteins with no apparent homology to other known proteins. PLSCR1 is palmitoylated and contains a potential protein kinase C phosphorylation site. It further contains multiple PxxP and PPxY motifs, representing potential binding motifs for SH3 and WW domains implicated in mediating protein-protein interactions. Although at least two proteins have been shown to associate with PLSCR1, the functional significance of such interaction remains to be elucidated. Evidence that PLSCR1 may serve functions other than its proposed activity as PL scramblase is also presented.

Key words

Phospholipid - phosphatidylserine - plasma membrane - phospholipid scramblase - phospholipid asymmetry

• References

• 1 Roelofsen B. Molecular architecture and dynamics of the plasma membrane lipid bilayer: the red blood cell as a model. Infection 1992; 19: S206-S209.
• 2 Schroit AJ, Zwaal RFA. Transbilayer movement of phospholipids in red cell and platelet membranes. Biochim Biophys Acta 1991; 1071: 313-29.
• 3 Devaux P. Static and dynamic lipid asymmetry in cell membranes. Biochemistry 1991; 30: 1163-73.
• 4 Williamson P, Kulick A, Zachowski A, Schlegel RA, Devaux PF. Ca²⁺ induces transbilayer redistribution of all major phospholipids in human erythrocytes. Biochemistry 1992; 31: 6355-60.
• 5 Chang C-P, Zhao J, Wiedmer T, Sims PJ. Contribution of platelet microparticle formation and granule secretion to the transmembrane migration of phosphatidylserine. J Biol Chem 1993; 268: 7171-8.
• 6 Bassé F, Gaffet P, Rendu F, Bienvenüe A. Translocation of spin-labeled phospholipids through plasma membrane during thrombin- and ionophore A23187-induced platelet activation. Biochemistry 1993; 32: 2337-44.
• 7 Connor J, Pak CH, Zwaal RF, Schroit AJ. Bidirectional transbilayer movement of phospholipid analogs in human red blood cells. Evidence for an ATP-dependent and protein- mediated process. J Biol Chem 1992; 267: 19412-7.
• 8 Comfurius P, Senden JM, Tilly RH, Schroit AJ, Bevers EM, Zwaal RF. Loss of membrane phospholipid asymmetry in platelets and red cells may be associated with calcium-induced shedding of plasma membrane and inhibition of aminophospholipid translocase. Biochim Biophys Acta 1990; 1026: 153-60.
• 9 Smeets EF, Comfurius P, Bevers EM, Zwaal RFA. Calcium-induced transbilayer scrambling of fluorescent phospholipid analogs in platelets and erythrocytes. Biochim Biophys Acta Biomembr 1994; 1195: 281-6.
• 10 Bevers EM, Comfurius P, Dekkers DWC, Zwaal RFA. Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta Mol Cell Biol Lipids 1999; 1439: 317-30.
• 11 Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 1992; 148: 2207-16.
• 12 Wang RH, Phillips Jr G, Medof ME, Mold C. Activation of the alternative complement pathway by exposure of phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients. J Clin Invest 1993; 92: 1326-35.
• 13 Pradhan D, Krahling S, Williamson P, Schlegel RA. Multiple systems for recognition of apoptotic lymphocytes by macrophages. Mol Biol Cell 1997; 8: 767-78.
• 14 Bevers EM, Comfurius P, Dekkers DWC, Harmsma M, Zwaal RFA. Transmembrane phospholipid distribution in blood cells: Control mechanisms and pathophysiological significance. Biol Chem Hoppe Seyler 1998; 379: 973-86.
• 15 Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature 2000; 407: 784-8.
• 16 Mann KG, Jenny RJ, Krishnaswamy S. Cofactor proteins in the assembly and expression of blood clotting enzymes. Annu Rev Biochem 1988; 57: 915-56.
• 17 Krishnaswamy S, Field KA, Edgington TS, Morrissey JH, Mann KG. Role of the membrane surface in the activation of human coagulation factor X. J Biol Chem 1992; 267: 26110-20.
