Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Lipid rafts: contentious only from simplistic standpoints

Nature Reviews Molecular Cell Biology volume 7, pages 456–462 (2006)Cite this article

Abstract

The hypothesis that lipid rafts exist in plasma membranes and have crucial biological functions remains controversial. The lateral heterogeneity of proteins in the plasma membrane is undisputed, but the contribution of cholesterol-dependent lipid assemblies to this complex, non-random organization promotes vigorous debate. In the light of recent studies with model membranes, computational modelling and innovative cell biology, I propose an updated model of lipid rafts that readily accommodates diverse views on plasma-membrane micro-organization.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Liquid-ordered domains in model membranes.
Figure 2: Revised raft model.

Similar content being viewed by others

References

  1. Simons, K. & Ikonen, E. Functional rafts in cell membranes. Nature 387, 569–572 (1997).

    Article  CAS  Google Scholar 

  2. Edidin, M. The state of lipid rafts: from model membranes to cells. Annu. Rev. Biophys. Biomol. Struct. 32, 257–283 (2003).

    Article  CAS  Google Scholar 

  3. Simons, K. & Vaz, W. L. Model systems, lipid rafts, and cell membranes. Annu. Rev. Biophys. Biomol. Struct. 33, 269–295 (2004).

    Article  CAS  Google Scholar 

  4. Munro, S. Lipid rafts: elusive or illusive? Cell 115, 377–388 (2003).

    Article  CAS  Google Scholar 

  5. Nichols, B. Cell biology: without a raft. Nature 436, 638–639 (2005).

    Article  CAS  Google Scholar 

  6. de Almeida, R. F., Fedorov, A. & Prieto, M. Sphingomyelin–phosphatidylcholine–cholesterol phase diagram: boundaries and composition of lipid rafts. Biophys. J. 85, 2406–2416 (2003).

    Article  CAS  Google Scholar 

  7. de Almeida, R. F., Loura, L. M., Fedorov, A. & Prieto, M. Lipid rafts have different sizes depending on membrane composition: a time-resolved fluorescence resonance energy transfer study. J. Mol. Biol. 346, 1109–1120 (2005).

    Article  CAS  Google Scholar 

  8. Brown, D. A. & Rose, J. K. Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68, 533–544 (1992).

    Article  CAS  Google Scholar 

  9. Brown, D. A. & London, E. Structure of detergent-resistant membrane domains: does phase separation occur in biological membranes? Biochem. Biophys. Res. Commun. 240, 1–7 (1997).

    Article  CAS  Google Scholar 

  10. London, E. & Brown, D. A. Insolubility of lipids in triton X-100: physical origin and relationship to sphingolipid–cholesterol membrane domains (rafts). Biochim. Biophys. Acta. 1508, 182–195 (2000).

    Article  CAS  Google Scholar 

  11. Heberle, F. A., Buboltz, J. T., Stringer, D. & Feigenson, G. W. Fluorescence methods to detect phase boundaries in lipid bilayer mixtures. Biochim. Biophys. Acta. 1746, 186–192 (2005).

    Article  CAS  Google Scholar 

  12. Silvius, J. R. Fluorescence energy transfer reveals microdomain formation at physiological temperatures in lipid mixtures modeling the outer leaflet of the plasma membrane. Biophys. J. 85, 1034–1045 (2003).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Yuan, C., Furlong, J., Burgos, P. & Johnston, L. J. The size of lipid rafts: an atomic force microscopy study of ganglioside GM1 domains in sphingomyelin–DOPC–cholesterol membranes. Biophys. J. 82, 2526–2535 (2002).

    Article  CAS  Google Scholar 

  15. Hsueh, Y. W., Gilbert, K., Trandum, C., Zuckermann, M. & Thewalt, J. The effect of ergosterol on dipalmitoyl-phosphatidylcholine bilayers: a deuterium NMR and calorimetric study. Biophys. J. 88, 1799–1808 (2005).

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. Veatch, S. L. & Keller, S. L. Seeing spots: Complex phase behavior in simple membranes. Biochim. Biophys. Acta. 1746, 172–185 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Kahya, N., Brown, D. A. & Schwille, P. Raft partitioning and dynamic behavior of human placental alkaline phosphatase in giant unilamellar vesicles. Biochemistry 44, 7479–7489 (2005).

