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How proteins move lipids and lipids move proteins

Nature Reviews Molecular Cell Biology volume 2, pages 504513 (2001) | Download Citation

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Abstract

Cells determine the bilayer characteristics of different membranes by tightly controlling their lipid composition. Local changes in the physical properties of bilayers, in turn, allow membrane deformation, and facilitate vesicle budding and fusion. Moreover, specific lipids at specific locations recruit cytosolic proteins involved in structural functions or signal transduction. We describe here how the distribution of lipids is directed by proteins, and, conversely, how lipids influence the distribution and function of proteins.

Key points

  • Cellular membranes have distinct compositions that reflect their unique functions. Membrane proteins, synthesized in the cytosol or at the endoplasmic reticulum (ER) membrane, are targeted to the different membranes by structural motifs.

  • Local lipid synthesis and hydrolysis cannot explain the differences in lipid composition between the various membranes and between the two leaflets of the bilayer. The intracellular transport of lipids is selective.

  • Lipids are transported as monomers across membranes. Various families of transporters have been identified that might provide the necessary directionality and lipid specificity.

  • The main transport mechanism for lipids and proteins between organelles is vesicular. Selectivity in these pathways is generated by the lateral segregation of anterograde from retrograde (or resident) components. Lipid sorting is based on a spontaneous phase separation into less fluid sphingolipid–cholesterol domains, that move towards the plasma membrane, and more fluid glycerophospholipid domains, that are preferentially included in transport vesicles towards the ER.

  • Special properties of the lipid domains are recognized by various classes of membrane protein. Some of these are cargo being sorted, others provide directionality to the resulting transport vesicles.

  • Topologically and temporally restricted metabolism of lipids modifies their molecular shape. This seems to be an integral part of vesicle fission and, potentially, fusion.

  • The local production of signalling lipids determines membrane flux by coat recruitment and the activation of fusion. The activity of the responsible enzymes — kinases, phosphatases and phospholipases — is subject to regulation and forms an integral part of the cellular signalling system.

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References

  1. 1.

    , I. & Specific proteins are required to translocate phosphatidylcholine bidirectionally across the endoplasmic reticulum. Curr. Biol. 10, 241–252 (2000).

  2. 2.

    & Sidedness of phospholipid synthesis on brain membranes. J. Neurochem. 39, 155–164 (1982).

  3. 3.

    & Asymmetric distribution of phosphatidylethanolamine in the endoplasmic reticulum demonstrated using trinitrobenzenesulphonic acid as a probe. Biochim. Biophys. Acta 693, 151–158 (1982).

  4. 4.

    & Intracellular functions of N-linked glycans. Science 291, 2364–2369 (2001).

  5. 5.

    et al. PIG-M transfers the first mannose to glycosylphosphatidylinositol on the lumenal side of the ER. EMBO J. 20, 250–261 (2001).This paper pinpoints the substrate for this lumenal mannosyltransferase, glucoseaminyl (GlcN) α1-6-phosphoinositol, which is synthesized on the cytosolic side, as the actual lipid that translocates across the endoplasmic reticulum membrane during GPI-anchor synthesis.

  6. 6.

    , , & Lactosylceramide is synthesized in the lumen of the Golgi apparatus. FEBS Lett. 342, 91–96 (1994).

  7. 7.

    , & van Topology of sphingolipid galactosyltransferases in ER and Golgi: transbilayer movement of monohexosyl sphingolipids is required for higher glycosphingolipid biosynthesis. J. Cell Biol. 133, 15–28 (1996).

  8. 8.

    et al. Identification of the major intestinal fatty acid transport protein. Mol. Cell 4, 299–308 (1999).

  9. 9.

    et al. Molecular cloning of human plasma membrane phospholipid scramblase. A protein mediating transbilayer movement of plasma membrane phospholipids. J. Biol. Chem. 272, 18240–18244 (1997).

  10. 10.

    & ATP-dependent asymmetric distribution of spin-labeled phospholipids in the erythrocyte membrane: relation to shape changes. Proc. Natl Acad. Sci. USA 81, 3751–3755 (1984).

  11. 11.

    , , & Enhancement of endocytosis due to aminophospholipid transport across the plasma membrane of living cells. Am. J. Physiol. 276, C725–C733 (1999).