• 18 Tracy PB. Regulation of thrombin generation at cell surfaces. Semin Thromb Hemost 1988; 14: 227-33.
• 19 Bevers EM, Comfurius P, Zwaal RF. Platelet procoagulant activity: physiological significance and mechanisms of exposure. Blood Rev 1991; 5: 146-54.
• 20 Wiedmer T, Esmon CT, Sims PJ. Complement proteins C5b-9 stimulate procoagulant activity through the platelet prothrombinase. Blood 1986; 68: 875-80.
• 21 Jones ME, Lentz BR, Dombrose FA, Sandberg H. Comparison of the abilities of synthetic and platelet-derived membranes to enhance thrombin formation. Thromb Res 1985; 39: 711-24.
• 22 Gilbert GE, Drinkwater D, Barter S, Clouse SB. Specificity of phosphatidylserine-containing membrane binding sites for factor VIII. Studies with model membranes supported by glass microspheres (lipospheres). J Biol Chem 1992; 267: 15861-8.
• 23 Gilbert GE, Arena AA. Activation of the factor VIIIa-factor IXa enzyme complex of blood coagulation by membranes containing phosphatidyl-Lserine. J Biol Chem 1996; 271: 11120-5.
• 24 Gilbert GE, Sims PJ, Wiedmer T, Furie B, Furie BC, Shattil SJ. Platelet-derived microparticles express high affinity receptors for factor VIII. J Biol Chem 1991; 266: 17261-8.
• 25 Thiagarajan P, Tait JF. Collagen-induced exposure of anionic phospholipid in platelets and platelet-derived microparticles. J Biol Chem 1991; 266: 24302-7.
• 26 Dachary-Prigent J, Freyssinet JM, Pasquet JM, Carron JC, Nurden AT. Annexin V as a probe of aminophospholipid exposure and platelet membrane vesiculation: a flow cytometry study showing a role for free sulfhydryl groups. Blood 1993; 81: 2554-65.
• 27 Miletich JP, Kane WH, Hofmann SL, Stanford N, Majerus PW. Deficiency of Factor-Xa-Factor Va binding sites on the platelets of a patient with a bleeding disorder. Blood 1979; 54: 1015-22.
• 28 Rosing J, Bevers EM, Comfurius P, Hemker HC, van Dieijen G, Weiss HJ, Zwaal RF. Impaired Factor X and prothrombin activation associated with decreased phospholipid exposure in platelets from a patient with a bleeding disorder. Blood 1985; 65: 1557-61.
• 29 Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem 1989; 264: 17049-57.
• 30 Ahmad SS, Rawala-Sheikh R, Ashby B, Walsh PN. Platelet receptor-mediated factor X activation by factor IXa: high-affinity factor IXa receptors induced by factor VIII are deficient on platelets in Scott syndrome. J Clin Invest 1989; 84: 824-8.
• 31 Neuenschwander PF, Bianco-Fisher E, Rezaie AR, Morrissey JH. Phosphatidylethanolamine augments factor VIIa-tissue factor activity: Enhancement of sensitivity to phosphatidylserine. Biochemistry 1995; 34: 13988-93.
• 32 Smirnov MD, Ford DA, Esmon CT, Esmon NL. The effect of membrane composition on the hemostatic balance. Biochemistry 1999; 38: 3591-8.
• 33 Blumenfeld N, Zachowski A, Galacteros F, Beuzard Y, Devaux PF. Transmembrane mobility of phospholipids in sickle erythrocytes: effect of deoxygenation on diffusion and asymmetry. Blood 1991; 77: 849-54.
• 34 Hamilton KK, Hattori R, Esmon CT, Sims PJ. Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex. J Biol Chem 1990; 265: 3809-14.