    Article  CAS  Google Scholar 

  21. Rao, M. & Mayor, S. Use of Forster's resonance energy transfer microscopy to study lipid rafts. Biochim. Biophys. Acta 1746, 221–233 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Mayor, S. & Rao, M. Rafts: scale-dependent, active lipid organization at the cell surface. Traffic 5, 231–240 (2004).

    Article  CAS  Google Scholar 

  24. Plowman, S., Muncke, C., Parton, R. G. & Hancock, J. F. H-ras, K-ras and inner plasma membrane raft proteins operate in nanoclusters that exhibit differential dependence on the actin cytoskeleton. Proc. Natl Acad. Sci. USA 102, 15500–15505 (2005).

    Article  CAS  Google Scholar 

  25. Prior, I. A., Muncke, C., Parton, R. G. & Hancock, J. F. Direct visualization of Ras proteins in spatially distinct cell surface microdomains. J. Cell Biol. 160, 165–170 (2003).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

  27. Kenworthy, A. K., Petranova, N. & Edidin, M. High-resolution FRET microscopy of cholera toxin B-subunit and GPI-anchored proteins in cell plasma membranes. Mol. Biol. Cell 11, 1645–1655 (2000).

    Article  CAS  Google Scholar 

  28. Kawasaki, K., Yin, J. J., Subczynski, W. K., Hyde, J. S. & Kusumi, A. Pulse EPR detection of lipid exchange between protein-rich raft and bulk domains in the membrane: methodology development and its application to studies of influenza viral membrane. Biophys. J. 80, 738–748 (2001).

    Article  CAS  Google Scholar 

  29. Zacharias, D. A., Violin, J. D., Newton, A. C. & Tsien, R. Y. Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. Science 296, 913–916 (2002).

    Article  CAS  Google Scholar 

  30. Nicolini, C. et al. Visualizing association of N-Ras in lipid microdomains: influence of domain structure and interfacial adsorption. J. Am. Chem. Soc. 128, 192–201 (2006).

    Article  CAS  Google Scholar 

  31. Douglass, A. D. & Vale, R. D. Single-molecule microscopy reveals plasma membrane microdomains created by protein–protein networks that exclude or trap signaling molecules in T cells. Cell 121, 937–950 (2005).

    Article  CAS  Google Scholar 

  32. Anderson, R. G. & Jacobson, K. A role for lipid shells in targeting proteins to caveolae, rafts, and other lipid domains. Science 296, 1821–1825 (2002).

    Article  CAS  Google Scholar 

  33. Huster, D. et al. Membrane insertion of a lipidated ras peptide studied by FTIR, solid-state NMR, and neutron diffraction spectroscopy. J. Am. Chem. Soc. 125, 4070–4079 (2003).

    Article  CAS  Google Scholar 

  34. Gorfe, A. A., Pellarin, R. & Caflisch, A. Membrane localization and flexibility of a lipidated ras peptide studied by molecular dynamics simulations. J. Am. Chem. Soc. 126, 15277–15286 (2004).

    Article  CAS  Google Scholar 

  35. Janosch, S. et al. Partitioning of dual-lipidated peptides into membrane microdomains: lipid sorting vs peptide aggregation. J. Am. Chem. Soc. 126, 7496–7503 (2004).

    Article  CAS  Google Scholar 

  36. Rowat, A. C. et al. Farnesylated peptides in model membranes: a biophysical investigation. Eur. Biophys. J. 33, 300–309 (2004).

    Article  CAS  Google Scholar 

  37. Rowat, A. C., Keller, D. & Ipsen, J. H. Effects of farnesol on the physical properties of DMPC membranes. Biochim. Biophys. Acta. 1713, 29–39 (2005).

    Article  CAS  Google Scholar 

  38. Jensen, M. O. & Mouritsen, O. G. Lipids do influence protein function — the hydrophobic matching hypothesis revisited. Biochim. Biophys. Acta. 1666, 205–226 (2004).

    Article  CAS  Google Scholar 

  39. Mitra, K., Ubarretxena-Belandia, I., Taguchi, T., Warren, G. & Engelman, D. M. Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol. Proc. Natl Acad. Sci. USA 101, 4083–4088 (2004).

