Phospholipid Asymmetry in Biological Membranes: Is the Role of Phosphatidylethanolamine Underappreciated?

Abstract

The asymmetric distribution of phospholipids in cell membranes has been the focus of a lot of important research keeping its biological importance in mind. Most of this research is focused on phosphatidylserine (PS) since it is an apoptotic marker, and there is a robust and easy method available its selective quantification. The aim of this commentary is to argue in favour of another highly abundant membrane lipid, phosphatidylethanolamine (PE) almost always associated with PS. PE has one of the smallest headgroups and shows distinctly asymmetric transbilayer distribution. It is a neutral aminophospholipid and capable of a vastly wider range of interactions as seen in its unique ability to act as a molecular chaperone, implicated role in disease biology and its possible role as an anti-cancer target. There are ample evidences to the fact that PE may also bind to Annexin V (ANV), the PS-specific probe, at higher than 10 mol% PE concentrations and absence of Ca2+ ions. An update of the major takeaways from the literature regarding PE asymmetry is also provided.

Graphic Abstract

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Fig. 1

Abbreviations

PC:

Phosphatidylcholine

SM:

Sphingomyelin

PE:

Phosphatidylethanolamine

PS:

Phosphatidylserine

SUV:

Small unilamellar vesicles

TNBS:

2,4,6-Trinitrobenzenesulphonate

ANV:

Annexin V

K d :

Apparent binding dissociation constant

References

  1. Andree HAM, Reutelingsperger CPM, Hauptmann R, Hemker HC, Hermens WT, Willems GM (1990) Binding of vascular anticoagulant α (VAC α) to planar phospholipids bilayers. J Biol Chem 265:4923–4928

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. Balasubramanian K, Gupta CM (1996) Transbilayer phosphatidylethanolamine movements in the yeast plasma membrane. Evidence for a protein-mediated, energy-dependent mechanism. Eur J Biochem 240:798–806

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. Balasubramanian K, Schroit AJ (2003) Aminophospholipid asymmetry: a matter of life and death. Annu Rev Physiol 65:701–734

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. Basu A, Chakrabarti A (2015) Defects in erythrocyte membrane skeletal architecture. Adv Exp Med Biol 842:41–59

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. Bazzi MD, Youakim MA, Nelsestuen GL (1992) Importance of phosphatidylethanolamine for association of protein kinase C and other cytoplasmic proteins with membranes. Biochemistry 31:1125–1134

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. Bogdanov M, Dowhan W (1998) Phospholipid-assisted protein folding : phosphatidylethanolamine is required at a late step of the conformational maturation of the polytopic membrane protein lactose permease. EMBO J 17:5255–5264

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Bogdanov M, Dowhan W (1999) Lipid-assisted protein folding. J Biol Chem 274:36827–36830

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. Bogdanov M, Umeda M, Dowhan W (1999) Phospholipid-assisted refolding of an integral membrane protein. Minimum structural features for phosphatidylethanolamine to act as a molecular chaperone. J Biol Chem 274:12339–12345

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. Bose D, Chakrabarti A (2019) Localizing the chaperone activity of erythroid spectrin. Cytoskeleton 76:383–397

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. Bretscher MS (1972) Asymmetrical lipid bilayer structure for biological membranes. Nat New Biol 236:11–12

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. Calzada E, Onguka O, Claypool SM (2016) Chapter two—phosphatidylethanolamine metabolism in health and disease. Int Rev Cell Mol Biol 321:29–88

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Choe HR, Schlegel RA, Rubin E, Williamson P, Westerman MP (1986) Alteration of red cell membrane organization in sickle cell anaemia. Brit J Haematol 63:761–773

    CAS  Article  Google Scholar 

  13. Connor J, Pak CH, Zwaal RFA, Schroit AJ (1992) Bidirectional transbilayer movement of phospholipid analogs in human red blood cells. J Biol Chem 267:19412–19417

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. Devaux PF (1991) Static and dynamic lipid asymmetry in cell membranes. Biochemistry 30:1163–1173

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. Devaux PF, Morris R (2004) Transmembrane asymmetry and lateral domains in biological membranes. Traffic 5:241–246