• 35 Kennedy SP, Rollins SA, Burton WV, Sims PJ, Bothwell ALM, Squinto SP, Zavoico GB. Protection of porcine aortic endothelial cells from complement-mediated cell lysis and activation by recombinant human CD59. Transplantation 1994; 57: 1494-501.
• 36 Dalmasso AP. The complement system in xenotransplantation. Immuno-pharmacology 1992; 24: 149-60.
• 37 Wiedmer T, Hall SE, Ortel TL, Kane WH, Rosse WF, Sims PJ. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria. Blood 1993; 82: 1192-6.
• 38 Roubey RAS. Antigenic specificities of “antiphospholipid” autoanti-bodies. Springer Semin Immunopathol 1994; 16: 211-22.
• 39 Rand JH, Wu XX, Andree HAM, Ross JBA, Rusinova E, Gascon-Lema MG, Calandri C, Harpel PC. Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: A “lupus procoagulant” phenomenon. Blood 1998; 92: 1652-60.
• 40 Willems GM, Janssen MP, Comfurius P, Galli M, Zwaal RFA, Bevers EM. Competition of annexin V and anticardiolipin antibodies for binding to phosphatidylserine containing membranes. Biochemistry 2000; 39: 1982-9.
• 41 Weiss HJ. Scott Syndrome: A disorder of platelet coagulant activity. Semin Hematol 1994; 31: 312-9.
• 42 Toti F, Satta N, Fressinaud E, Meyer D, Freyssinet J-M. Scott syndrome, characterized by impaired transmembrane migration of procoagulant phosphatidylserine and hemorrhagic complications, is an inherited disorder. Blood 1996; 87: 1409-15.
• 43 Bevers EM, Wiedmer T, Comfurius P, Shattil SJ, Weiss HJ, Zwaal RF, Sims PJ. Defective Ca²⁺-induced microvesiculation and deficient expression of procoagulant activity in erythrocytes from a patient with a bleeding disorder: a study of the red blood cells of Scott syndrome. Blood 1992; 79: 380-8.
• 44 Kojima H, Newton-Nash D, Weiss HJ, Zhao J, Sims PJ, Wiedmer T. Production and characterization of transformed B-lymphocytes expressing the membrane defect of Scott syndrome. J Clin Invest 1994; 94: 2237-44.
• 45 Martínez MC, Martin S, Toti F, Fressinaud E, Dachary-Prigent J, Meyer D, Freyssinet JM. Significance of capacitative Ca²⁺ entry in the regulation of phosphatidylserine expression at the surface of stimulated cells. Biochemistry 1999; 38: 10092-8.
• 46 Satta N, Toti F, Fressinaud E, Meyer D, Freyssinet J-M. Scott syndrome: an inherited defect of the procoagulant activity of platelets. Platelets 1997; 8: 117-24.
• 47 Martin S, Laude-Lemaire I, Kerbiriou-Nabias D, Freyssinet J-M, Martínez MC. Relation between phosphatidylserine exposure and store-operated Ca²⁺ entry in stimulated cells. Biochem Biophys Res Commun 2000; 279: 639-45.
• 48 Zhou QS, Sims PJ, Wiedmer T. Expression of proteins controlling transbilayer movement of plasma membrane phospholipids in the B lymphocytes from a patient with Scott syndrome. Blood 1998; 92: 1707-12.
• 49 Toti F, Schindler V, Riou JF, Lombard-Platet G, Fressinaud E, Meyer D, Uzan A, Le Pecq JB, Mandel JL, Freyssinet JM. Another-link between phospholipid transmembrane migration and ABC transporter gene family, inferred from a rare inherited disorder of phosphatidylserine externalization. Biochem Biophys Res Commun 1997; 241: 548-52.
• 50 Connor J, Pak CC, Schroit AJ. Exposure of phosphatidylserine in the outer leaflet of human red blood cells. Relationship to cell density, cell age, and clearance by mononuclear cells. J Biol Chem 1994; 269: 2399-404.