  12. 12.

    , , & A subfamily of P-type ATPases with aminophospholipid transporting activity. Science 272, 1495–1497 (1996).

  13. 13.

    & Identification and purification of aminophospholipid flippases. Biochim. Biophys. Acta 1486, 108–127 (2000).

  14. 14.

    J. M. et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75, 451–462 (1993).

  15. 15.

    , & Evidence for the presence of a phosphatidylcholine translocator in isolated rat liver canalicular plasma membrane vesicles. J. Biol. Chem. 268, 3976–3979 (1993).

  16. 16.

    et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 87, 507–517 (1996).

  17. 17.

    & Secretion of platelet-activating factor is mediated by MDR1 P-glycoprotein in cultured human mesangial cells. J. Am. Soc. Nephrol. 10, 2306–2313 (1999).

  18. 18.

    , & van MDR1 P-glycoprotein (ABCB1) secretes platelet activating factor (PAF). Biochem. J. (in the press).

  19. 19.

    , & Transbilayer movement of cholesterol in the human erythrocyte membrane. J. Lipid Res. 29, 481–489 (1988).

  20. 20.

    et al. ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nature Cell Biol. 2, 399–406 (2000).

  21. 21.

    et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290, 1771–1775 (2000).

  22. 22.

    , & Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. J. Biol. Chem. 274, 8269–8281 (1999).

  23. 23.

    et al. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell 98, 13–23 (1999).

  24. 24.

    , & Transmembrane molecular pump activity of Niemann-Pick C1 protein. Science 290, 2295–2298 (2000).

  25. 25.

    et al. Type C Niemann-Pick disease: a murine model of the lysosomal cholesterol lipidosis accumulates sphingosine and sphinganine in liver. Biochim. Biophys. Acta 1127, 303–311 (1992).

  26. 26.

    et al. Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290, 2298–2301 (2000).

  27. 27.

    & Import of lipids into mitochondria. Prog. Lipid Res. 36, 103–130 (1997).

  28. 28.

    , , , & Golgi structure in three dimensions: functional insights from the normal rat kidney cell. J. Cell Biol. 144, 1135–1149 (1999).

  29. 29.

    et al. Essential role for diacylglycerol in protein transport from the yeast Golgi complex. Nature 387, 101–105 (1997).

  30. 30.

    , , , & Rapid replenishment of sphingomyelin in the plasma membrane upon degradation by sphingomyelinase in NIH3T3 cells overexpressing the phosphatidylinositol transfer protein-β. Biochem. J. 346, 537–543 (2000).

  31. 31.

    et al. Mice without phosphatidylcholine transfer protein have no defects in the secretion of phosphatidylcholine into bile or into lung airspaces. Proc. Natl Acad. Sci. USA 96, 11501–11506 (1999).

  32. 32.

    et al. The STAR homolog MLN64: a late endosomal cholesterol binding protein. J. Biol. Chem. 276, 4261–4269 (2001).

  33. 33.

    , , , & Subcellular localization of Forssman glycolipid in epithelial MDCK cells by immuno-electronmicroscopy after freeze-substitution. J. Cell Biol. 115, 1009–1019 (1991).

  34. 34.

    & Kinetics of phosphatidylcholine and lysophosphatidylcholine exchange between unilamellar vesicles. Biochemistry 23, 4624–4630 (1984).

  35. 35.

    & Sterol partitioning among intracellular membranes. Testing a model for cellular sterol distribution. J. Biol. Chem. 258, 2284–2289 (1983).

  36. 36.

    & Enzyme and phospholipid asymmetry in liver microsomal membranes. J. Cell Biol. 72, 568–583 (1977).

  37. 37.

    Lipid traffic in animal cells. Annu. Rev. Cell Biol. 5, 247–275 (1989).

  38. 38.

    et al. Evidence for segregation of sphingomyelin and cholesterol during formation of COPI-coated vesicles. J. Cell Biol. 151, 507–518 (2000).

  39. 39.

