Advertisement

Super-Resolution Imaging of Membrane Heterogeneity

  • Jing Gao
  • Junling Chen
  • Hongda WangEmail author
Chapter

Abstract

The cell membrane is a very complicated biological complex that is largely composed of lipids, proteins, and carbohydrates to mediate numerous cellular functions. Some proposed membrane models have described the heterogeneous arrangement of membrane compositions; however, these models are more or less controversial and do not provide detailed information of cellular membranes at the nanoscale. Recently, super-resolution microscopy can serve as powerful tools to reveal the membrane heterogeneity and quantitatively analyze membrane organization at the single molecular level, and importantly, many of these tools are compatible with living cells. Here, we introduce the classification and mechanism of the super-resolution imaging technology and analytical methods of characterizing cellular membrane morphology and dynamics. We also illustrate the new progress regarding membrane heterogeneity using super-resolution techniques, which may shed light on the study of the structure and functions of cell membranes.

Notes

Acknowledgements

This work was supported by the National Key R&D Program of China (No. 2017YFA0505300), the National Natural Science Foundation of China (No. 21525314, 21703231 and 21721003).

References

  1. 1.
    Singer S, Nicolson GL (1972) The fluid mosaic model of the structure of cell membranes. In: Day SB, Good RA (eds) Membranes and viruses in immunopathology, pp 7–47Google Scholar
  2. 2.
    Abbe E (1873) Beiträge zur Theorie des Mikroskops und der mikroskopischen Wahrnehmung. Archiv für mikroskopische Anatomie 9(1):413–418CrossRefGoogle Scholar
  3. 3.
    Hell SW, Wichmann J (1994) Breaking the diffraction resolution limit by stimulated emission: stimulated-emission-depletion fluorescence microscopy. Opt Lett 19(11):780–782CrossRefGoogle Scholar
  4. 4.
    Klar TA, Hell SW (1999) Subdiffraction resolution in far-field fluorescence microscopy. Opt Lett 24(14):954–956CrossRefGoogle Scholar
  5. 5.
    Birka H, Katrin IW, Stefan WH (2008) Stimulated emission depletion (STED) nanoscopy of a fluorescent protein-labeled organelle inside a living cell. Proc Natl Acad Sci USA 105(38):14271–14276CrossRefGoogle Scholar
  6. 6.
    Birka H, Willig KI, Wurm CA et al (2010) Stimulated emission depletion nanoscopy of living cells using SNAP-tag fusion proteins. Biophys J 98(1):158–163CrossRefGoogle Scholar
  7. 7.
    Mueller V, Ringemann C, Honigmann A et al (2011) STED nanoscopy reveals molecular details of cholesterol- and cytoskeleton-modulated lipid interactions in living cells. Biophys J 101(7):1651–1660CrossRefGoogle Scholar
  8. 8.
    Blom H, Brismar H (2014) STED microscopy: increased resolution for medical research? J Intern Med 276(6):560–578CrossRefGoogle Scholar
  9. 9.
    Willig KI, Rizzoli SO, Westphal V et al (2006) STED microscopy reveals that synaptotagmin remains clustered after synaptic vesicle exocytosis. Nature 440(7086):935–939CrossRefGoogle Scholar
  10. 10.
    Nägerl UV, Willig KI, Hein B et al (2008) Live-cell imaging of dendritic spines by STED microscopy. Proc Natl Acad Sci 105(48):18982–18987CrossRefGoogle Scholar
  11. 11.
    Kittel RJ, Wichmann C, Rasse TM et al (2006) Bruchpilot promotes active zone assembly, Ca < sup > 2 + </sup > channel clustering, and vesicle release. Science 312(5776):1051–1054CrossRefGoogle Scholar
  12. 12.
    van den Bogaart G, Meyenberg K, Risselada HJ et al (2011) Membrane protein sequestering by ionic protein-lipid interactions. Nature 479(7374):552–555CrossRefGoogle Scholar
  13. 13.
    Bailey B, Farkas DL, Taylor DL et al (1993) Enhancement of axial resolution in fluorescence microscopy by standing-wave excitation. Nature 366(6450):44–48CrossRefGoogle Scholar