• 51 Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RAB, Henson PM. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 2000; 405: 85-90.
• 52 Allen TM, Williamson P, Schlegel RA. Phosphatidylserine as a determinant of reticuloendothelial recognition of liposome models of the erythrocyte surface. Proc Natl Acad Sci USA 1988; 85: 8067-71.
• 53 Connor J, Bucana C, Fidler IJ, Schroit AJ. Differentiation-dependent expression of phosphatidylserine in mammalian plasma membranes: Quantitative assessment of outer-leaflet lipid by prothrombinase complex formation. Proc Natl Acad Sci USA 1989; 86: 3184-8.
• 54 Geldwerth D, Kuypers FA, Bütikofer P, Allary M, Lubin BH, Devaux PF. Transbilayer mobility and distribution of red cell phospholipids during storage. J Clin Invest 1993; 92: 308-14.
• 55 Gaffet P, Bassé F, Bienvenüe A. Loss of phospholipid asymmetry in human platelet plasma membrane after 1-12 days of storage. An ESR study. Eur J Biochem 1994; 222: 1033-40.
• 56 Diaz C, Morkowski J, Schroit AJ. Generation of phenotypically aged phosphatidylserine-expressing erythrocytes by dilauroylphosphatidylcho-line-induced vesiculation. Blood 1996; 87: 2956-61.
• 57 Shapira S, Friedman Z, Shapiro H, Presseizen K, Radnay J, Ellis MH. The effect of storage on the expression of platelet membrane phosphatidylserine and the subsequent impact on the coagulant function of stored platelets. Transfusion 2000; 40: 1257-63.
• 58 Balasubramanian K, Schroit AJ. Characterization of phosphatidylserine-dependent β₂-glycoprotein I macrophage interactions - Implications for apoptotic cell clearance by phagocytes. J Biol Chem 1998; 273: 29272-7.
• 59 Fadok VA, de Cathelineau A, Daleke DL, Henson PM, Bratton DL. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibro-blasts. J Biol Chem. In press.
• 60 Marguet D, Luciani MF, Moynault A, Williamson P, Chimini G. Engulfment of apoptotic cells involves the redistribution of membrane phosphatidylserine on phagocyte and prey. Nature Cell Biology 1999; 1: 454-6.
• 61 Callahan MK, Williamson P, Schlegel RA. Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes. Cell Death Differ 2000; 7: 645-53.
• 62 Tepper AD, Ruurs P, Wiedmer T, Sims PJ, Borst J, Van Blitterswijk WJ. Sphingomyelin hydrolysis to ceramide during the execution phase of apoptosis results from phospholipid scrambling and alters cell-surface morphology. J Cell Biol 2000; 150: 155-64.
• 63 Wilson HA, Waldrip JB, Nielson KH, Judd AM, Han SK, Cho WW, Sims PJ, Bell JD. Mechanisms by which elevated intracellular calcium induces S49 cell membranes to become susceptible to the action of secretory phospholipase A2. J Biol Chem 1999; 274: 11494-504.
• 64 Murakami M, Kambe T, Shimbara S, Higashino K, Hanasaki K, Arita H, Horiguchi M, Arita M, Arai H, Inoue K, Kudo I. Different functional aspects of the group II subfamily (types IIA and V) and type X secretory phospholipase A₂s in regulating arachidonic acid release and prostaglandin generation – Implications of cyclooxygenase-2 induction and phospholipid scramblase-mediated cellular membrane perturbation. J Biol Chem 1999; 274: 31435-44.
• 65 Seigneuret M, Devaux PF. ATP-dependent asymmetric distribution of spin-labeled phospholipids in the erythrocyte membrane: Relation to shape changes. Proc Natl Acad Sci USA 1984; 81: 3751-5.
• 66 Beleznay Z, Zachowski A, Devaux PF, Navazo MP, Ott P. ATP-dependent aminophospholipid translocation in erythrocyte vesicles: stoichiometry of transport. Biochemistry 1993; 32: 3146-52.