    Article  CAS  Google Scholar 

  40. Cho, W. & Stahelin, R. V. Membrane–protein interactions in cell signaling and membrane trafficking. Annu. Rev. Biophys. Biomol. Struct. 34, 119–151 (2005).

    Article  CAS  Google Scholar 

  41. Larson, D. R., Gosse, J. A., Holowka, D. A., Baird, B. A. & Webb, W. W. Temporally resolved interactions between antigen-stimulated IgE receptors and Lyn kinase on living cells. J. Cell Biol. 171, 527–536 (2005).

    Article  CAS  Google Scholar 

  42. Gaus, K., Chklovskaia, E., Fazekas de St Groth, B., Jessup, W. & Harder, T. Condensation of the plasma membrane at the site of T lymphocyte activation. J. Cell Biol. 171, 121–131 (2005).

    Article  CAS  Google Scholar 

  43. Murakoshi, H. et al. Single-molecule imaging analysis of Ras activation in living cells. Proc. Natl Acad. Sci. USA 101, 7317–7322 (2004).

    Article  CAS  Google Scholar 

  44. Hancock, J. F. & Parton, R. G. Ras plasma membrane signalling platforms. Biochem. J. 389, 1–11 (2005).

    Article  CAS  Google Scholar 

  45. Turner, M. S., Sens, P. & Socci, N. D. Nonequilibrium raft-like domains under continuous recycling. Phys. Rev. Lett. 95, 168301 (2005).

    Article  Google Scholar 

  46. Kirkham, M. et al. Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles. J. Cell Biol. 168, 465–476 (2005).

    Article  CAS  Google Scholar 

  47. Rotblat, B. et al. Three separable domains regulate GTP-dependent association of H-ras with the plasma membrane. Mol. Cell. Biol. 24, 6799–6810 (2004).

    Article  CAS  Google Scholar 

  48. Roy, S. et al. Individual palmitoyl residues serve distinct roles in H-ras trafficking, microlocalization, and signaling. Mol. Cell. Biol. 25, 6722–6733 (2005).

    Article  CAS  Google Scholar 

  49. Nicolau, D. V. Jr, Burrage, K., Parton, R. G. & Hancock, J. F. Identifying optimal lipid raft characteristics required to promote nanoscale protein–protein interactions on the plasma membrane. Mol. Biol. Cell 26, 313–323 (2006).

    Article  CAS  Google Scholar 

  50. McConnell, H. M. & Radhakrishnan, A. Condensed complexes of cholesterol and phospholipids. Biochim. Biophys. Acta. 1610, 159–173 (2003).

    Article  CAS  Google Scholar 

  51. McConnell, H. M. & Vrljic, M. Liquid–liquid immiscibility in membranes. Annu. Rev. Biophys. Biomol. Struct. 32, 469–492 (2003).

    Article  CAS  Google Scholar 

  52. Huang, J. & Feigenson, G. W. A microscopic interaction model of maximum solubility of cholesterol in lipid bilayers. Biophys. J. 76, 2142–2157 (1999).

    Article  CAS  Google Scholar 

  53. Pandit, S. A., Jakobsson, E. & Scott, H. L. Simulation of the early stages of nano-domain formation in mixed bilayers of sphingomyelin, cholesterol, and dioleylphosphatidylcholine. Biophys. J. 87, 3312–3322 (2004).

    Article  CAS  Google Scholar 

  54. Pandit, S. A. et al. Sphingomyelin–cholesterol domains in phospholipid membranes: atomistic simulation. Biophys. J. 87, 1092–1100 (2004).

    Article  CAS  Google Scholar 

  55. Foster, L. J., De Hoog, C. L. & Mann, M. Unbiased quantitative proteomics of lipid rafts reveals high specificity for signaling factors. Proc. Natl Acad. Sci. USA 100, 5813–5818 (2003).

    Article  CAS  Google Scholar 

  56. Lichtenberg, D., Goni, F. M. & Heerklotz, H. Detergent-resistant membranes should not be identified with membrane rafts. Trends Biochem. Sci. 30, 430–436 (2005).