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. Dressler V, Haest CWM, Plasa G, Deuiticke B, Erusalimsky JD (1984) Stabilizing factors of phospholipid asymmetry in the erythrocyte membrane. Biochim Biophys Acta 775:189–196

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. Emoto K, Umeda M (2000) An essential role for a membrane lipid in cytokinesis. Regulation of contractile ring disassembly by redistribution of phosphatidylethanolamine. J Cell Biol 149:1215–1224

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Emoto K, Kobayashi T, Yamaji A, Aizawa H, Yahara I et al (1996) Redistribution of phosphatidylethanolamine at the cleavage furrow of dividing cells during cytokinesis. Proc Natl Acad Sci USA 93:12867–12872

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. Emoto K, Toyama-Sorimachi N, Karasuyama H, Inoue K, Umeda M (1997) Exposure of phosphatidylethanolamine on the surface of apoptotic cells. Exp Cell Res 232:430–434

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. Etemadi AH (1980) Membrane asymmetry. A survey and critical appraisal of the methodology II. Methods for assessing the unequal distribution of lipids. Biochim Biophys Acta 604:423–475

    CAS  PubMed  Google Scholar 

  21. Fadeel B, Xue D (2009) The ins and outs of phospholipid asymmetry in the plasma membrane: roles in health and disease. Crit Rev Biochem Mol Biol 44:264–277

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Fujimoto T, Parmryd I (2017) Inter leaflet coupling, pinning, and leaflet asymmetry—major players in plasma membrane nanodomain formation. Front Cell Dev Biol 4:155

    PubMed  PubMed Central  Article  Google Scholar 

  23. Gennis RB (1989a) The structures and properties of membrane lipids. In: Cantor CR (ed) Biomembranes: molecular structure and function. Springer-Verlag, New York, pp 63–65

    Google Scholar 

  24. Gennis RB (1989b) Lateral and transverse asymmetry in membranes. In: Cantor CR (ed) Biomembranes: molecular structure and function. Springer-Verlag, New York, pp 151–158

    Google Scholar 

  25. Giri RP, Mukhopadhyay MK, Mitra M, Chakrabarti A, Sanyal MK et al (2017) Differential adsorption of a membrane skeletal protein, spectrin, in phospholipid membranes. Europhy Lett 118:58002

    Article  CAS  Google Scholar 

  26. Grzybek M, Chorzalska A, Bok E, Hryniewicz-Jankowska A, Czogalla A, Diakowski W, Sikorski AF (2006) Spectrin-phospholipid interactions. Existence of multiple kinds of binding sites ? Chem Phys Lipids 141:133–141

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. Gupta CM, Mishra GC (1981) Transbilayer phospholipid asymmetry in Plasmodium knowlesi-infected host cell membrane. Science 212:1047–1049

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. Gurtovenko AA, Vattulainen I (2008) Membrane potential and electrostatics of phospholipid bilayers with asymmetric transmembrane distribution of anionic lipids. J Phys Chem B 112:4629–4634

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. Haest CW, Erusalimsky J, Dressler V, Kunze I, Deuticke B (1983) Transbilayer mobility of phospholipids in the erythrocyte membrane. Influence of the membrane skeleton. Biomed Biochim Acta 42:S17-21

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hoviusa R, Thijssen J, van der Linden P, Nicolay K, de Kruijff B (1993) Phospholipid asymmetry of the outer membrane of rat liver mitochondria: evidence for the presence of cardiolipin on the outside of the outer membrane. FEBS Lett 330:71–76

    Article  Google Scholar 

  31. Ikemoto A, Kobayashi T, Emoto K, Umeda M, Watanabe S et al (1999) Effects of docosahexaenoic and arachidonic acids on the synthesis and distribution of aminophospholipids during neuronal differentiation of PC12 cells. Arch Biochem Biophys 364:67–74

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. Julien M, Tournier JF, Tocanne JF (1993) Differences in the transbilayer and lateral motions of fluorescent analogs of phosphatidylcholine and phosphatidylethanolamine in the apical plasma membrane of bovine aortic endothelial cells. Exp Cell Res 208:387–397