• 67 Devaux PF, Zachowski A. Maintenance and consequences of membrane phospholipid asymmetry. Chem Phys Lipids 1994; 73: 107-20.
• 68 Zachowski A, Favre E, Cribier S, Herve P, Devaux PF. Outside-inside translocation of aminophospholipids in the human erythrocyte membrane is mediated by a specific enzyme. Biochemistry 1986; 25: 2585-90.
• 69 Bitbol M, Fellmann P, Zachowski A, Devaux PF. Ion regulation of phosphatidylserine and phosphatidylethanolamine outside-inside translocation in human erythrocytes. Biochim Biophys Acta 1987; 904: 268-82.
• 70 Diaz C, Schroit AJ. Role of translocases in the generation of phosphatidylserine asymmetry. J Memb Biol 1996; 151: 1-9.
• 71 Tang XJ, Halleck MS, Schlegel RA, Williamson P. A subfamily of P-type ATPases with aminophospholipid transporting activity. Science 1996; 272: 1495-7.
• 72 Mouro I, Halleck MS, Schlegel RA, Mattei MG, Williamson P, Zachowski A, Devaux P, Cartron JP, Colin Y. Cloning, expression, and chromosomal mapping of a human ATPase II gene, member of the third subfamily of P-type ATPases and orthologous to the presumed bovine and murine aminophospholipid translocase. Biochem Biophys Res Commun 1999; 257: 333-9.
• 73 Siegmund A, Grant A, Angeletti C, Malone L, Nichols JW, Rudolph HK. Loss of Drs2p does not abolish transfer of fluorescence-labeled phospholipids across the plasma membrane of Saccharomyces cerevisiae. J Biol Chem 1998; 273: 34399-405.
• 74 Daleke DL, Lyles JV. Identification and purification of aminophospholipid flippases. Biochim Biophys Acta Mol Cell Biol Lipids 2000; 1486: 108-27.
• 75 Kamp D, Haest CWM. Evidence for a role of the multidrug resistance protein (MRP) in the outward translocation of NBD-phospholipids in the erythrocyte membrane. Biochim Biophys Acta 1998; 1372: 91-101.
• 76 Dekkers DW, Comfurius P, Schroit AJ, Bevers EM, Zwaal RF. Transbilayer movement of NBD-labeled phospholipids in red blood cell membranes: Outward-directed transport by the multidrug resistance protein 1 (MRP1). Biochemistry 1998; 37: 14833-7.
• 77 Dekkers DWC, Comfurius P, Van Gool RGJ, Bevers EM, Zwaal RFA. Multidrug resistance protein 1 regulates lipid asymmetry in erythrocyte membranes. Biochem J 2000; 350: 531-5.
• 78 Bosch I, Dunussi-Joannopoulos K, Wu RL, Furlong ST, Croop J. Phosphatidylcholine and phosphatidylethanolamine behave as substrates of the human MDR1 P-glycoprotein. Biochemistry 1997; 36: 5685-94.
• 79 Van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel AH, Borst P, van Meer G. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 1996; 87: 507-17.
• 80 Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Ann Rev Biochem 1993; 62: 385-427.
• 81 Elferink RPJO, Tytgat GNJ, Groen AK. The role of mdr2 P-glycoprotein in hepatobiliary lipid transport. FASEB J 1997; 11: 19-28.
• 82 Langmann T, Klucken J, Reil M, Liebisch G, Luciani MF, Chimini G, Kaminski WE, Schmitz G. Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): Evidence for sterol-dependent regulation in macrophages. Biochem Biophys Res Commun 1999; 257: 29-33.
• 83 Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999; 22: 347-51.
• 84 Hamon Y, Broccardo C, Chambenoit O, Luciani MF, Toti F, Chaslin S, Freyssinet JM, Devaux PF, McNeish J, Marguet D, Chimini G. ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nature Cell Biology 2000; 2: 399-406.
