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.

  • Innovation
  • Published:

A visual approach to proteomics

Nature Reviews Molecular Cell Biology volume 7, pages 225–230 (2006)Cite this article

Abstract

Cryo-electron tomography is an emerging imaging technique that has unique potential for molecular cell biology. At the present resolution of 4–5 nm, large supramolecular structures can be studied in unperturbed cellular environments and, in the future, it will become possible to map molecular landscapes inside cells in a more comprehensive manner. 'Visual proteomics' aims to complement and extend mass-spectrometry-based inventories, and to provide a quantitative description of the macromolecular interactions that underlie cellular functions.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Principles of electron tomography.
Figure 2: The advantage of tomographic imaging for visualizing the architecture of cryosectioned eukaryotic cells.
Figure 3: From proteomics inventories to a cellular protein atlas.

Similar content being viewed by others

References

  1. Frey-Wyssling, A. The submicroscopic structure of the cytoplasm. J. R. Microsc. Soc. 60, 128–139 (1940).

    Article  CAS  Google Scholar 

  2. Frey-Wyssling, A. Submicroscopic Morphology of Protoplasm and its Derivatives (Elsevier, New York, 1948).

    Google Scholar 

  3. Afzelius, B. A. & Maunsbach, A. B. Biological ultrastructure research; the first 50 years. Tissue Cell 36, 83–94 (2004).

    Article  CAS  Google Scholar 

  4. Ball, P. Portrait of a molecule. Nature 421, 421–422 (2003).

    Article  Google Scholar 

  5. Baumeister, W. From proteomic inventory to architecture. FEBS Lett. 579, 933–937 (2005).

    Article  CAS  Google Scholar 

  6. Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003).

    Article  CAS  Google Scholar 

  7. Huh, W.-K. et al. Global analysis of protein localization in budding yeast. Nature 425, 686–691 (2003).

    Article  CAS  Google Scholar 

  8. Phizicky, E., Bastiaens, P. I. H., Zhu, H., Snyder, M. & Fields, S. Protein analysis on a proteomic scale. Nature 422, 208–215 (2003).

    Article  CAS  Google Scholar 

  9. Hell, S. W., Dyba, M. & Jakobs, S. Concepts for nanoscale resolution in fluorescence microscopy. Curr. Opin. Neurobiol. 14, 599–609 (2004).

    Article  CAS  Google Scholar 

  10. Miyawaki, A., Sawano, A. & Kogure, T. Lighting up cells: labelling proteins with fluorophores. Nature Cell Biol. 5, S1–S7 (2003).

    Article  Google Scholar 

  11. Grunewald, K., Medalia, O., Gross, A., Steven, A. C. & Baumeister, W. Prospects of electron cryotomography to visualize macromolecular complexes inside cellular compartments: implications of crowding. Biophys. Chem. 100, 577–591 (2003).

    Article  CAS  Google Scholar 

  12. Koster, A. J. et al. Perspectives of molecular and cellular electron tomography. J. Struct. Biol. 120, 276–308 (1997).

    Article  CAS  Google Scholar 

  13. Grimm, R. et al. Energy filtered electron tomography of ice-embedded actin and vesicles. Biophys. J. 72, 482–489 (1997).

    Article  CAS  Google Scholar 

  14. Grimm, R. et al. Electron tomography of ice-embedded prokaryotic cells. Biophys. J. 74, 1031–1042 (1998).

    Article  CAS  Google Scholar 

  15. Dierksen, K. et al. Three-dimensional structure of lipid vesicles embedded in vitreous ice and investigated by automated electron tomography. Biophys. J. 68, 1416–1422 (1995).

    Article  CAS  Google Scholar 

  16. Wolosewick, J. J. & Porter, K. R. Stereo high-voltage electron-microscopy of whole cells of human diploid line, WI-38. Am. J. Anat. 147, 303–323 (1976).

    Article  CAS  Google Scholar 

  17. Heuser, J. Whatever happened to the 'microtrabecular concept'? Biol. Cell 94, 561–596 (2003).

    Article  Google Scholar 

  18. Matricardi, V. R., Moretz, R. C. & Parsons, D. F. Electron-diffraction of wet proteins — catalase. Science 177, 268–270 (1972).