    Article  CAS  Google Scholar 

  57. Heerklotz, H. Triton promotes domain formation in lipid raft mixtures. Biophys. J. 83, 2693–2701 (2002).

    Article  CAS  Google Scholar 

  58. Heerklotz, H., Szadkowska, H., Anderson, T. & Seelig, J. The sensitivity of lipid domains to small perturbations demonstrated by the effect of Triton. J. Mol. Biol. 329, 793–799 (2003).

    Article  CAS  Google Scholar 

  59. Kwik, J. et al. Membrane cholesterol, lateral mobility, and the phosphatidylinositol 4,5-bisphosphate-dependent organization of cell actin. Proc. Natl Acad. Sci. USA 100, 13964–13969 (2003).

    Article  CAS  Google Scholar 

  60. Subtil, A. et al. Acute cholesterol depletion inhibits clathrin-coated pit budding. Proc. Natl Acad. Sci. USA 96, 6775–6780 (1999).

    Article  CAS  Google Scholar 

  61. Pichler, H. & Riezman, H. Where sterols are required for endocytosis. Biochim. Biophys. Acta. 1666, 51–61 (2004).

    Article  CAS  Google Scholar 

  62. Hao, M., Mukherjee, S., Sun, Y. & Maxfield, F. R. Effects of cholesterol depletion and increased lipid unsaturation on the properties of endocytic membranes. J. Biol. Chem. 279, 14171–14178 (2004).

    Article  CAS  Google Scholar 

  63. Goodwin, J. S., Drake, K. R., Remmert, C. L. & Kenworthy, A. K. Ras diffusion is sensitive to plasma membrane viscosity. Biophys. J. 89, 1398–1410 (2005).

    Article  CAS  Google Scholar 

  64. Niv, H., Gutman, O., Kloog, Y. & Henis, Y. I. Activated K-Ras and H-Ras display different interactions with saturable nonraft sites at the surface of live cells. J. Cell Biol. 157, 865–872 (2002).

    Article  CAS  Google Scholar 

  65. Pike, L. J., Han, X., Chung, K. N. & Gross, R. W. Lipid rafts are enriched in arachidonic acid and plasmenylethanolamine and their composition is independent of caveolin-1 expression: a quantitative electrospray ionization/mass spectrometric analysis. Biochemistry 41, 2075–2088 (2002).

    Article  CAS  Google Scholar 

  66. Hao, M. & Maxfield, F. R. Characterization of rapid membrane internalization and recycling. J. Biol. Chem. 275, 15279–15286 (2000).

    Article  CAS  Google Scholar 

  67. Fujiwara, T., Ritchie, K., Murakoshi, H., Jacobson, K. & Kusumi, A. Phospholipids undergo hop diffusion in compartmentalized cell membrane. J. Cell Biol. 157, 1071–1081 (2002).

    Article  CAS  Google Scholar 

  68. Murase, K. et al. Ultrafine membrane compartments for molecular diffusion as revealed by single molecule techniques. Biophys. J. 86, 4075–4093 (2004).

    Article  CAS  Google Scholar 

  69. Schutz, G. J., Kada, G., Pastushenko, V. P. & Schindler, H. Properties of lipid microdomains in a muscle cell membrane visualized by single molecule microscopy. EMBO J. 19, 892–901 (2000).

    Article  CAS  Google Scholar 

  70. Zhang, W. et al. Structural analysis of sterol distributions in the plasma membrane of living cells. Biochemistry 44, 2864–2884 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I thank A. Yap, R. Parton and anonymous reviewers for helpful comments on the manuscript, and the National Health and Medical Research Council, Australia, and the National Institutes of Health, USA, for their continuing support. The Institute for Molecular Bioscience is a Special Research Centre of the Australian Research Council.

Author information

Authors and Affiliations

  1. the Institute for Molecular Bioscience, University of Queensland, Brisbane, 4072, Australia

    John F. Hancock

Authors
  1. John F. Hancock
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

John Hancock's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hancock, J. Lipid rafts: contentious only from simplistic standpoints. Nat Rev Mol Cell Biol 7, 456–462 (2006). https://doi.org/10.1038/nrm1925

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1925

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing