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Membrane lipids: where they are and how they behave

Key Points

  • Lipids function as essential structural components of membranes, as signalling molecules, as chemical identifiers of specific membranes and as energy storage molecules. The synthesis of lipids is non-uniformly distributed among a few cellular membranes, which requires most organelles to depend on lipid transport processes to achieve their full complement of lipids.

  • Organelles differ both quantitatively and qualitatively in their lipid content. In many organelles, the lipid composition of separate leaflets of the membrane bilayer is significantly different, which produces asymmetry across the bilayer — a situation that is maintained by ATP-dependent flippases.

  • Lipid transport between and within organelles is poorly understood, but a growing number of genes that are involved in these processes have been unambiguously identified, and their mechanisms of action are under active investigation. There is clear evidence that several lipids are transported between organelles by non-vesicular mechanisms that involve zones of apposition between donor and acceptor compartments, and macromolecular assemblies that involve multiple lipids and proteins.

  • Several dozen lipids participate in intra- and intercellular signalling processes. In most instances, the levels of signalling molecules are exceedingly low compared with the complement of structural lipids that is present in membranes.

  • Lipids adopt defined phases depending on their molecular structure and the physical conditions. In lipid mixtures, two fluid phases can coexist with different physical properties: liquid-disordered and liquid-ordered.

  • Liquid-ordered assemblies in biomembranes, known as lipid rafts, are small and transient but can coalesce and become stabilized during signalling and vesicle budding. How proteins contribute to phase separation and preferentially distribute into one of the two different phases (or at their interface) is presently unclear.

Abstract

Throughout the biological world, a 30 Å hydrophobic film typically delimits the environments that serve as the margin between life and death for individual cells. Biochemical and biophysical findings have provided a detailed model of the composition and structure of membranes, which includes levels of dynamic organization both across the lipid bilayer (lipid asymmetry) and in the lateral dimension (lipid domains) of membranes. How do cells apply anabolic and catabolic enzymes, translocases and transporters, plus the intrinsic physical phase behaviour of lipids and their interactions with membrane proteins, to create the unique compositions and multiple functionalities of their individual membranes?

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Figure 1: Membrane lipids and lipid second messengers.
Figure 2: Lipid synthesis and steady-state composition of cell membranes.
Figure 3: Mechanisms for generating asymmetric lipid distribution.
Figure 4: Emerging models for lipid transport.

References

  1. 1

    Sud, M. et al. LMSD: LIPID MAPS structure database. Nucleic Acids Res. 35, D527–D532 (2007).

    CAS  PubMed  Google Scholar 

  2. 2

    Feigenson, G. W. Phase behavior of lipid mixtures. Nature Chem. Biol. 2, 560–563 (2006).

    CAS  Google Scholar 

  3. 3

    Feigenson, G. W. Phase boundaries and biological membranes. Annu. Rev. Biophys. Biomol. Struct. 36, 63–77 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Marsh, M. & Helenius, A. Virus entry: open sesame. Cell 124, 729–740 (2006). Cell biology studies, live-cell imaging and systems biology show that many of the multiple and subtly different pathways that animal viruses use to enter host cells require specific lipids.

    CAS  PubMed  Google Scholar 

  5. 5

    van Meer, G. Cellular lipidomics. EMBO J. 24, 3159–3165 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Marsh, D. Lateral pressure profile, spontaneous curvature frustration, and the incorporation and conformation of proteins in membranes. Biophys. J. 93, 3884–3899 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Dowhan, W. & Bogdanov, M. in Biochemistry of Lipids, Lipoproteins and Membranes Vol. 36 (eds Vance, D. E. & Vance, J. E.) 1–35 (Elsevier, Amsterdam, 2002).

    Google Scholar 

  8. 8

    van Meer, G. & Lisman, Q. Sphingolipid transport: rafts and translocators. J. Biol. Chem. 277, 25855–25858 (2002).

    CAS  PubMed  Google Scholar 

  9. 9

    Huang, J. & Feigenson, G. W. A microscopic interaction model of maximum solubility of cholesterol in lipid bilayers. Biophys. J. 76, 2142–2157 (1999). The interactions of cholesterol with membrane lipid lead to abrupt jumps in cholesterol chemical potential because of the hydrophobic interaction, which forces phospholipid headgroups to shield cholesterol from water, as described here by the umbrella model.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Ali, M. R., Cheng, K. H. & Huang, J. Ceramide drives cholesterol out of the ordered lipid bilayer phase into the crystal phase in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/cholesterol/ceramide ternary mixtures. Biochemistry 45, 12629–12638 (2006).