    Article  CAS  Google Scholar 

  19. Parsons, D. F. Structure of wet specimens in electron-microscopy. Science 186, 407–414 (1974).

    Article  CAS  Google Scholar 

  20. Taylor, K. A. & Glaeser, R. M. Electron-diffraction of frozen, hydrated protein crystals. Science 186, 1036–1037 (1974).

    Article  CAS  Google Scholar 

  21. Burton, E. F. & Oliver, W. F. The crystal structure of ice at low temperature. Proc. R. Soc. Lond. A 153, 166–172 (1935).

    Article  CAS  Google Scholar 

  22. Mayer, E. & Brüggeller, P. Complete vitrification in pure liquid water and dilute aqueous solutions. Nature 288, 569–571 (1980).

    Article  Google Scholar 

  23. Dubochet, J. & McDowall, A. W. Vitrification of pure water for electron microscopy. J. Microsc. 124, RP3–RP4 (1981).

    Article  Google Scholar 

  24. Steven, A. C. & Aebi, U. The next ice age: cryo-electron tomography of intact cells. Trends Cell Biol. 13, 107–110 (2003).

    Article  CAS  Google Scholar 

  25. Dubochet, J. et al. Cryo-electron microscopy of vitrified specimens. Q. Rev. Biophys. 21, 129–228 (1988).

    Article  CAS  Google Scholar 

  26. McIntosh, J. R., Nicastro, D. & Mastronarde, D. New views of cells in 3D: an introduction to electron tomography. Trends Cell Biol. 15, 43–51 (2005).

    Article  CAS  Google Scholar 

  27. Marsh, B. J. Lessons from tomographic studies of the mammalian Golgi. Biochim. Biophys. Acta 1744, 273–292 (2005).

    Article  CAS  Google Scholar 

  28. Nicastro, D., McIntosh, J. R. & Baumeister, W. 3D structure of eukaryotic flagella in a quiescent state revealed by cryo-electron tomography. Proc. Natl Acad. Sci. USA 102, 15889–15894 (2005).

    Article  CAS  Google Scholar 

  29. Zhang, P. et al. Direct visualization of receptor arrays in frozen-hydrated sections and plunge-frozen specimens of E. coli engineered to overproduce the chemotaxis receptor Tsr. J. Microsc. 216, 76–83 (2004).

    Article  CAS  Google Scholar 

  30. Al-Amoudi, A. et al. Cryo-electron microscopy of vitreous sections. EMBO J. 23, 3583–3588 (2004).

    Article  CAS  Google Scholar 

  31. Medalia, O. et al. Macromolecular architecture in eukaryotic cells visualized by cryoelectron tomography. Science 298, 1209–1213 (2002).

    Article  CAS  Google Scholar 

  32. Grunewald, K. et al. Three-dimensional structure of herpes simplex virus from cryo-electron tomography. Science 302, 1396–1398 (2003).

    Article  Google Scholar 

  33. Beck, M. et al. Nuclear pore complex structure and dynamics revealed by cryoelectron tomography. Science 306, 1387–1390 (2004).

    Article  CAS  Google Scholar 

  34. Mercogliano, C. P. & DeRosier, D. J. Gold nanocluster formation using metallothionein: mass spectrometry and electron microscopy. J. Mol. Biol. 355, 211–223 (2006).

    Article  CAS  Google Scholar 

  35. Bohm, J. et al. Toward detecting and identifying macromolecules in a cellular context: template matching applied to electron tomograms. Proc. Natl Acad. Sci. USA 97, 14245–14250 (2000).

    Article  CAS  Google Scholar 

  36. Frangakis, A. S. et al. Identification of macromolecular complexes in cryoelectron tomograms of phantom cells. Proc. Natl Acad. Sci. USA 99, 14153–14158 (2002).

    Article  CAS  Google Scholar 

  37. Frangakis, A. S. & Forster, F. Computational exploration of structural information from cryo-electron tomograms. Curr. Opin. Struct. Biol. 14, 325–331 (2004).

    Article  CAS  Google Scholar 

  38. Sali, A., Glaeser, R., Earnest, T. & Baumeister, W. From words to literature in structural proteomics. Nature 422, 216–225 (2003).

