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PMID: 20861879 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Revitalizing membrane rafts: new tools and insights.

Nature reviews. Molecular cell biology ·Vol. 11 ·No. 10 ·2010-10-00 ·Pages 688-99

Simons K, Gerl MJ

Abstract

Ten years ago, we wrote a Review on lipid rafts and signalling in the launch issue of Nature Reviews Molecular Cell Biology. At the time, this field was suffering from ambiguous methodology and imprecise nomenclature. Now, new techniques are deepening our insight into the dynamics of membrane organization. Here, we discuss how the field has matured and present an evolving model in which membranes are occupied by fluctuating nanoscale assemblies of sphingolipids, cholesterol and proteins that can be stabilized into platforms that are important in signalling, viral infection and membrane trafficking.

MeSH Terms
Biophysics/methods Caveolae/physiology,ultrastructure Cell Membrane/physiology,ultrastructure Detergents Humans Major Histocompatibility Complex Mass Spectrometry/methods Membrane Microdomains/genetics,physiology,ultrastructure Signal Transduction Solubility Spectrometry, Fluorescence/methods T-Lymphocytes/immunology,physiology
Chemicals
Detergents
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Simons Kai
Max Planck Institute of Cell Biology and Genetics, Dresden, Germany. [email protected]
Gerl Mathias J
References (125)
125 references, click to expand
  1. T cells as a self-referential, sensory organ.
    Annu Rev Immunol. 2007;25:681-95 PMID: 17291190
  2. GPI-anchored cell-surface molecules complexed to protein tyrosine kinases.
    Science. 1991 Nov 15;254(5034):1016-9 PMID: 1719635
  3. Critical fluctuations in plasma membrane vesicles.
    ACS Chem Biol. 2008 May 16;3(5):287-93 PMID: 18484709
  4. Membrane proteins diffuse as dynamic complexes with lipids.
    J Am Chem Soc. 2010 Jun 9;132(22):7574-5 PMID: 20469857
  5. Concentration of GPI-anchored proteins upon ER exit in yeast.
    Traffic. 2009 Feb;10(2):186-200 PMID: 19054390
  6. Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling.
    J Exp Med. 2005 Oct 17;202(8):1031-6 PMID: 16216891
  7. The multiple faces of caveolae.
    Nat Rev Mol Cell Biol. 2007 Mar;8(3):185-94 PMID: 17318224
  8. Dynamics of putative raft-associated proteins at the cell surface.
    J Cell Biol. 2004 Jun 7;165(5):735-46 PMID: 15173190
  9. Polyunsaturated fatty acid-cholesterol interactions: domain formation in membranes.
    Biochim Biophys Acta. 2009 Jan;1788(1):24-32 PMID: 19014904
  10. Automated identification and quantification of glycerophospholipid molecular species by multiple precursor ion scanning.
    Anal Chem. 2006 Sep 1;78(17):6202-14 PMID: 16944903
  11. Nanoscale imaging of domains in supported lipid membranes.
    Langmuir. 2007 May 22;23(11):5886-95 PMID: 17428076
  12. Inositol deacylation by Bst1p is required for the quality control of glycosylphosphatidylinositol-anchored proteins.
    Mol Biol Cell. 2006 Feb;17(2):834-50 PMID: 16319176
  13. Cholesterol-dependent phase separation in cell-derived giant plasma-membrane vesicles.
    Biochem J. 2009 Nov 11;424(2):163-7 PMID: 19811449
  14. Structure of the shiga-like toxin I B-pentamer complexed with an analogue of its receptor Gb3.
    Biochemistry. 1998 Feb 17;37(7):1777-88 PMID: 9485303
  15. Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly.
    Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11364-9 PMID: 16840558
  16. Lipidomics joins the omics evolution.
    Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2089-90 PMID: 19211786
  17. Tracking microdomain dynamics in cell membranes.
    Biochim Biophys Acta. 2009 Jan;1788(1):245-53 PMID: 19041847
  18. Biological aspects of ceramide-enriched membrane domains.
    Prog Lipid Res. 2007 May-Jul;46(3-4):161-70 PMID: 17490747
  19. Parallel secretory pathways to the cell surface in yeast.
    J Cell Biol. 1995 Oct;131(2):297-310 PMID: 7593160
  20. Two endoplasmic reticulum (ER) membrane proteins that facilitate ER-to-Golgi transport of glycosylphosphatidylinositol-anchored proteins.
    Mol Biol Cell. 1999 Apr;10(4):1043-59 PMID: 10198056
  21. PER1 is required for GPI-phospholipase A2 activity and involved in lipid remodeling of GPI-anchored proteins.
    Mol Biol Cell. 2006 Dec;17(12):5253-64 PMID: 17021251
  22. Fluorescence correlation spectroscopy diffusion laws to probe the submicron cell membrane organization.
    Biophys J. 2005 Dec;89(6):4029-42 PMID: 16199500
  23. Lipid raft proteins have a random distribution during localized activation of the T-cell receptor.
    Nat Cell Biol. 2004 Mar;6(3):238-43 PMID: 14767481
  24. Virus entry by endocytosis.
    Annu Rev Biochem. 2010;79:803-33 PMID: 20196649
  25. Lipid rafts: now you see them, now you don't.
    Nat Immunol. 2006 Nov;7(11):1139-42 PMID: 17053798
  26. Phase coexistence and connectivity in the apical membrane of polarized epithelial cells.
    Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):329-34 PMID: 16407160
  27. TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity.
    Nature. 2010 Feb 18;463(7283):963-7 PMID: 20164930
  28. Model systems, lipid rafts, and cell membranes.
    Annu Rev Biophys Biomol Struct. 2004;33:269-95 PMID: 15139814
  29. Protein area occupancy at the center of the red blood cell membrane.
    Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2848-52 PMID: 18287056
  30. Transmembrane asymmetry and lateral domains in biological membranes.
    Traffic. 2004 Apr;5(4):241-6 PMID: 15030565
  31. Signalling ballet in space and time.
    Nat Rev Mol Cell Biol. 2010 Jun;11(6):414-26 PMID: 20495582
  32. Shiga toxin induces tubular membrane invaginations for its uptake into cells.
    Nature. 2007 Nov 29;450(7170):670-5 PMID: 18046403
  33. Plasma membrane-associated proteins are clustered into islands attached to the cytoskeleton.
    Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):18992-7 PMID: 17146050
  34. Membrane lipids: where they are and how they behave.
    Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24 PMID: 18216768
  35. Tether and trap: regulation of membrane-raft dynamics by actin-binding proteins.
    Nat Rev Immunol. 2007 Nov;7(11):889-96 PMID: 17948020
  36. Dynamic molecular confinement in the plasma membrane by microdomains and the cytoskeleton meshwork.
    EMBO J. 2006 Jul 26;25(14):3245-56 PMID: 16858413
  37. Lipids and membrane microdomains in HIV-1 replication.
    Virus Res. 2009 Aug;143(2):162-76 PMID: 19383519
  38. Detergent-resistant membranes should not be identified with membrane rafts.
    Trends Biochem Sci. 2005 Aug;30(8):430-6 PMID: 15996869
  39. Sphingolipid-cholesterol rafts diffuse as small entities in the plasma membrane of mammalian cells.
    J Cell Biol. 2000 Mar 6;148(5):997-1008 PMID: 10704449
  40. Lipidomics: coming to grips with lipid diversity.
    Nat Rev Mol Cell Biol. 2010 Aug;11(8):593-8 PMID: 20606693
  41. NSOM/QD-based direct visualization of CD3-induced and CD28-enhanced nanospatial coclustering of TCR and coreceptor in nanodomains in T cell activation.
    PLoS One. 2009 Jun 17;4(6):e5945 PMID: 19536289
  42. Lipid rafts reconstituted in model membranes.
    Biophys J. 2001 Mar;80(3):1417-28 PMID: 11222302
  43. Yeast ARV1 is required for efficient delivery of an early GPI intermediate to the first mannosyltransferase during GPI assembly and controls lipid flow from the endoplasmic reticulum.
    Mol Biol Cell. 2008 May;19(5):2069-82 PMID: 18287539
  44. Raft nanodomains contribute to Akt/PKB plasma membrane recruitment and activation.
    Nat Chem Biol. 2008 Sep;4(9):538-47 PMID: 18641634
  45. Quantitative proteomic analysis of B cell lipid rafts reveals that ezrin regulates antigen receptor-mediated lipid raft dynamics.
    Nat Immunol. 2006 Jun;7(6):625-33 PMID: 16648854
  46. Fast molecular tracking maps nanoscale dynamics of plasma membrane lipids.
    Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6829-34 PMID: 20351247
  47. A genome-wide visual screen reveals a role for sphingolipids and ergosterol in cell surface delivery in yeast.
    Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):17981-6 PMID: 16330752
  48. Steric and not structure-specific factors dictate the endocytic mechanism of glycosylphosphatidylinositol-anchored proteins.
    J Cell Biol. 2009 Aug 24;186(4):615-28 PMID: 19687251
  49. FRET imaging reveals that functional neurokinin-1 receptors are monomeric and reside in membrane microdomains of live cells.
    Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2138-43 PMID: 16461466
  50. Lipid rafts: elusive or illusive?
    Cell. 2003 Nov 14;115(4):377-88 PMID: 14622593
  51. Lipid rafts in epithelial brush borders: atypical membrane microdomains with specialized functions.
    Biochim Biophys Acta. 2003 Oct 31;1617(1-2):1-9 PMID: 14637014
  52. An introduction to critical points for biophysicists; observations of compositional heterogeneity in lipid membranes.
    Biochim Biophys Acta. 2009 Jan;1788(1):53-63 PMID: 18930706
  53. Retroviruses human immunodeficiency virus and murine leukemia virus are enriched in phosphoinositides.
    J Virol. 2008 Nov;82(22):11228-38 PMID: 18799574
  54. Order of lipid phases in model and plasma membranes.
    Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16645-50 PMID: 19805351
  55. Molecular dynamics and interactions for creation of stimulation-induced stabilized rafts from small unstable steady-state rafts.
    Traffic. 2004 Apr;5(4):213-30 PMID: 15030563
  56. The lipidomes of vesicular stomatitis virus, semliki forest virus, and the host plasma membrane analyzed by quantitative shotgun mass spectrometry.
    J Virol. 2009 Aug;83(16):7996-8003 PMID: 19474104
  57. Crosslinking a lipid raft component triggers liquid ordered-liquid disordered phase separation in model plasma membranes.
    Proc Natl Acad Sci U S A. 2005 May 3;102(18):6320-5 PMID: 15851688
  58. Influenza viruses select ordered lipid domains during budding from the plasma membrane.
    J Biol Chem. 1999 Jan 22;274(4):2038-44 PMID: 9890962
  59. Live-cell photoactivated localization microscopy of nanoscale adhesion dynamics.
    Nat Methods. 2008 May;5(5):417-23 PMID: 18408726
  60. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes.
    Cell. 2004 Feb 20;116(4):577-89 PMID: 14980224
  61. The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells.
    J Cell Biol. 2009 May 4;185(3):521-34 PMID: 19398758
  62. The HIV lipidome: a raft with an unusual composition.
    Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2641-6 PMID: 16481622
  63. Sphingolipids are required for the stable membrane association of glycosylphosphatidylinositol-anchored proteins in yeast.
    J Biol Chem. 2002 Dec 20;277(51):49538-44 PMID: 12393888
  64. Actin restricts FcepsilonRI diffusion and facilitates antigen-induced receptor immobilization.
    Nat Cell Biol. 2008 Aug;10(8):955-63 PMID: 18641640
  65. Nanoscale organization of hedgehog is essential for long-range signaling.
    Cell. 2008 Jun 27;133(7):1214-27 PMID: 18585355
  66. Pathways followed by protein toxins into cells.
    Int J Med Microbiol. 2004 Apr;293(7-8):483-90 PMID: 15149022
  67. Detecting microdomains in intact cell membranes.
    Annu Rev Phys Chem. 2005;56:309-36 PMID: 15796703
  68. Lipid sorting in epithelial cells.
    Biochemistry. 1988 Aug 23;27(17):6197-202 PMID: 3064805
  69. Critical fluctuations in domain-forming lipid mixtures.
    Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17650-5 PMID: 17962417
  70. T-cell antigen receptor triggering and lipid rafts: a matter of space and time scales. Talking Point on the involvement of lipid rafts in T-cell activation.
    EMBO Rep. 2008 Jun;9(6):525-30 PMID: 18516087
  71. Plasma membranes are poised for activation of raft phase coalescence at physiological temperature.
    Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10005-10 PMID: 18621689
  72. Phase separation in biological membranes: integration of theory and experiment.
    Annu Rev Biophys. 2010;39:207-26 PMID: 20192775
  73. TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation.
    Nat Immunol. 2010 Jan;11(1):90-6 PMID: 20010844
  74. GM1 structure determines SV40-induced membrane invagination and infection.
    Nat Cell Biol. 2010 Jan;12(1):11-8; sup pp 1-12 PMID: 20023649
  75. Large-scale fluid/fluid phase separation of proteins and lipids in giant plasma membrane vesicles.
    Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3165-70 PMID: 17360623
  76. The fluid mosaic model of the structure of cell membranes.
    Science. 1972 Feb 18;175(4023):720-31 PMID: 4333397
  77. A nanometer scale optical view on the compartmentalization of cell membranes.
    Biochim Biophys Acta. 2010 Apr;1798(4):777-87 PMID: 19800861
  78. GPI-anchored receptor clusters transiently recruit Lyn and G alpha for temporary cluster immobilization and Lyn activation: single-molecule tracking study 1.
    J Cell Biol. 2007 May 21;177(4):717-30 PMID: 17517964
  79. The transmembrane protein CBP plays a role in transiently anchoring small clusters of Thy-1, a GPI-anchored protein, to the cytoskeleton.
    J Cell Sci. 2009 Nov 1;122(Pt 21):3966-72 PMID: 19825940
  80. Far-field optical nanoscopy.
    Science. 2007 May 25;316(5828):1153-8 PMID: 17525330
  81. Temperature-dependent phase behavior and protein partitioning in giant plasma membrane vesicles.
    Biochim Biophys Acta. 2010 Jul;1798(7):1427-35 PMID: 20230780
  82. Lipid rafts and signal transduction.
    Nat Rev Mol Cell Biol. 2000 Oct;1(1):31-9 PMID: 11413487
  83. Phase separation dynamics and lateral organization of two-component lipid membranes.
    Biophys J. 1995 Sep;69(3):942-54 PMID: 8519994
  84. The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness.
    Nature. 2010 Apr 8;464(7290):932-6 PMID: 20357766
  85. Dynamics of HIV-1 assembly and release.
    PLoS Pathog. 2009 Nov;5(11):e1000652 PMID: 19893629
  86. Single-molecule microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T cells.
    Cell. 2005 Jun 17;121(6):937-50 PMID: 15960980
  87. Signal initiation in T-cell receptor microclusters.
    Immunol Rev. 2008 Feb;221:90-106 PMID: 18275477
  88. Fluorescence correlation studies of lipid domains in model membranes.
    Mol Membr Biol. 2006 Jan-Feb;23(1):29-39 PMID: 16611578
  89. Wrapping it up: the cell biology of myelination.
    Curr Opin Neurobiol. 2007 Oct;17(5):533-40 PMID: 17923405
  90. Yeast lipids can phase-separate into micrometer-scale membrane domains.
    J Biol Chem. 2010 Sep 24;285(39):30224-32 PMID: 20647309
  91. Evidence for budding of human immunodeficiency virus type 1 selectively from glycolipid-enriched membrane lipid rafts.
    J Virol. 2000 Apr;74(7):3264-72 PMID: 10708443
  92. Detergent resistance as a tool in membrane research.
    Nat Protoc. 2007;2(9):2159-65 PMID: 17853872
  93. Lipid rafts as a membrane-organizing principle.
    Science. 2010 Jan 1;327(5961):46-50 PMID: 20044567
  94. Aggregation and vesiculation of membrane proteins by curvature-mediated interactions.
    Nature. 2007 May 24;447(7143):461-4 PMID: 17522680
  95. Role of GAP-43 in sequestering phosphatidylinositol 4,5-bisphosphate to Raft bilayers.
    Biophys J. 2008 Jan 1;94(1):125-33 PMID: 17827240
  96. Actin dynamics drive membrane reorganization and scission in clathrin-independent endocytosis.
    Cell. 2010 Feb 19;140(4):540-53 PMID: 20178746
  97. Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies.
    Biochim Biophys Acta. 2007 Jun;1768(6):1311-24 PMID: 17493580
  98. A role for lipid shells in targeting proteins to caveolae, rafts, and other lipid domains.
    Science. 2002 Jun 7;296(5574):1821-5 PMID: 12052946
  99. DySCo: quantitating associations of membrane proteins using two-color single-molecule tracking.
    Biophys J. 2009 Aug 19;97(4):L5-7 PMID: 19686638
  100. Lipid rafts: at a crossroad between cell biology and physics.
    Nat Cell Biol. 2007 Jan;9(1):7-14 PMID: 17199125
  101. Dynamic partitioning of a glycosyl-phosphatidylinositol-anchored protein in glycosphingolipid-rich microdomains imaged by single-quantum dot tracking.
    Traffic. 2009 Jun;10(6):691-712 PMID: 19416475
  102. Lipid reorganization induced by Shiga toxin clustering on planar membranes.
    PLoS One. 2009 Jul 16;4(7):e6238 PMID: 19606209
  103. Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM).
    Nat Methods. 2006 Oct;3(10):793-5 PMID: 16896339
  104. Mechanisms for segregating T cell receptor and adhesion molecules during immunological synapse formation in Jurkat T cells.
    Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20296-301 PMID: 18077330
  105. Accumulation of raft lipids in T-cell plasma membrane domains engaged in TCR signalling.
    EMBO J. 2009 Mar 4;28(5):466-76 PMID: 19177148
  106. Lipid rafts and T cell receptor signaling: a critical re-evaluation.
    Eur J Immunol. 2002 Nov;32(11):3082-91 PMID: 12385028
  107. Segregation of sphingolipids and sterols during formation of secretory vesicles at the trans-Golgi network.
    J Cell Biol. 2009 May 18;185(4):601-12 PMID: 19433450
  108. Have we become overly reliant on lipid rafts? Talking Point on the involvement of lipid rafts in T-cell activation.
    EMBO Rep. 2008 Jun;9(6):531-5 PMID: 18516088
  109. Nanoclusters of GPI-anchored proteins are formed by cortical actin-driven activity.
    Cell. 2008 Dec 12;135(6):1085-97 PMID: 19070578
  110. Taking T cells beyond the diffraction limit.
    Nat Immunol. 2010 Jan;11(1):51-2 PMID: 20016513
  111. Constitutively active Lck kinase in T cells drives antigen receptor signal transduction.
    Immunity. 2010 Jun 25;32(6):766-77 PMID: 20541955
  112. Phase behavior of lipid mixtures.
    Nat Chem Biol. 2006 Nov;2(11):560-3 PMID: 17051225
  113. A guide to super-resolution fluorescence microscopy.
    J Cell Biol. 2010 Jul 26;190(2):165-75 PMID: 20643879
  114. Dynamic recruitment of phospholipase C gamma at transiently immobilized GPI-anchored receptor clusters induces IP3-Ca2+ signaling: single-molecule tracking study 2.
    J Cell Biol. 2007 May 21;177(4):731-42 PMID: 17517965
  115. Tuning lipid mixtures to induce or suppress domain formation across leaflets of unsupported asymmetric bilayers.
    Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):124-8 PMID: 18172219
  116. Functional rafts in cell membranes.
    Nature. 1997 Jun 5;387(6633):569-72 PMID: 9177342
  117. Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry.
    Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2136-41 PMID: 19174513
  118. Probing HIV-1 membrane liquid order by Laurdan staining reveals producer cell-dependent differences.
    J Biol Chem. 2009 Aug 14;284(33):22238-22247 PMID: 19553682
  119. PIP(2) and proteins: interactions, organization, and information flow.
    Annu Rev Biophys Biomol Struct. 2002;31:151-75 PMID: 11988466
  120. Lipid rafts: contentious only from simplistic standpoints.
    Nat Rev Mol Cell Biol. 2006 Jun;7(6):456-62 PMID: 16625153
  121. Direct observation of the nanoscale dynamics of membrane lipids in a living cell.
    Nature. 2009 Feb 26;457(7233):1159-62 PMID: 19098897
  122. Polarized sorting in epithelial cells: raft clustering and the biogenesis of the apical membrane.
    J Cell Sci. 2004 Dec 1;117(Pt 25):5955-64 PMID: 15564373
  123. Diffusion analysis within single nanometric apertures reveals the ultrafine cell membrane organization.
    Biophys J. 2007 Feb 1;92(3):913-9 PMID: 17085499
  124. A comprehensive comparison of transmembrane domains reveals organelle-specific properties.
    Cell. 2010 Jul 9;142(1):158-69 PMID: 20603021
  125. Single-molecule level analysis of the subunit composition of the T cell receptor on live T cells.
    Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17662-7 PMID: 17971442
Article Info
Journal
Nature reviews. Molecular cell biology
Abbr.
Nat Rev Mol Cell Biol
ISSN
1471-0080
DOI
10.1038/nrm2977
Email
[email protected]
Published
2010-10-00
Pages
688-99
Language
English
Region
England
NLM ID
100962782
Subset
IM
External Links
PubMed source DOI: 10.1038/nrm2977 View journal details
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