• 85 Borst P, Zelcer N, Van Helvoort A. ABC transporters in lipid transport. Biochim Biophys Acta Mol Cell Biol Lipids 2000; 1486: 128-44.
• 86 Zwaal RFA, Comfurius P, Bevers EM. Platelet procoagulant activity and microvesicle formation. Its putative role in hemostasis and thrombosis. Biochim Biophys Acta 1992; 1180: 1-8.
• 87 Verhoven B, Schlegel RA, Williamson P. Rapid loss and restoration of lipid asymmetry by different pathways in resealed erythrocyte ghosts. Biochim Biophys Acta 1992; 1104: 15-23.
• 88 Connor J, Schroit AJ. Aminophospholipid translocation in erythrocytes: Evidence for the involvement of a specific transporter and an endofacial protein. Biochemistry 1990; 29: 37-43.
• 89 Gaffet P, Bettache N, Bienvenüe A. Transverse redistribution of phospholipids during human platelet activation: evidence for a vectorial outflux specific to aminophospholipids. Biochemistry 1995; 34: 6762-9.
• 90 Williamson P, Bevers EM, Smeets EF, Comfurius P, Schlegel RA, Zwaal RFA. Continuous analysis of the mechanism of activated transbilayer lipid movement in platelets. Biochemistry 1995; 34: 10448-55.
• 91 Bratton DL. Polyamine inhibition of transbilayer movement of plasma membrane phospholipids in the erythrocyte ghost. J Biol Chem 1994; 269: 22517-23.
• 92 Wiedmer T, Shattil SJ, Cunningham M, Sims PJ. Role of calcium and cal-pain in complement-induced vesiculation of the platelet plasma membrane and in the exposure of the platelet factor Va receptor. Biochemistry 1990; 29: 623-32.
• 93 Sims PJ, Faioni EM, Wiedmer T, Shattil SJ. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 1988; 263: 18205-12.
• 94 Sandberg H, Bode AP, Dombrose FA, Hoechli M, Lentz BR. Expression of coagulant activity in human platelets: Release of membranous vesicles providing Platelet Factor 1 and Platelet Factor 3. Thromb Res 1985; 39: 63-79.
• 95 Bailey AL, Cullis PR. Modulation of membrane fusion by asymmetric transbilayer distributions of amino lipids. Biochemistry 1994; 33: 12573-80.
• 96 Bassé F, Gaffet P, Rendu F, Bienvenüe A. Phospholipid transverse mobility modifications in plasma membranes of activated platelets: An ESR study. Biochem Biophys Res Commun 1992; 189: 465-71.
• 97 Dachary-Prigent J, Pasquet JM, Freyssinet JM, Nurden AT. Calcium involvement in aminophospholipid exposure and microparticle formation during platelet activation: A study using Ca²⁺-ATPase inhibitors. Biochemistry 1995; 34: 11625-34.
• 98 Bucki R, Bachelot-Loza C, Zachowski A, Giraud F, Sulpice JC. Calcium induces phospholipid redistribution and microvesicle release in human erythrocyte membranes by independent pathways. Biochemistry 1998; 37: 15383-91.
• 99 Düzgünes N, Nir S, Wilschut J, Bentz J, Newton C, Portis A, Papahadjopoulos D. Calcium- and magnesium-induced fusion of mixed phosphatidylserine/phosphatidylcholine vesicles: effect of ion binding. J Memb Biol 1981; 59: 115-25.
• 100 de Kruijff B, Cullis PR, Verkleij AJ. Non-bilayer lipid structures in model and biological membranes. Trends Biochem Sci 1980; 5: 79-81.
• 101 Sulpice JC, Zachowski A, Devaux PF, Giraud F. Requirement for phosphatidylinositol 4,5-bisphosphate in the Ca²⁺-induced phospholipid redistribution in the human erythrocyte membrane. J Biol Chem 1994; 269: 6347-54.