    CAS  PubMed  Google Scholar 

  11. 11

    Meyer zu Heringdorf, D. & Jakobs, K. H. Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim. Biophys. Acta 1768, 923–940 (2007).

    CAS  PubMed  Google Scholar 

  12. 12

    Fernandis, A. Z. & Wenk, M. R. Membrane lipids as signaling molecules. Curr. Opin. Lipidol. 18, 121–128 (2007).

    CAS  PubMed  Google Scholar 

  13. 13

    Kolesnick, R. & Hannun, Y. A. Ceramide and apoptosis. Trends Biochem. Sci. 24, 224–225 (1999).

    CAS  PubMed  Google Scholar 

  14. 14

    Tepper, A. D. et al. Sphingomyelin hydrolysis to ceramide during the execution phase of apoptosis results from phospholipid scrambling and alters cell-surface morphology. J. Cell Biol. 150, 155–164 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Megha, Sawatzki, P., Kolter, T., Bittman, R. & London, E. Effect of ceramide N-acyl chain and polar headgroup structure on the properties of ordered lipid domains (lipid rafts). Biochim. Biophys. Acta 1768, 2205–2212 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Bell, R. M., Ballas, L. M. & Coleman, R. A. Lipid topogenesis. J. Lipid Res. 22, 391–403 (1981).

    CAS  PubMed  Google Scholar 

  17. 17

    Sprong, H. et al. UDP-galactose:ceramide galactosyltransferase is a class I integral membrane protein of the endoplasmic reticulum. J. Biol. Chem. 273, 25880–25888 (1998).

    CAS  PubMed  Google Scholar 

  18. 18

    Rusinol, A. E., Cui, Z., Chen, M. H. & Vance, J. E. A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins. J. Biol. Chem. 269, 27494–27502 (1994). Provides evidence for stable physical associations between the ER and mitochondria, and also identifies biochemical properties of this compartment that are distinct from the individual organelles.

    CAS  PubMed  Google Scholar 

  19. 19

    Pichler, H. et al. A subfraction of the yeast endoplasmic reticulum associates with the plasma membrane and has a high capacity to synthesize lipids. Eur. J. Biochem. 268, 2351–2361 (2001).

    CAS  PubMed  Google Scholar 

  20. 20

    Futerman, A. H. & Riezman, H. The ins and outs of sphingolipid synthesis. Trends Cell Biol. 15, 312–318 (2005).

    CAS  PubMed  Google Scholar 

  21. 21

    Henneberry, A. L., Wright, M. M. & McMaster, C. R. The major sites of cellular phospholipid synthesis and molecular determinants of fatty acid and lipid head group specificity. Mol. Biol. Cell 13, 3148–3161 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Voelker, D. R. Bridging gaps in phospholipid transport. Trends Biochem. Sci. 30, 396–404 (2005). Summarizes biochemical and genetic elements of non-vesicular phospholipid transport with highlighted emphasis on PtdSer transport processes in yeast.

    CAS  PubMed  Google Scholar 

  23. 23

    Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006).

    CAS  PubMed  Google Scholar 

  24. 24

    Geta Tafesse, F. et al. Both sphingomyelin synthases SMS1 and SMS2 are required for sphingomyelin homeostasis and growth in human HeLa cells. J. Biol. Chem. 282, 17537–17547 (2007).

    Google Scholar 

  25. 25

    Li, Z. et al. Inhibition of sphingomyelin synthase (SMS) affects intracellular sphingomyelin accumulation and plasma membrane lipid organization. Biochim. Biophys. Acta 1771, 1186–1194 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Kobayashi, T. et al. Separation and characterization of late endosomal membrane domains. J. Biol. Chem. 277, 32157–32164 (2002).

    CAS  PubMed  Google Scholar 

  27. 27

    Matsuo, H. et al. Role of LBPA and Alix in multivesicular liposome formation and endosome organization. Science 303, 531–534 (2004).

    CAS  PubMed  Google Scholar 

  28. 28

    Kolter, T. & Sandhoff, K. Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu. Rev. Cell Dev. Biol. 21, 81–103 (2005).

    CAS  PubMed  Google Scholar 

  29. 29

    Vance, D. E. & Vance, J. E. Biochemistry of Lipids, Lipoproteins and Membranes (Elsevier, Amsterdam, 2002).