  14. 14.
    Gustafsson MGL (2000) Surpassing the lateral resolution limit by a factor of two using structured illumination microscopy. Journal of Microscopy-Oxford 198:82–87CrossRefGoogle Scholar
  15. 15.
    Gustafsson MGL, Shao L, Carlton PM et al (2008) Three-dimensional resolution doubling in wide-field fluorescence microscopy by structured illumination. Biophys J 94(12):4957–4970CrossRefGoogle Scholar
  16. 16.
    Hirvonen LM, Smith TA (2011) Imaging on the nanoscale: super-resolution fluorescence microscopy. Aust J Chem 64(1):41–45CrossRefGoogle Scholar
  17. 17.
    Gustafsson MG (2005) Nonlinear structured-illumination microscopy: wide-field fluorescence imaging with theoretically unlimited resolution. Proc Natl Acad Sci USA 102(37):13081–13086CrossRefGoogle Scholar
  18. 18.
    Reto F, Lin S, Hesper R E et al (2012) Time-lapse two-color 3D imaging of live cells with doubled resolution using structured illumination. Proceedings of the National Academy of Science 109(14):5311–5315CrossRefGoogle Scholar
  19. 19.
    Fitzgibbon J, Bell K, King E et al (2010) Super-resolution imaging of plasmodesmata using three-dimensional structured illumination microscopy. Plant Physiol 153(4):1453–1463CrossRefGoogle Scholar
  20. 20.
    Whelan DR, Bell TDM (2015) Super-resolution single-molecule localization microscopy: tricks of the trade. J Phys Chem Lett 6(3):374–382CrossRefGoogle Scholar
  21. 21.
    Betzig E, Patterson GH, Sougrat R et al (2006) Imaging intracellular fluorescent proteins at nanometer resolution. Science 313(5793):1642–1645CrossRefGoogle Scholar
  22. 22.
    Hess ST, Girirajan TPK, Mason MD (2006) Ultra-high resolution imaging by fluorescence photoactivation localization microscopy. Biophys J 91(11):4258–4272CrossRefGoogle Scholar
  23. 23.
    Rust MJ, Bates M, Zhuang X (2006) Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat Methods 3(10):793–795CrossRefGoogle Scholar
  24. 24.
    Bates M, Huang B, Dempsey GT et al (2007) Multicolor super-resolution imaging with photo-switchable fluorescent probes. Science 317(5845):1749–1753CrossRefGoogle Scholar
  25. 25.
    Heilemann M, van de Linde S, Mukherjee A et al (2009) Super-resolution imaging with small organic fluorophores. Angew Chemie-Intern Ed 48(37):6903–6908CrossRefGoogle Scholar
  26. 26.
    Dani A, Huang B, Bergan J et al (2010) Superresolution imaging of chemical synapses in the brain. Neuron 68(5):843–856CrossRefGoogle Scholar
  27. 27.
    Matsuda A, Shao L, Boulanger J et al (2010) Condensed mitotic chromosome structure at nanometer resolution using PALM and EGFP—histones. PLoS ONE 5(9):12CrossRefGoogle Scholar
  28. 28.
    Veatch SL, Cicuta P, Sengupta P et al (2008) Critical fluctuations in plasma membrane vesicles. ACS Chem Biol 3(5):287–293CrossRefGoogle Scholar
  29. 29.
    Sengupta P, Jovanovic-Talisman T, Skoko D et al (2011) Probing protein heterogeneity in the plasma membrane using PALM and pair correlation analysis. Nat Methods 8(11):969–975CrossRefGoogle Scholar
  30. 30.
    Sengupta P, Jovanovic-Talisman T, Lippincott-Schwartz J (2013) Quantifying spatial organization in point-localization super resolution images using pair correlation analysis. Nat Protocols 8(2):345–354CrossRefGoogle Scholar
  31. 31.
    Ripley BD (1979) Tests of randomness for spatial point patterns. J R Stat Soc Ser B-Methodol 41(3):368–374Google Scholar
  32. 32.
    Lehmann M, Rocha S, Mangeat B et al. (2011) Quantitative multicolor super-resolution microscopy reveals tetherin HIV-1 interaction. Plos Pathog 7(12)Google Scholar
  33. 33.
    Malkusch S, Muranyi W, Müller B et al (2013) Single-molecule coordinate-based analysis of the morphology of HIV-1 assembly sites with near-molecular spatial resolution. Histochem Cell Biol 139(1):173–179CrossRefGoogle Scholar
  34. 34.
    Owen DM, Rentero C, Rossy J et al (2008) PALM imaging and cluster analysis of protein heterogeneity at the cell surface. J Biophotonics 3(7):446–454CrossRefGoogle Scholar
  35. 35.
    Gao J, Wang Y, Cai M et al (2015) Mechanistic insights into EGFR membrane clustering revealed by super-resolution imaging. Nanoscale 7(6):2511–2519CrossRefGoogle Scholar
  36. 36.
    Chen J, Gao J, Wu J et al (2015) Revealing the carbohydrate pattern on a cell surface by super-resolution imaging. Nanoscale 7(8):3373–3380CrossRefGoogle Scholar
  37. 37.
    Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387(6633):569–572CrossRefGoogle Scholar
  38. 38.
    Kusumi A, Koyama-Honda I, Suzuki K (2004) Molecular dynamics and interactions for creation of stimulation-induced stabilized rafts from small unstable steady-state rafts. Traffic 5(4):213–230CrossRefGoogle Scholar
  39. 39.
    Klymchenko AS, Kreder R (2014) Fluorescent probes for lipid rafts: from model membranes to living cells. Chem Biol 21(1):97–113CrossRefGoogle Scholar
  40. 40.
    Pike LJ (2006) Rafts defined: a report on the keystone symposium on lipid rafts and cell function. J Lipid Res 47(7):1597–1598CrossRefGoogle Scholar
  41. 41.
    Kellner RR, Baier CJ, Willig KI et al (2007) Nanoscale organization of nicotinic acetylcholine receptors revealed by stimulated emission depletion microscopy. Neuroscience 144(1):135–143CrossRefGoogle Scholar
  42. 42.
    Hess ST, Gould TJ, Gudheti MV et al (2007) Dynamic clustered distribution of hemagglutinin resolved at 40 nm in living cell membranes discriminates between raft theories. Proc Natl Acad Sci 104(44):17370–17375CrossRefGoogle Scholar
  43. 43.
    Takeda M, Leser GP, Russell CJ et al (2003) Influenza virus hemagglutinin concentrates in lipid raft microdomains for efficient viral fusion. Proc Natl Acad Sci 100(25):14610–14617CrossRefGoogle Scholar
  44. 44.
    Gudheti Manasa V, Curthoys Nikki M, Gould Travis J et al (2013) Actin mediates the nanoscale membrane organization of the clustered membrane protein influenza hemagglutinin. Biophys J 104(10):2182–2192CrossRefGoogle Scholar
  45. 45.
    Sengupta P, Jovanovic-Talisman T, Skoko D et al (2011) Probing protein heterogeneity in the plasma membrane using PALM and pair correlation analysis. Nat Meth 8(11):969–975CrossRefGoogle Scholar
  46. 46.
    Mizuno H, Abe M, Dedecker P et al (2011) Fluorescent probes for superresolution imaging of lipid domains on the plasma membrane. Chemical Science 2(8):1548–1553CrossRefGoogle Scholar
  47. 47.
    Owen DM, Rentero C, Rossy J et al (2010) PALM imaging and cluster analysis of protein heterogeneity at the cell surface. J Biophotonics 3(7):446–454CrossRefGoogle Scholar
  48. 48.
    Rossy J, Owen DM, Williamson DJ et al (2013) Conformational states of the kinase Lck regulate clustering in early T cell signaling. Nat Immunol 14(1):82–89CrossRefGoogle Scholar
  49. 49.
    Williamson DJ, Owen DM, Rossy J et al (2011) Pre-existing clusters of the adaptor Lat do not participate in early T cell signaling events. Nat Immunol 12(7):655–662CrossRefGoogle Scholar
  50. 50.
    Eggeling C, Ringemann C, Medda R et al (2009) Direct observation of the nanoscale dynamics of membrane lipids in a living cell. Nature 457(7233):1159–1162CrossRefGoogle Scholar
  51. 51.
    Gunewardene MS, Subach FV, Gould TJ et al (2011) Super-resolution imaging of multiple fluorescent proteins with highly overlapping emission spectra in living cells. Biophys J 101(6):1522–1528CrossRefGoogle Scholar
  52. 52.
    Wu J, Gao J, Qi M et al (2013) High-efficiency localization of Na+-K+ ATPases on the cytoplasmic side by direct stochastic optical reconstruction microscopy. Nanoscale 5(23):11582–11586CrossRefGoogle Scholar
  53. 53.
    Lillemeier BF, Mörtelmaier MA, Forstner MB et al (2010) TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nat Immunol 11(1):90–96CrossRefGoogle Scholar
  54. 54.
    Scarselli M, Annibale P, Radenovic A (2012) Cell type-specific β2-adrenergic receptor clusters identified using photoactivated localization microscopy are not lipid raft related, but depend on actin cytoskeleton integrity. J Biol Chem 287(20):16768–16780CrossRefGoogle Scholar
  55. 55.
    Shroff H, Galbraith CG, Galbraith JA et al (2007) Dual-color superresolution imaging of genetically expressed probes within individual adhesion complexes. Proc Natl Acad Sci 104(51):20308–20313CrossRefGoogle Scholar
  56. 56.
    Manley S, Gillette JM, Patterson GH et al. (2008) High-density mapping of single-molecule trajectories with photoactivated localization microscopy. Nature methods 5 (2):155–157Google Scholar
  57. 57.
    Lehmann M, Rocha S, Mangeat B et al (2011) Quantitative multicolor super-resolution microscopy reveals tetherin HIV-1 interaction. PLoS Pathog 7(12):e1002456CrossRefGoogle Scholar
  58. 58.
    Rabinovich GA, Toscano MA, Jackson SS et al (2007) Functions of cell surface galectin-glycoprotein lattices. Curr Opin Struct Biol 17(5):513–520CrossRefGoogle Scholar
  59. 59.
    Shroff H, Galbraith CG, Galbraith JA et al (2008) Live-cell photoactivated localization microscopy of nanoscale adhesion dynamics. Nat Methods 5(5):417–423CrossRefGoogle Scholar
  60. 60.
    Hein B, Willig KI, Wurm CA et al (2010) Stimulated emission depletion nanoscopy of living cells using SNAP-tag fusion proteins. Biophys J 98(1):158–163CrossRefGoogle Scholar
  61. 61.
    Wang Y, Gao J, Guo X et al (2014) Regulation of EGFR nanocluster formation by ionic protein-lipid interaction. Cell Res 24(8):959–976CrossRefGoogle Scholar
  62. 62.
    Jones SA, Shim SH, He J et al (2011) Fast, three-dimensional super-resolution imaging of live cells. Nat Methods 8(6):499–505CrossRefGoogle Scholar
  63. 63.
    Subach FV, Patterson GH, Renz M et al (2010) Bright monomeric photoactivatable red fluorescent protein for two-color super-resolution sptPALM of live cells. J Am Chem Soc 132(18):6481–6491CrossRefGoogle Scholar
  64. 64.
    Gudheti Manasa V, Curthoys Nikki M, Gould Travis J et al. Actin mediates the nanoscale membrane organization of the clustered membrane protein influenza hemagglutinin. Biophys J 104(10):2182–2192Google Scholar
  65. 65.
    D’Amico F, Skarmoutsou E (2008) Quantifying immunogold labelling in transmission electron microscopy. J Microsc 230(1):9–15CrossRefGoogle Scholar
  66. 66.
    Purbhoo MA, Liu H, Oddos S et al. (2010) Dynamics of subsynaptic vesicles and surface microclusters at the immunological synapse. Sci Signal 3(121):ra36–ra36Google Scholar
  67. 67.
    Williamson DJ, Owen DM, Rossy J et al (2011) Pre-existing clusters of the adaptor Lat do not participate in early T cell signaling events. Nat Immunol 12(7):655–662CrossRefGoogle Scholar
  68. 68.
    Sherman E, Barr V, Manley S et al (2011) Functional nanoscale organization of signaling molecules downstream of the T cell antigen receptor. Immunity 35(5):705–720CrossRefGoogle Scholar
  69. 69.
    Monks CR, Freiberg BA, Kupfer H et al (1998) Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395(6697):82–86CrossRefGoogle Scholar
  70. 70.
    McGill MA, McKinley RFA, Harris TJC (2009) Independent cadherin-catenin and Bazooka clusters interact to assemble adherens junctions. J Cell Biol 185(5):787–796CrossRefGoogle Scholar
  71. 71.
    Binh-An Truong Q, Mani M, Markova O et al (2013) Principles of E-Cadherin Supramolecular Organization In Vivo. Curr Biol 23(22):2197–2207CrossRefGoogle Scholar
  72. 72.
    Greenfield D, McEvoy AL, Shroff H et al (2009) Self-organization of the Escherichia coli chemotaxis network imaged with super-resolution light microscopy. PLoS Biol 7(6):e1000137CrossRefGoogle Scholar
  73. 73.
    Quang B-AT, Mani M, Markova O et al (2013) Principles of E-cadherin supramolecular organization in vivo. Curr Biol 23(22):2197–2207CrossRefGoogle Scholar
  74. 74.
    Goñi FM (2014) The basic structure and dynamics of cell membranes: An update of the Singer-Nicolson model. Biochim Biophys Acta 1838(6):1467–1476CrossRefGoogle Scholar
  75. 75.
    Nicolson GL (2014) The Fluid—mosaic model of membrane structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years. Biochim Biophys Acta 1838(6):1451–1466CrossRefGoogle Scholar
  76. 76.
    Truong_quang B, Lenne P (2014) Membrane microdomains: from seeing to understanding. Front Plant Sci 5:18Google Scholar
  77. 77.
    Li S, Zhang X, Wang W (2014) Selective aggregation of membrane proteins by membrane-mediated interactions. Sci China Chem 57(12):1683–1689CrossRefGoogle Scholar
  78. 78.
    Shan Y, Wang H (2015) The structure and function of cell membranes examined by atomic force microscopy and single-molecule force spectroscopy. Chem Soc Rev 44(11):3617–3638CrossRefGoogle Scholar
  79. 79.
    Zhao W, Tian Y, Cai M et al (2014) Studying the nucleated mammalian cell membrane by single molecule approaches. PLoS ONE 9(5):e91595CrossRefGoogle Scholar
  80. 80.
    Wang Y, Gao J, Guo X et al (2014) Regulation of EGFR nanocluster formation by ionic protein-lipid interaction. Cell Res 24(8):959–976CrossRefGoogle Scholar
  81. 81.
    Saka SK, Honigmann A, Eggeling C et al (2014) Multi-protein assemblies underlie the mesoscale organization of the plasma membrane. Nat commun 5:4509–4522Google Scholar
  82. 82.
    Letschert S, Göhler A, Franke C et al (2014) Super-resolution imaging of plasma membrane glycans. Angew Chem Int Ed 53(41):10921–10924CrossRefGoogle Scholar
  83. 83.
    Hang HC, Yu C, Kato DL et al (2003) A metabolic labeling approach toward proteomic analysis of mucin-type O-linked glycosylation. Proc Natl Acad Sci 100(25):14846–14851CrossRefGoogle Scholar
  84. 84.
    Boyce M, Carrico IS, Ganguli AS et al (2011) Metabolic cross-talk allows labeling of O-linked β-N-acetylglucosamine-modified proteins via the N-acetylgalactosamine salvage pathway. Proc Natl Acad Sci 108(8):3141–3146CrossRefGoogle Scholar
  85. 85.
    Stairs S, Neves AA, Stöckmann H et al (2013) Metabolic glycan imaging by isonitrile–tetrazine click chemistry. ChemBioChem 14(9):1063–1067CrossRefGoogle Scholar
  86. 86.
    Chen J, Gao J, Zhang M et al (2016) Systemic localization of seven major types of carbohydrates on cell membranes by dSTORM imaging. Sci Rep 6:30247CrossRefGoogle Scholar
  87. 87.
    Chen J, Gao J, Cai M et al (2016) Mechanistic insights into the distribution of carbohydrate clusters on cell membranes revealed by dSTORM imaging. Nanoscale 8(28):13611–13619CrossRefGoogle Scholar
  88. 88.
    Torreno-Pina JA, Castro BM, Manzo C et al (2014) Enhanced receptor–clathrin interactions induced by N-glycan–mediated membrane micropatterning. Proc Natl Acad Sci 111(30):11037–11042CrossRefGoogle Scholar
  89. 89.
    Lajoie P, Partridge EA, Guay G et al (2007) Plasma membrane domain organization regulates EGFR signaling in tumor cells. J Cell Biol 179(2):341–356CrossRefGoogle Scholar
  90. 90.
    Henriques R, Lelek M, Fornasiero EF et al (2010) QuickPALM: 3D real-time photoactivation nanoscopy image processing in ImageJ. Nat Methods 7(5):339–340CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.State Key Laboratory of Electroanalytical ChemistryChangchun Institute of Applied Chemistry, Chinese Academy of SciencesChangchunPeople’s Republic of China

Personalised recommendations