• 102 Shiffer KA, Rood L, Emerson RK, Kuypers FA. Effects of phosphatidylinositol diphosphate on phospholipid asymmetry in the human erythrocyte membrane. Biochemistry 1998; 37: 3449-58.
• 103 Bevers EM, Wiedmer T, Comfurius P, Zhao J, Smeets EF, Schlegel RA, Schroit AJ, Weiss HJ, Williamson P, Zwaal RFA, Sims PJ. The complex of phosphatidylinositol 4,5-bisphosphate and calcium ions is not responsible for Ca²⁺-induced loss of phospholipid asymmetry in the human erythrocyte. A study in Scott Syndrome, a disorder of calcium-induced phospholipid scrambling. Blood 1995; 86: 1983-91.
• 104 Sulpice JC, Moreau C, Devaux PF, Zachowski A, Giraud F. Antagonist effects of Ca²⁺ and spermine on phosphatidylinositol 4,5-bisphosphate-mediated transmembrane redistribution of phospholipids in large unilamellar vesicles and in erythrocytes. Biochemistry 1996; 35: 13345-52.
• 105 Bucki R, Giraud F, Sulpice JC. Phosphatidylinositol 4,5-bisphosphate domain inducers promote phospholipid transverse redistribution in biological membranes. Biochemistry 2000; 39: 5838-44.
• 106 Cohen AM, Liu SC, Derick LH, Palek J. Ultrastructural studies of the interaction of spectrin with phosphatidylserine liposomes. Blood 1986; 68: 920-6.
• 107 Rybicki AC, Heath R, Lubin B, Schwartz RS. Human erythrocyte protein 4.1 is a phosphatidylserine binding protein. J Clin Invest 1988; 81: 255-60.
• 108 Shiffer KA, Goerke J, Duzgunes N, Fedor J, Shohet SB. Interaction of erythrocyte protein 4.1 with phospholipids. A monolayer and liposome study. Biochim Biophys Acta 1988; 937: 269-80.
• 109 Haest CWM, Erusalimsky J, Dressler V, Kunze I, Deuticke B. Transbilayer mobility of phospholipids in the erythrocyte membrane. Influence of the membrane skeleton. Biomed Biochim Acta 1983; 42: S17-S21.
• 110 Comfurius P, Bevers EM, Zwaal RF. Interaction between phosphatidylserine and the isolated cytoskeleton of human blood platelets. Biochim Biophys Acta 1989; 983: 212-6.
• 111 Franck PF, Bevers EM, Lubin BH, Comfurius P, Chiu DTY, Op den Kamp JAF, Zwaal RFA. Uncoupling of the membrane skeleton from the lipid bi-layer. The cause of accelerated phospholipid flip-flop leading to an enhanced procoagulant activity of sickled cells. J Clin Invest 1985; 75: 183-90.
• 112 Comfurius P, Williamson P, Smeets EF, Schlegel RA, Bevers EM, Zwaal RFA. Reconstitution of phospholipid scramblase activity from human blood platelets. Biochemistry 1996; 35: 7631-4.
• 113 Bassé F, Stout JG, Sims PJ, Wiedmer T. Isolation of an erythrocyte membrane protein that mediates Ca²⁺-dependent transbilayer movement of phospholipid. J Biol Chem 1996; 271: 17205-10.
• 114 Zhou Q, Zhao J, Stout JG, Luhm RA, Wiedmer T, Sims PJ. Molecular cloning of human plasma membrane phospholipid scramblase – A protein mediating transbilayer movement of plasma membrane phospholipids. J Biol Chem 1997; 272: 18240-4.
• 115 Zhou Q, Sims PJ, Wiedmer T. Identity of a conserved motif in phospholipid scramblase that is required for Ca2+-accelerated transbilayer movement of membrane phospholipids. Biochemistry 1998; 37: 2356-60.