    , & Condensed complexes, rafts, and the chemical activity of cholesterol in membranes. Proc. Natl Acad. Sci. USA 97, 12422–12427 (2000).This paper, and several other papers from the same group in 1999/2000, bridge a gap between physical chemistry and cell biology by showing liquid–liquid phase separations in lipid mixtures of biological relevance. McConnell first demonstrated such phase separations 20 years ago.

  40. 40.

    & Phospholipid class and fatty acid composition of Golgi apparatus isolated from rat liver and comparison with other cell fractions. Biochemistry 9, 19–25 (1970).

  41. 41.

    et al. Appendix: do basic peptides form large lateral domains with acidic lipids when they bind to phospholipid vesicles? Biophys. J. 77, 3185–3188 (1999).

  42. 42.

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

  43. 43.

    , & Endocytic sorting of lipid analogues differing solely in the chemistry of their hydrophobic tails. J. Cell Biol. 144, 1271–1284 (1999).

  44. 44.

    et al. The recycling endosome of Madin–Darby Canine Kidney cells is a mildly acidic compartment rich in raft components. Mol. Biol. Cell 11, 2775–2791 (2000).

  45. 45.

    et al. Cholesterol modulates membrane traffic along the endocytic pathway in sphingolipid-storage diseases. Nature Cell Biol. 1, 386–388 (1999).

  46. 46.

    & Jamming the endosomal system: lipid rafts and lysosomal storage diseases. Trends Cell Biol. 10, 459–462 (2000).

  47. 47.

    & Cholesterol and the Golgi apparatus. Science 261, 1280–1281 (1993).Great paper noticing the difference in the length of the transmembrane domains between proteins of the Golgi and of the plasma membrane.

  48. 48.

    , & Cytomembrane differentiation in the endoplasmic reticulum-Golgi apparatus-vesicle complex. Science 161, 171–173 (1968).

  49. 49.

    , & Lipid-dependent targeting of G proteins into rafts. J. Biol. Chem. 275, 2191–2198 (2000).

  50. 50.

    et al. Lipid rafts reconstituted in model membranes. Biophys. J. 80, 1417–1428 (2001).

  51. 51.

    Ultrastructural localization of gangliosides; GM1 is concentrated in caveolae. J. Histochem. Cytochem. 42, 155–166 (1994).This paper provides solid morphological evidence for the concentration of a glycolipid in caveolae.

  52. 52.

    , , & Lipid domain structure of the plasma membrane revealed by patching of membrane components. J. Cell Biol. 141, 929–942 (1998).

  53. 53.

    & Transmembrane domain-dependent sorting of proteins to the ER and plasma membrane in yeast. EMBO J. 16, 1832–1841 (1997).

  54. 54.

    et al. SNAREs are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis. EMBO J. 20, 2202–2213 (2001).

  55. 55.

    Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking. Annu. Rev. Cell Dev. Biol. 14, 231–264 (1998).

  56. 56.

    , & Phosphoinositide signaling and the regulation of membrane trafficking in yeast. Trends Biochem. Sci. 25, 229–235 (2000).

  57. 57.

    et al. Multivesicular body morphogenesis requires phosphatidyl-inositol 3-kinase activity. Curr. Biol. 9, 55–58 (1999).

  58. 58.

    , & Cellular functions of phosphatidylinositol 3-phosphate and FYVE domain proteins. Biochem. J. 355, 249–258 (2001).

  59. 59.

    & Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Cell Biol. 8, 442–446 (1998).

  60. 60.

    & Turning on ARF: the Sec7 family of guanine-nucleotide-exchange factors. Trends Cell Biol. 10, 60–67 (2000).

  61. 61.

    et al. FYVE fingers bind PtdIns(3)P. Nature 394, 432–433 (1998).

  62. 62.

    et al. EEA1 links PI(3)K function to rab5 regulation of endosome fusion. Nature 394, 494–498 (1998).References 61 and 62 describe for the first time the function of FYVE domains in mammalian cells and provide a link to the Rab5 GTPase switch in endosome dynamics.

  63. 63.

    et al. Phosphatidylinositol 4,5-bisphosphate regulates two steps of homotypic vacuole fusion. Mol. Biol. Cell 11, 807–817 (2000).

  64. 64.

    et al. Impaired membrane traffic in defective ether lipid biosynthesis. Hum. Mol. Genet. 10, 127–136 (2001).

  65. 65.

    et al. Reversible phosphorylation-dephosphorylation determines the localization of rab4 during the cell cycle. EMBO J. 11, 4379–4389 (1992).

  66. 66.

    Cell control by membrane-cytoskeleton adhesion. Nature Rev. Mol. Cell Biol. 2, 392–396 (2001).

  67. 67.

    et al. Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature 401, 133–141 (1999).This paper demonstrates that both the acyltransferase activity of the protein and its localization to the budding site through binding to dynamin are required for vesicle fission.

  68. 68.

    et al. CtBP/BARS induces fission of Golgi membranes by acylating lysophosphatidic acid. Nature 402, 429–433 (1999).Shows that acylation of lysophosphatidic acid is also essential for budding from the Golgi.

  69. 69.

    & Structure and functional properties of diacylglycerols in membranes. Prog. Lipid Res. 38, 1–48 (1999).

  70. 70.

    , , & Phospholipase D as an effector for ADP-ribosylation factor in the regulation of vesicular traffic. Chem. Phys. Lipids 98, 141–152 (1999).

  71. 71.

    , , & Membrane tubule-mediated reassembly and maintenance of the Golgi complex is disrupted by phospholipase A2 antagonists. Mol. Biol. Cell 10, 1763–1782 (1999).

  72. 72.

    Anterograde transport through the Golgi complex: do Golgi tubules hold the key? Trends Cell Biol. 5, 302–305 (1995).

  73. 73.

    & The debate about transport in the Golgi. Two sides of the same coin? Cell 102, 713–719 (2000).

  74. 74.

    et al. Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nature Cell Biol. 1, 113–118 (1999).

  75. 75.

    , & Vesicle fusion and formation at the surface of pinocytic vacuoles in macrophages. J. Cell Biol. 38, 629–632 (1968).Elegant morphogical study showing that internal vesicles budding from the limiting membrane of an endosome have a different membrane structure, indicative of a different membrane composition.

  76. 76.

    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).

  77. 77.

    et al. Sphingosine-1-phosphate as a ligand for the G protein coupled receptor EDG-1. Science 279, 1552–1555 (1998).

  78. 78.

    , & Lysophosphatidic acid receptors. Mol. Pharmacol. 58, 1188–1196 (2000).

  79. 79.

    , & Biochemical characterization of the Golgi complex of mammalian cells. J. Supramol. Struct. 2, 737–750 (1974).

  80. 80.

    , & Lipid components of two different regions of an intestinal epithelial cell membrane of mouse. Biochim. Biophys. Acta 369, 222–233 (1974).

  81. 81.

    & 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).

  82. 82.

    , & Caveolar endocytosis of simian virus 40 reveals a new two-step vesicular-transport pathway to the ER. Nature Cell Biol. 3, 473–483 (2001).

  83. 83.

    & (Glyco)sphingolipids are sorted in sub-apical compartments in HepG2 cells: a role for non-Golgi-related intracellular sites in the polarized distribution of (glyco)sphingolipids. J. Cell Biol. 142, 683–696 (1998).

  84. 84.

    , , & Different biosynthetic transport routes to the plasma membrane in BHK and CHO cells. J. Cell Biol. 133, 247–256 (1996).

  85. 85.

    , , , & Lipid translocation across the human erythrocyte membrane. Regulatory factors. J. Biol. Chem. 257, 6537–6543 (1982).

  86. 86.

    , & Mechanism and consequences of cellular cholesterol exchange and transfer. Biochim. Biophys. Acta 906, 223–276 (1987).

  87. 87.

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

  88. 88.

    & Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62, 385–427 (1993).

  89. 89.

    et al. Functionally different GPI proteins are organized in different domains on the neuronal surface. EMBO J. 18, 6917–6926 (1999).

  90. 90.

    , , , & Separation of caveolae from associated microdomains of GPI-anchored proteins. Science 269, 1435–1439 (1995).

  91. 91.

    & Interactions of N-stearoyl sphingomyelin with cholesterol and dipalmitoylphosphatidylcholine in bilayer membranes. Biophys. J. 70, 2256–2265 (1996).

  92. 92.

    & X-ray diffraction and calorimetric study of N-lignoceryl sphingomyelin membranes. Biophys. J. 69, 1909–1916 (1995).

  93. 93.

    & Combined influence of cholesterol and synthetic amphiphillic peptides upon bilayer thickness in model membranes. Biophys. J. 61, 1176–1183 (1992).

  94. 94.

    & Lipid polymorphism and the functional roles of lipids in biological membranes. Biochim. Biophys. Acta 559, 399–420 (1979).

  95. 95.

    & Membrane fusion. Adv. Drug Deliv. Rev. 38, 197–205 (1999).

  96. 96.

    , , & Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nature Cell Biol. 2, 42–49 (2000).

  97. 97.

    , & Influence of lipid composition on physical properties and PEG–mediated fusion of curved and uncurved model membrane vesicles: 'nature's own' fusogenic lipid bilayer. Biochemistry 40, 4340–4348 (2001).

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Acknowledgements

We apologize that out of 30,000 PubMed papers on lipid and transport, we quote only 97.

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Affiliations

  1. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam. g.vanmeer@amc.uva.nl

    • Hein Sprong
    •  & Gerrit van Meer
  2. Department of Cell Biology, University Medical Center, Institute of Biomembranes, 3584 CX Utrecht, The Netherlands.

    • Hein Sprong
    •  & Peter van der Sluijs

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Glossary

EXOCYTIC PATHWAY

Secretory or membrane proteins are inserted into the endoplasmic reticulum. They are then transported through the Golgi to the trans-Golgi network, where they are sorted to their final destination.

ENDOCYTIC PATHWAY

Macromolecules are endocytosed at the plasma membrane. They first arrive in early endosomes, then late endosomes, and finally lysosomes where they are degraded by hydrolases. Molecules can recycle to the plasma membrane from early endosomes, and there are also connections with the exocytic pathway.

LIPID CONCENTRATION

The density of a given lipid at a certain lateral position on one surface of a particular membrane, expressed here as mol% of total lipids. Mol% of phospholipids does not take into account the presence of glycosphingolipids and cholesterol.

VESICULAR TRANSPORT

Transport from one organelle to another, during which cargo-containing vesicles bud from the donor membrane and fuse with an acceptor membrane.

GPI

The general function of GPI anchors is to attach proteins to membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is linked to the protein through an ethanolamine phosphate moiety.

ABC TRANSPORTERS

Large protein family of transporters that contain an ATP-binding cassette. They hydrolyse ATP and transfer a diverse array of small molecules across membranes.

MULTIDRUG TRANSPORTER

Energy-dependent efflux pump that is responsible for decreased drug accumulation in multidrug-resistant cells. Multidrug resistance is an acquired simultaneous resistance to a wide spectrum of drugs arising from the administration of drugs typically over long periods.

HDL

The smallest type of lipoprotein found in blood plasma, which functions in reverse transport from tissues to the liver.

DISC

The phototransduction apparatus in the outer segment of rod cells contains a stack of discs, each formed by a closed membrane in which rhodopsin molecules are embedded.

DOMAIN

An area in a membrane with a concentration of proteins and/or lipids that is different from its immediate environment. The term 'domain' carries no information about its size relative to the total membrane area, whereas terms such as 'microdomain' or 'raft' suggest that that they cover far less than half of the surface.

COPI VESICLES

Coated vesicles involved in transport through the Golgi and probably in retrograde transport from the Golgi to the endoplasmic reticulum. The COPI coatomer is made of seven subunits (α-, β-, β'-, γ-, δ-, ɛ- and ζ-COP).

CAVEOLA

Flask-shaped, cholesterol-rich invagination of the plasma membrane that might mediate the uptake of some extracellular materials, and is probably involved in cell signalling.

SNARES

(Soluble NSF attachment protein receptor, where NSF stands for N-ethyl-maleimide-sensitive fusion protein.) Proteins required for membrane fusion in exocytosis and other membrane transport events. When trans-SNARE complexes are formed between vesicle SNAREs and target-membrane SNAREs, they pull the two membranes close together, presumably causing them to fuse.

ARF1

Small GTPase responsible for recruiting different types of coat, leading to vesicle budding.

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https://doi.org/10.1038/35080071