    Google Scholar 

  30. 30

    Nagle, C. A. et al. Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance. J. Biol. Chem. 282, 14807–14815 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Choi, J. Y., Wu, W. I. & Voelker, D. R. Phosphatidylserine decarboxylases as genetic and biochemical tools for studying phospholipid traffic. Anal. Biochem. 347, 165–175 (2005).

    CAS  PubMed  Google Scholar 

  32. 32

    Daum, G. Lipids of mitochondria. Biochim. Biophys. Acta 822, 1–42 (1985).

    CAS  PubMed  Google Scholar 

  33. 33

    Strauss, J. F., Kishida, T., Christenson, L. K., Fujimoto, T. & Hiroi, H. START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells. Mol. Cell. Endocrinol. 202, 59–65 (2003).

    CAS  PubMed  Google Scholar 

  34. 34

    Devaux, P. F. & Morris, R. Transmembrane asymmetry and lateral domains in biological membranes. Traffic 5, 241–246 (2004).

    CAS  PubMed  Google Scholar 

  35. 35

    Daleke, D. L. Phospholipid flippases. J. Biol. Chem. 282, 821–825 (2007).

    CAS  PubMed  Google Scholar 

  36. 36

    Pomorski, T. & Menon, A. K. Lipid flippases and their biological functions. Cell. Mol. Life Sci. 63, 2908–2921 (2006).

    CAS  PubMed  Google Scholar 

  37. 37

    Anglin, T. C., Liu, J. & Conboy, J. C. Facile lipid flip-flop in a phospholipid bilayer induced by gramicidin A measured by sum-frequency vibrational spectroscopy. Biophys. J. 92, L01–L03 (2007).

    CAS  PubMed  Google Scholar 

  38. 38

    Papadopulos, A. et al. Flippase activity detected with unlabeled lipids by shape changes of giant unilamellar vesicles. J. Biol. Chem. 282, 15559–15568 (2007).

    CAS  PubMed  Google Scholar 

  39. 39

    López-Montero, I. et al. Rapid transbilayer movement of ceramides in phospholipid vesicles and in human erythrocytes. J. Biol. Chem. 280, 25811–25819 (2005).

    PubMed  Google Scholar 

  40. 40

    Ganong, B. R. & Bell, R. M. Transmembrane movement of phosphatidylglycerol and diacylglycerol sulfhydryl analogues. Biochemistry 23, 4977–4983 (1984).

    CAS  PubMed  Google Scholar 

  41. 41

    Bai, J. & Pagano, R. E. Measurement of spontaneous transfer and transbilayer movement of BODIPY-labeled lipids in lipid vesicles. Biochemistry 36, 8840–8848 (1997).

    CAS  PubMed  Google Scholar 

  42. 42

    Steck, T. L., Ye, J. & Lange, Y. Probing red cell membrane cholesterol movement with cyclodextrin. Biophys. J. 83, 2118–2125 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Cullis, P. R. et al. Influence of pH gradients on the transbilayer transport of drugs, lipids, peptides and metal ions into large unilamellar vesicles. Biochim. Biophys. Acta 1331, 187–211 (1997).

    CAS  PubMed  Google Scholar 

  44. 44

    Kol, M. A., de Kroon, A. I., Killian, J. A. & de Kruijff, B. Transbilayer movement of phospholipids in biogenic membranes. Biochemistry 43, 2673–2681 (2004). Summarizes the data and hypotheses that support a generic system for the non-selective transbilayer movement of lipids in the ER of eukaryotes and in the cytoplasmic membranes of bacteria.

    CAS  PubMed  Google Scholar 

  45. 45

    Helenius, J. et al. Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein. Nature 415, 447–450 (2002).

    CAS  PubMed  Google Scholar 

  46. 46

    Alaimo, C. et al. Two distinct but interchangeable mechanisms for flipping of lipid-linked oligosaccharides. EMBO J. 25, 967–976 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Graham, T. R. Flippases and vesicle-mediated protein transport. Trends Cell Biol. 14, 670–677 (2004). Summarizes important relationships between vesicular protein traffic and transbilayer phospholipid transport by P-type ATPases.

    CAS  PubMed  Google Scholar 

  48. 48

    Pomorski, T. et al. Drs2p-related P-type ATPases Dnf1p and Dnf2p are required for phospholipid translocation across the yeast plasma membrane and serve a role in endocytosis. Mol. Biol. Cell 14, 1240–1254 (2003). An important paper defining the participation of plasma membrane P-type ATPases in yeast in the transbilayer movement of aminoglycerophospholipids and their interplay with endocytic processes.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Riekhof, W. R. & Voelker, D. R. Uptake and utilization of lyso-phosphatidylethanolamine by Saccharomyces cerevisiae. J. Biol. Chem. 281, 36588–36596 (2006).

    CAS  PubMed  Google Scholar 

  50. 50

    Riekhof, W. R. et al. Lyso-phosphatidylcholine metabolism in Saccharomyces cerevisiae. The role of P-type ATPases in transport and a broad specificity acyltransferase in acylation. J. Biol. Chem. 21 Oct 2007 (doi:10.1074/jbc.M706718200)

    CAS  PubMed  Google Scholar 

  51. 51

    Natarajan, P., Wang, J., Hua, Z. & Graham, T. R. Drs2p-coupled aminophospholipid translocase activity in yeast Golgi membranes and relationship to in vivo function. Proc. Natl. Acad. Sci. USA 101, 10614–10619 (2004).

    CAS  PubMed  Google Scholar 

  52. 52

    Alder-Baerens, N., Lisman, Q., Luong, L., Pomorski, T. & Holthuis, J. C. Loss of P4 ATPases Drs2p and Dnf3p disrupts aminophospholipid transport and asymmetry in yeast post-Golgi secretory vesicles. Mol. Biol. Cell 17, 1632–1642 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Wang, X. et al. C. elegans mitochondrial factor WAH-1 promotes phosphatidylserine externalization in apoptotic cells through phospholipid scramblase SCRM-1. Nature Cell Biol. 9, 541–549 (2007).

    CAS  PubMed  Google Scholar 

  54. 54

    Züllig, S. et al. Aminophospholipid translocase TAT-1 promotes phosphatidylserine exposure during C. elegans apoptosis. Curr. Biol. 17, 994–999 (2007).

    PubMed  Google Scholar 

  55. 55

    van Meer, G. & Simons, K. The function of tight junctions in maintaining differences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells. EMBO J. 5, 1455–1464 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Young, W. W. Jr, Lutz, M. S. & Blackburn, W. A. Endogenous glycosphingolipids move to the cell surface at a rate consistent with bulk flow estimates. J. Biol. Chem. 267, 12011–12015 (1992).

    CAS  PubMed  Google Scholar 

  57. 57

    Baumann, N. A. et al. Transport of newly synthesized sterol to the sterol-enriched plasma membrane occurs via nonvesicular equilibration. Biochemistry 44, 5816–5826 (2005).

    CAS  PubMed  Google Scholar 

  58. 58

    Simons, K. & van Meer, G. Lipid sorting in epithelial cells. Biochemistry 27, 6197–6202 (1988).

    CAS  PubMed  Google Scholar 

  59. 59

    Halter, D. et al. Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis J. Cell Biol. 179, 101–115 (2007). Suggests that the late Golgi protein FAPP2 transports GlcCer that is destined for complex glycolipid synthesis back to the ER, whereas GlcCer translocation to the cell surface depends on a proton gradient.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Smith, D. C. et al. The association of Shiga-like toxin with detergent-resistant membranes is modulated by glucosylceramide and is an essential requirement in the endoplasmic reticulum for a cytotoxic effect. Mol. Biol. Cell 17, 1375–1387 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Sharma, D. K. et al. Glycosphingolipids internalized via caveolar-related endocytosis rapidly merge with the clathrin pathway in early endosomes and form microdomains for recycling. J. Biol. Chem. 278, 7564–7572 (2003). Demonstrates the non-uniform distribution of fluorescent phospholipids within individual endosomes.

    CAS  PubMed  Google Scholar 

  62. 62

    Wang, T. Y. & Silvius, J. R. Different sphingolipids show differential partitioning into sphingolipid/cholesterol-rich domains in lipid bilayers. Biophys. J. 79, 1478–1489 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Singh, R. D. et al. Inhibition of caveolar uptake, SV40 infection, and β1-integrin signaling by a nonnatural glycosphingolipid stereoisomer. J. Cell Biol. 176, 895–901 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Sleight, R. G. & Pagano, R. E. Rapid appearance of newly synthesized phosphatidylethanolamine at the plasma membrane. J. Biol. Chem. 258, 9050–9058 (1983).