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. Koopman G, Reutelingsperger CPM, Kuijten GA, Keehnen RM, Pals ST, van Oers MH (1994) Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84:1415–1420

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. Larson MC, Woodliff JE, Hillery CA, Kearl TJ, Zhao M (2012) Phosphatidylethanolamine is externalized at the surface of microparticles. Biochim Biophys Acta 1821:1501–1507

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. Lelong I, Frechard E, Cremel G, Langley K, Rebel G et al (1991) Expression of plasma membrane and cell surface phospholipids and gangliosides of chick embryo neurons grown in primary cultures: developmental studies. Dev Neurosci 13:54–60

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. Machaidze G, Seelig J (2003) Specific binding of cinnamycin (Ro 09-0198) to phosphatidylethanolamine. Comparison between micellar and membrane environments. Biochemistry 42:12570–12576

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. Meers P, Mealy T (1994) Phospholipid determinants for annexin V binding sites and the role of tryptophan 187. Biochemistry 33:5829–5837

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. Mohandas N, Rossi M, Bernstein S, Ballas S, Ravindranath Y et al (1985) The structural organization of skeletal proteins influences lipid translocation across erythrocyte membrane. J Biol Chem 260:14264–14268

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. Musters RJ, Otten E, Biegelmann E, Bijvelt J, Keijzer JJ et al (1993) Loss of asymmetric distribution of sarcolemmal phosphatidylethanolamine during simulated ischemia in the isolated neonatal rat cardiomyocyte. Circ Res 73:514–523

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. Musters RJ, Pröbstl-Biegelmann E, van Veen TA, Hoebe KH, Op den Kamp JA et al (1996) Sarcolemmal phosphatidylethanolamine reorganization during simulated ischaemia and reperfusion: reversibility and ATP dependency. Mol Membr Biol 13:159–164

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. Nordlund JR, Schmidt CF, Dicken SN, Thompson TE (1981) Transbilayer distribution of phosphatidylethanolamine in large and small unilamellar vesicles. Biochemistry 20:3237–3241

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. Op den Kamp JAF (1979) Lipid asymmetry in membranes. Annu Rev Biochem 48:47–71

    Article  Google Scholar 

  43. Op den Kamp JAF (1981) The asymmetric architecture of membranes. In: Finean JB, Michell RH (eds) Membrane structure. Elsevier, New York, pp 83–126

    Google Scholar 

  44. Pradhan D, Williamson P, Schlegel RA (1991) Bilayer/cytoskeleton interactions in lipid-symmetric erythrocytes assessed by a photoactivable phospholipid analogue. Biochemistry 30:7754–7758

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. Ray S, Chakrabarti A (2004) Membrane interaction of erythroid spectrin: surface-density-dependent high-affinity binding to phosphatidylethanolamine. Mol Membr Biol 21:93–100

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. Salomao M, Zhang X, Yang Y, Lee S, Hartwig JH et al (2008) Protein 4.1R-dependent multiprotein complex: new insights into the structural organization of the red blood cell membrane. Proc Natl Acad Sci USA 105:8026–8031

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. Sánchez-Yagüe J, Cabezas JA, Llanillo M (1991) Fatty acid composition of subcellular particles from sheep platelets and topological distribution of phosphatidylethanolamine fatty acids in the plasma membrane. Lipids 26:878–883

    PubMed  Article  PubMed Central  Google Scholar 

  48. Schick PK, Kurica KB, Chacko GK (1976) Location of phosphatidylethanolamine and phosphatidylserine in the human platelet plasma membrane. J Clin Invest 57:1221–1226

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Sessions A, Horwitz AF (1983) Differentiation-related differences in the plasma membrane phospholipid asymmetry of myogenic and fibrogenic cells. Biochim Biophys Acta 728:103–111

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. Shin H-W, Takatsu H (2019) Substrates of P4-ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine). FASEB J 33:3087–3096

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. Smeets EF, Comfurius P, Bevers EM, Zwaal RFA (1994) Calcium-induced transbilayer scrambling of fluorescent phospholipid analogs in platelets and erythrocytes. Biochim Biophys Acta 1195:281–286