• 116 Stout JG, Bassé F, Luhm RA, Weiss HJ, Wiedmer T, Sims PJ. Scott syndrome erythrocytes contain a membrane protein capable of mediating Ca²⁺-dependent transbilayer migration of membrane phospholipids. J Clin Invest 1997; 99: 2232-8.
• 117 Wiedmer T, Zhou QS, Kwoh DY, Sims PJ. Identification of three new members of the phospholipid scramblase gene family. Biochim Biophys Acta 2000; 1467: 244-53.
• 118 Zhao J, Zhou Q, Wiedmer T, Sims PJ. Palmitoylation of phospholipid scramblase is required for normal function in promoting Ca²⁺-activated transbilayer movement of membrane phospholipids. Biochemistry 1998; 37: 6361-6.
• 119 Frasch SC, Henson PM, Kailey JM, Richter DA, Janes MS, Fadok VA, Bratton DL. Regulation of phospholipid scramblase activity during apoptosis and cell activation by protein kinase Cd. J Biol Chem 2000; 275: 23065-73.
• 120 Der SD, Zhou AM, Williams BR, Silverman RH. Identification of genes differentially regulated by interferon α, β, or gamma using oligonucleotide arrays. Proc Natl Acad Sci USA 1998; 95: 15623-8.
• 121 Zhou QS, Zhao J, Al Zoghaibi F, Zhou AM, Wiedmer T, Silverman RH, Sims PJ. Transcriptional control of the human plasma membrane phospholipid scramblase 1 gene is mediated by interferon-α. Blood 2000; 95: 2593-9.
• 122 Kasukabe T, Okabe-Kado J, Honma Y. TRA1, a novel mRNA highly expressed in leukemogenic mouse monocytic sublines but not in nonleukemogenic sublines. Blood 1997; 89: 2975-85.
• 123 Kasukabe T, Kobayashi H, Kaneko Y, Okabe-Kado J, Honma Y. Identity of human normal counterpart (MmTRA1b) of mouse leukemogenesis-associated gene (MmTRA1a) product as plasma membrane phospholipid scramblase and chromosome mapping of the human MmTRA1b phospholipid scramblase gene. Biochem Biophys Res Commun 1998; 249: 449-55.
• 124 Silverman RH, Al-Zoghaibi F, Kushner D, Zhou A, Nie H, Halloum A, Zhou Q, Zhao J, Wiedmer T, Sims PJ. Involvement of a novel IFN stimulated gene for phospholipid scramblase in IFN action. J Interferon Cytokine Res 1999; 19: S68.
• 125 Woon LA, Holland JW, Kable EP, Roufogalis BD. Ca²⁺ sensitivity of phospholipid scrambling in human red cell ghosts. Cell Calcium 1999; 25: 313-20.
• 126 Stout JG, Zhou QS, Wiedmer T, Sims PJ. Change in conformation of plasma membrane phospholipid scramblase induced by occupancy of its Ca²⁺ binding site. Biochemistry 1998; 37: 14860-6.
• 127 Zhao J, Zhou Q, Wiedmer T, Sims PJ. Level of expression of phospholipid scramblase regulates induced movement of phosphatidylserine to the cell surface. J Biol Chem 1998; 273: 6603-6.
• 128 Tseng CC, Tseng CP. Identification of a novel secretory leukocyte protease inhibitor-binding protein involved in membrane phospholipid movement. FEBS Lett 2000; 475: 232-6.
• 129 Sun J, Wiedmer T, Sims PJ. c-Abl tyrosine kinase binds and phosphorylates phospholipid scramblase. FASEB J. In press.
• 130 Fadeel B, Gleiss B, Högstrand K, Chandra J, Wiedmer T, Sims PJ, Henter J-I, Orrenius S, Samali A. Phosphatiylserine exposure during apoptosis is a cell-type-specific event and does not correlate with plasma membrane phospholipid scramblase expression. Biochem Biophys Res Commun 1999; 266: 504-11.