    Article  CAS  Google Scholar 

  39. Aloy, P. & Russell, R. B. Structure-based systems biology: a zoom lens for the cell. FEBS Lett. 579, 1854–1858 (2005).

    Article  CAS  Google Scholar 

  40. Aebersold, R. & Mann, M. Mass spectrometry-based proteomics. Nature 422, 198–207 (2003).

    Article  CAS  Google Scholar 

  41. Suloway, C. et al. Automated molecular microscopy: the new Leginon system. J. Struct. Biol. 151, 41–60 (2005).

    Article  CAS  Google Scholar 

  42. Glaeser, R. M. Historical background: why is it important to improve automated particle selection methods? J. Struct. Biol. 145, 15–18 (2004).

    Article  CAS  Google Scholar 

  43. Radon, J. Über die Bestimmung von Funktionen durch ihre Integralwerte längs gewisser Mannigfaltigkeiten. Berichte über die Verhandlungen der Königlich Sächsischen Gesellschaft der Wissenschaften zu Leipzig. Math. Phys. Klasse 69, 262–277 (1917) (in German).

    Google Scholar 

  44. Bracewell, R. N. & Riddle, A. C. Inversion of fan-beam scans in radio astronomy. Astrophys. J. 150, 427–434 (1967).

    Article  Google Scholar 

  45. DeRosier, D. J. & Klug, A. Reconstruction of three dimensional structures from electron micrographs. Nature 217, 130–134 (1968).

    Article  CAS  Google Scholar 

  46. Unwin, P. N. T. & Henderson, R. Molecular-structure determination by electron-microscopy of unstained crystalline specimens. J. Mol. Biol. 94, 425–440 (1975).

    Article  CAS  Google Scholar 

  47. Henderson, R. & Unwin, P. N. T. Three-dimensional model of purple membrane obtained by electron-microscopy. Nature 257, 28–32 (1975).

    Article  CAS  Google Scholar 

  48. Frank, J. Single-particle imaging of macromolecules by cryo-electron microscopy. Annu. Rev. Biophys. Biomol. Struct. 31, 303–319 (2002).

    Article  CAS  Google Scholar 

  49. Hart, R. G. Electron microscopy of unstained material: the polytropic montage. Science 159, 1464–1467 (1968).

    Article  CAS  Google Scholar 

  50. Lücić, V., Foerster, F. & Baumeister, W. Structural studies by electron tomography: from cells to molecules. Annu. Rev. Biophys. Biomol. Struct. 74, 833–865 (2005).

    Google Scholar 

  51. Leis, A. et al. Cryo-electron tomography and fluorescence microscopy of unicellular algae in vitreous cryosections. Microsc. Microanal. 11 (Suppl. 2), 330–331 (2005).

    Google Scholar 

  52. Ruepp, A. et al. The genome sequence of the thermoacidophilic scavenger Thermoplasma acidophilum. Nature 407, 508–513 (2000).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. the Department of Structural Biology, Max Planck Institute for Biochemistry, Am Klopferspitz 18, Martinsried, D-82152, Germany

    Stephan Nickell, Christine Kofler, Andrew P. Leis & Wolfgang Baumeister

Authors
  1. Stephan Nickell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine Kofler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew P. Leis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wolfgang Baumeister
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wolfgang Baumeister.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

3D electron microscopy at Utrecht University

Cryo-electron tomography of Dictyostelium discoideum (movie)

High Resolution Electron Microscopy at the National Cancer Institute

Institute for Molecular Bioscience, The University of Queensland, Australia

Max-Planck-Institute for Biochemistry, Department of Molecular Structural Biology

Molecular Art | Molecular Science, Home of David S. Goodsell

Resource for the Visualization of Biological Complexity, Wadsworth Center

The Boulder Laboratory for 3-D Electron Microscopy of Cells

The Jensen Laboratory for Cryo-Electron Microscopy

The Three Dimensional Electron Microscopy (3D-EM) Network of Excellence

University of California San Francisco, Macromolecular Structure Group

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nickell, S., Kofler, C., Leis, A. et al. A visual approach to proteomics. Nat Rev Mol Cell Biol 7, 225–230 (2006). https://doi.org/10.1038/nrm1861

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1861

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