    PubMed  Article  PubMed Central  Google Scholar 

  52. Son M, London E (2013) The dependence of lipid asymmetry upon polar headgroup structure. J Lipid Res 54:3385–3393

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Spangenberg P, Heller R, Wagner C, Till U (1985) Localization of phosphatidylethanolamine in the plasma membrane of diamide-treated human blood platelets. Biomed Biochim Acta 44:1335–1341

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Spector AA, Yorek MA (1985) Membrane lipid composition and cellular function. J Lipid Res 26:1015–1035

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. Steck TL, Lange Y (2018) Transverse distribution of plasma membrane bilayer cholesterol: picking sides. Traffic 19:750–760

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. Stuart MCA, Reutelingsperger CPM, Frederik PM (1998) Binding of Annexin V to bilayers with various phospholipid compositions using glass beads in a flow cytometer. Cytometry 33:414–419

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. Supattapone S (2012) Phosphatidylethanolamine as a prion cofactor: potential implications for disease pathogenesis. Prion 6:417–419

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Tait JF, Gibson D, Fujikawa K (1989) Phospholipid binding properties of human placental anticoagulant protein-I, a member of the lipocortin family. J Biol Chem 264:7944–7949

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. Tan LT, Chan KG, Pusparajah P, Lee WL, Chuah LH et al (2017) Targeting membrane lipid a potential cancer cure? Front Pharmacol 8:12

    PubMed  PubMed Central  Google Scholar 

  60. Thiagarajan P, Tait JF (1990) Binding of Annexin V/Placental anticoagulant protein I to platelets. J Biol Chem 265:17420–17423

    CAS  PubMed  Article  Google Scholar 

  61. van den Eijnde SM, van den Hoff MJ, Reutelingsperger CPM, van Heerde WL, Henfling ME et al (2001) Transient expression of phosphatidylserine at cell–cell contact areas is required for myotube formation. J Cell Sci 114:3631–3642

    PubMed  Google Scholar 

  62. Vance JE (2008) Thematic review series: glycerolipids. Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res 49:1377–1387

    CAS  PubMed  Article  Google Scholar 

  63. Verkleji AJ, Zwaal RFA, Roelofsen B, Comfurius P, Kastelijin D et al (1973) The asymmetric distribution of phospholipids in the human red cell membrane. Biochim Biophys Acta 323:178–193

    Article  Google Scholar 

  64. Wali RK, Jaffe S, Kumar D, Kalra VK (1988) Alterations in organization of phospholipids in erythrocytes as factor in adherence to endothelial cells in diabetes mellitus. Diabetes 37:104–111

    CAS  PubMed  Article  Google Scholar 

  65. Williamson P, Schlegel RA (1994) Back and forth: the regulation and function of transbilayer phospholipid movement in eukaryotic cells. Mol Membr Biol 11:199–216

    CAS  PubMed  Article  Google Scholar 

  66. Wilson MJ, Richter-Lowney K, Daleke DL (1993) Hyperglycemia induces a loss of phospholipid asymmetry in human erythrocytes. Biochemistry 32:11302–11310

    CAS  PubMed  Article  Google Scholar 

  67. Yen T-C, Wey S-P, Liao C-H, Yeh C-H, Shen D-W et al (2010) Measurement of the binding parameters of annexin derivatives-erythrocyte membrane interactions. Anal Biochem 406:70–79

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Zachowski A (1993) Phospholipids in animal eukaryotic membranes: transverse asymmetry and movement. Biochem J 294(Pt1):1–14

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Zwaal RFA, Schroit AJ (1997) Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 89:1121–1132

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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Acknowledgements

The author would like to acknowledge Dipayan Bose for a critical reading of the manuscript and G Aditya Kumar for making the graphical representation of the proposed model. The work was funded by the Department of Atomic Energy, Govt. of India.

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Chakrabarti, A. Phospholipid Asymmetry in Biological Membranes: Is the Role of Phosphatidylethanolamine Underappreciated?. J Membrane Biol (2021). https://doi.org/10.1007/s00232-020-00163-w

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Keywords

  • Aminophospholipids
  • Membrane asymmetry
  • Phosphatidylethanolamine
  • Annexin V