    CAS  PubMed  Google Scholar 

  65. 65

    Kaplan, M. R. & Simoni, R. D. Intracellular transport of phosphatidylcholine to the plasma membrane. J. Cell Biol. 101, 441–445 (1985).

    CAS  PubMed  Google Scholar 

  66. 66

    Voelker, D. R. Characterization of phosphatidylserine synthesis and translocation in permeabilized animal cells. J. Biol. Chem. 265, 14340–14346 (1990).

    CAS  PubMed  Google Scholar 

  67. 67

    Vance, J. E., Aasman, E. J. & Szarka, R. Brefeldin A does not inhibit the movement of phosphatidylethanolamine from its sites of synthesis to the cell surface. J. Biol. Chem. 266, 8241–8247 (1991).

    CAS  PubMed  Google Scholar 

  68. 68

    Wu, W. I. & Voelker, D. R. Characterization of phosphatidylserine transport to the locus of phosphatidylserine decarboxylase 2 in permeabilized yeast. J. Biol. Chem. 276, 7114–7121 (2001).

    CAS  PubMed  Google Scholar 

  69. 69

    Schumacher, M. M., Choi, J. Y. & Voelker, D. R. Phosphatidylserine transport to the mitochondria is regulated by ubiquitination. J. Biol. Chem. 277, 51033–51042 (2002).

    CAS  PubMed  Google Scholar 

  70. 70

    Papadopoulos, V. et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol. Sci. 27, 402–409 (2006). Summarizes the major protein constituents involved in non-vesicular import of cholesterol into the mitochondria of cells involved in steroid hormone synthesis.

    CAS  PubMed  Google Scholar 

  71. 71

    Hanada, K. et al. Molecular machinery for non-vesicular trafficking of ceramide. Nature 426, 803–809 (2003). An important paper defining the genetic and biochemical mechanisms for non-vesicular transport of ceramide between the ER and the Golgi apparatus.

    CAS  Google Scholar 

  72. 72

    Warnock, D. E., Lutz, M. S., Blackburn, W. A., Young, W. W. Jr & Baenziger, J. U. Transport of newly synthesized glucosylceramide to the plasma membrane by a non-Golgi pathway. Proc. Natl. Acad. Sci. USA 91, 2708–2712 (1994).

    CAS  PubMed  Google Scholar 

  73. 73

    Trotter, P. J., Wu, W. I., Pedretti, J., Yates, R. & Voelker, D. R. A genetic screen for aminophospholipid transport mutants identifies the phosphatidylinositol 4-kinase, STT4p, as an essential component in phosphatidylserine metabolism. J. Biol. Chem. 273, 13189–13196 (1998).

    CAS  PubMed  Google Scholar 

  74. 74

    Wu, W. I. & Voelker, D. R. Reconstitution of phosphatidylserine transport from chemically defined donor membranes to phosphatidylserine decarboxylase 2 implicates specific lipid domains in the process. J. Biol. Chem. 279, 6635–6642 (2004).

    CAS  PubMed  Google Scholar 

  75. 75

    Raychaudhuri, S., Im, Y. J., Hurley, J. H. & Prinz, W. A. Nonvesicular sterol movement from plasma membrane to ER requires oxysterol-binding protein-related proteins and phosphoinositides. J. Cell Biol. 173, 107–119 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    D'Angelo, G. et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449, 62–67 (2007). Shows that FAPP2, a protein that is associated with the generation of transport carriers from the Golgi to the plasma membrane, appears to be a GlcCer transfer protein with a pivotal role in complex GSL synthesis.

    CAS  Google Scholar 

  77. 77

    Awai, K., Xu, C., Tamot, B. & Benning, C. A phosphatidic acid-binding protein of the chloroplast inner envelope membrane involved in lipid trafficking. Proc. Natl Acad. Sci. USA 103, 10817–10822 (2006). Defines transport and intermembrane recognition components for moving phospholipids between the outer and inner chloroplast membranes.

    CAS  PubMed  Google Scholar 

  78. 78

    Tefsen, B., Geurtsen, J., Beckers, F., Tommassen, J. & de Cock, H. Lipopolysaccharide transport to the bacterial outer membrane in spheroplasts. J. Biol. Chem. 280, 4504–4509 (2005).

    CAS  PubMed  Google Scholar 

  79. 79

    Mousley, C. J., Tyeryar, K. R., Vincent-Pope, P. & Bankaitis, V. A. The Sec14-superfamily and the regulatory interface between phospholipid metabolism and membrane trafficking. Biochim. Biophys. Acta 1771, 727–736 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Litvak, V., Dahan, N., Ramachandran, S., Sabanay, H. & Lev, S. Maintenance of the diacylglycerol level in the Golgi apparatus by the Nir2 protein is critical for Golgi secretory function. Nature Cell Biol. 7, 225–234 (2005).

    CAS  PubMed  Google Scholar 

  81. 81

    Chernomordik, L., Kozlov, M. M. & Zimmerberg, J. Lipids in biological membrane fusion. J. Membr. Biol. 146, 1–14 (1995).

    CAS  PubMed  Google Scholar 

  82. 82

    Shemesh, T., Luini, A., Malhotra, V., Burger, K. N. & Kozlov, M. M. Prefission constriction of Golgi tubular carriers driven by local lipid metabolism: a theoretical model. Biophys. J. 85, 3813–3827 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Gennis, R. B. Biomembranes. Molecular Structure and Function (Springer Verlag, New York, 1989).

    Google Scholar 

  84. 84

    Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831–846 (2006). A careful reconstruction of synaptic vesicles shows that cholesterol and phospholipids (molar ratio 0.8) cover 70% of the surface while transmembrane helices cover 20%, with a lipid/protein ratio of 0.75 (w/w).

    CAS  Google Scholar 

  85. 85

    Dietrich, C., Volovyk, Z. N., Levi, M., Thompson, N. L. & Jacobson, K. Partitioning of Thy-1, GM1, and cross-linked phospholipid analogs into lipid rafts reconstituted in supported model membrane monolayers. Proc. Natl Acad. Sci. USA 98, 10642–10647 (2001).

    CAS  PubMed  Google Scholar 

  86. 86

    Morse, S. A. Basalts and Phase Diagrams (Springer-Verlag, New York, 1980).

    Google Scholar 

  87. 87

    Parton, R. G. Ultrastructural localization of gangliosides: GM1 is concentrated in caveolae. J. Histochem. Cytochem. 42, 155–166 (1994).

    CAS  PubMed  Google Scholar 

  88. 88

    Kusumi, A. et al. Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. Annu. Rev. Biophys. Biomol. Struct. 34, 351–378 (2005). Biological membrane lipids and proteins are divided into regions, some tens of nanometres in size, which have distinct molecular components and properties.

    CAS  PubMed  Google Scholar 

  89. 89

    Lagerholm, B. C., Weinreb, G. E., Jacobson, K. & Thompson, N. L. Detecting microdomains in intact cell membranes. Annu. Rev. Phys. Chem. 56, 309–336 (2005).

    CAS  PubMed  Google Scholar 

  90. 90

    Feigenson, G. W. & Buboltz, J. T. Ternary phase diagram of dipalmitoyl-PC/dilauroyl-PC/cholesterol: nanoscopic domain formation driven by cholesterol. Biophys. J. 80, 2775–2788 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Meder, D., Moreno, M. J., Verkade, P., Vaz, W. L. & Simons, K. Phase coexistence and connectivity in the apical membrane of polarized epithelial cells. Proc. Natl Acad. Sci. USA 103, 329–334 (2006).

    CAS  PubMed  Google Scholar 

  92. 92

    Kusumi, A., Koyama-Honda, I. & Suzuki, K. Molecular dynamics and interactions for creation of stimulation-induced stabilized rafts from small unstable steady-state rafts. Traffic 5, 213–230 (2004).

    CAS  PubMed  Google Scholar 

  93. 93

    Bollinger, C. R., Teichgraber, V. & Gulbins, E. Ceramide-enriched membrane domains. Biochim. Biophys. Acta 1746, 284–294 (2005).

    CAS  PubMed  Google Scholar 

  94. 94

    Roux, A. et al. Role of curvature and phase transition in lipid sorting and fission of membrane tubules. EMBO J. 24, 1537–1545 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Chiantia, S., Kahya, N., Ries, J. & Schwille, P. Effects of ceramide on liquid-ordered domains investigated by simultaneous AFM and FCS. Biophys. J. 90, 4500–4508 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Sot, J., Bagatolli, L. A., Goni, F. M. & Alonso, A. Detergent-resistant, ceramide-enriched domains in sphingomyelin/ceramide bilayers. Biophys. J. 90, 903–914 (2006).

    CAS  PubMed  Google Scholar 

  97. 97

    Anishkin, A., Sukharev, S. & Colombini, M. Searching for the molecular arrangement of transmembrane ceramide channels. Biophys. J. 90, 2414–2426 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Dietrich, C., Yang, B., Fujiwara, T., Kusumi, A. & Jacobson, K. Relationship of lipid rafts to transient confinement zones detected by single particle tracking. Biophys. J. 82, 274–284 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Sengupta, P., Baird, B. & Holowka, D. Lipid rafts, fluid/fluid phase separation, and their relevance to plasma membrane structure and function. Semin. Cell Dev. Biol. 18, 583–590 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Dibble, A. R. & Feigenson, G. W. Detection of coexisting fluid phospholipid phases by equilibrium Ca2+ binding: peptide-poor Lα and peptide-rich HII phase coexistence in gramicidin A′/phospholipid dispersions. Biochemistry 33, 12945–12953 (1994).

    CAS  PubMed  Google Scholar 

  101. 101

    Lewis, R. N. et al. Studies of the minimum hydrophobicity of α-helical peptides required to maintain a stable transmembrane association with phospholipid bilayer membranes. Biochemistry 46, 1042–1054 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Jacobson, K., Mouritsen, O. G. & Anderson, R. G. Lipid rafts: at a crossroad between cell biology and physics. Nature Cell Biol. 9, 7–14 (2007). Proposes a model whereby transmembrane helices cover 15% of the surface and physically contact 30% of the membrane lipids, termed shell lipids. On receiving a signal, proteins control phase behaviour by combining their shell with similar lipid shells of other proteins.

    CAS  PubMed  Google Scholar 

  103. 103

    Shogomori, H. et al. Palmitoylation and intracellular domain interactions both contribute to raft targeting of linker for activation of T cells. J. Biol. Chem. 280, 18931–18942 (2005).

    CAS  PubMed  Google Scholar 

  104. 104

    Brown, D. A. Lipid rafts, detergent-resistant membranes, and raft targeting signals. Physiology 21, 430–439 (2006). The use of detergent resistance to study the properties of biological membranes gives indirect information about protein and lipid phase preferences, but does not capture a snapshot of actual phase behaviour.

    CAS  PubMed  Google Scholar 

  105. 105

    Epand, R. M. Cholesterol and the interaction of proteins with membrane domains. Prog. Lipid Res. 45, 279–294 (2006).

    CAS  PubMed  Google Scholar 

  106. 106

    Hancock, J. F. Lipid rafts: contentious only from simplistic standpoints. Nature Rev. Mol. Cell Biol. 7, 456–462 (2006). A critical discussion of lipid rafts, stressing that protein–protein interactions make major contributions to the stability of lipid-based domains, and that proteins and specific lipids such as cholesterol may accumulate at and affect domain boundaries.

    CAS  Google Scholar 

  107. 107

    London, E. & Feigenson, G. W. Fluorescence quenching in model membranes. 2. Determination of local lipid environment of the calcium adenosinetriphosphatase from sarcoplasmic reticulum. Biochemistry 20, 1939–1948 (1981).

    CAS  PubMed  Google Scholar 

  108. 108

    Caffrey, M. & Feigenson, G. W. Fluorescence quenching in model membranes. 3. Relationship between calcium adenosinetriphosphatase enzyme activity and the affinity of the protein for phosphatidylcholines with different acyl chain characteristics. Biochemistry 20, 1949–1961 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Esmann, M. & Marsh, D. Lipid–protein interactions with the Na, K-ATPase. Chem. Phys. Lipids 141, 94–104 (2006).

    CAS  PubMed  Google Scholar 

  110. 110

    Soubias, O., Teague, W. E. & Gawrisch, K. Evidence for specificity in lipid–rhodopsin interactions. J. Biol. Chem. 281, 33233–33241 (2006).

    CAS  PubMed  Google Scholar 

  111. 111

    Andersen, O. S. & Koeppe, R. E. 2nd. Bilayer thickness and membrane protein function: an energetic perspective. Annu. Rev. Biophys. Biomol. Struct. 36, 107–130 (2007).

    CAS  PubMed  Google Scholar 

  112. 112

    Sharma, P. et al. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 116, 577–589 (2004).

    CAS  PubMed  Google Scholar 

  113. 113

    Recktenwald, D. J. & McConnell, H. M. Phase equilibria in binary mixtures of phosphatidylcholine and cholesterol. Biochemistry 20, 4505–4510 (1981).

    CAS  PubMed  Google Scholar 

  114. 114

    Wang, T. Y. & Silvius, J. R. Cholesterol does not induce segregation of liquid-ordered domains in bilayers modeling the inner leaflet of the plasma membrane. Biophys. J. 81, 2762–2773 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Kiessling, V., Crane, J. M. & Tamm, L. K. Transbilayer effects of raft-like lipid domains in asymmetric planar bilayers measured by single molecule tracking. Biophys. J. 91, 3313–3326 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    van Meer, G., Halter, D., Sprong, H., Somerharju, P. & Egmond, M. R. ABC lipid transporters: extruders, flippases, or flopless activators? FEBS Lett. 580, 1171–1177 (2006).

    CAS  PubMed  Google Scholar 

  117. 117

    Veatch, S. L. & Keller, S. L. Separation of liquid phases in giant vesicles of ternary mixtures of phospholipids and cholesterol. Biophys. J. 85, 3074–3083 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Veatch, S. L., Polozov, I. V., Gawrisch, K. & Keller, S. L. Liquid domains in vesicles investigated by NMR and fluorescence microscopy. Biophys. J. 86, 2910–2922 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Wassall, S. R. et al. Order from disorder, corralling cholesterol with chaotic lipids. The role of polyunsaturated lipids in membrane raft formation. Chem. Phys. Lipids 132, 79–88 (2004).

    CAS  PubMed  Google Scholar 

  120. 120

    Veatch, S. L., Gawrisch, K. & Keller, S. L. Closed-loop miscibility gap and quantitative tie-lines in ternary membranes containing diphytanoyl PC. Biophys. J. 90, 4428–4436 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Bakht, O., Pathak, P. & London, E. Effect of the structure of lipids favoring disordered domain formation on the stability of cholesterol-containing ordered domains (lipid rafts): identification of multiple raft-stabilization mechanisms. Biophys. J. 93, 4307–4318 (2007). Polyunsaturated acyl chains of membrane lipids can effectively drive the formation of membrane rafts because of especially poor packing with cholesterol.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Kucerka, N., Tristram-Nagle, S. & Nagle, J. F. Closer look at structure of fully hydrated fluid phase DPPC bilayers. Biophys. J. 90, L83–L85 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Liu, K., Hua, Z., Nepute, J. A. & Graham, T. R. Yeast P4-ATPases Drs2p and Dnf1p are essential cargos of the NPFXD/Sla1p endocytic pathway. Mol. Biol. Cell 18, 487–500 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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Glossary

Triacylglycerol

A family of storage lipids consisting of glycerol esterified to three fatty acids, forming the hydrophobic core of lipid droplets and blood lipoproteins together with steryl esters.

Steryl ester

A family of storage lipids consisting of sterol esterified to one fatty acid, forming the hydrophobic core of lipid droplets and blood lipoproteins together with triacylglycerol molecules.

Amphipathic

The characteristic of being polar on one side of the molecule and apolar on the opposite side.

Lysosomal hydrolase

An enzyme that hydrolyses biomolecules in lysosomes.

Dolichol

A family of long-chain, unsaturated and methylated hydrocarbons that consist of varying numbers of isoprene units that terminate in an α-saturated isoprenoid group and contain an alcohol functional group. Dolicholphosphate and dolicholpyrophosphate anchor sugar molecules to the ER membrane for transfer to proteins in the ER lumen.

Multivesicular body

An endosome containing internal vesicles that originate from inward budding. This direction of budding is away from the cytosol (opposite to the regular budding of transport vesicles) and a different molecular machinery has been found to be responsible.

P-type ATPase

One of a family of membrane-embedded transporters that share a phosphorylated intermediate as part of their reaction cycle. It includes the Ca2+- and Na+/K+-ATPases and the P4 family of lipid flippases.

Scramblase

A mechanism (involving incompletely characterized components) that allows transmembrane movement of lipids and relaxation of lipid asymmetry on cell stimulation.

Caveolin

The coat protein of caveolae. It is anchored by a hydrophobic loop and 1–3 palmitoylated cysteines. Caveolin interacts with cholesterol and oligomerizes.

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van Meer, G., Voelker, D. & Feigenson, G. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9, 112–124 (2008). https://doi.org/10.1038/nrm2330

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