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.

  • Timeline
  • Published:

Spatial expression of the genome: the signal hypothesis at forty

Nature Reviews Molecular Cell Biology volume 12, pages 333–340 (2011)Cite this article

Subjects

Abstract

The signal hypothesis, formulated by Günter Blobel and David Sabatini in 1971, and elaborated by Blobel and his colleagues between 1975 and 1980, fundamentally expanded our view of cells by introducing the concept of topogenic signals. Cells were no longer just morphological entities with compartmentalized biochemical functions; they were now active participants in the creation and perpetuation of their own form and identity, the decoders of linear genetic information into three dimensions.

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: Genealogy of the signal hypothesis.
Figure 2: The key players.
Figure 3: Demonstrating a precursor–product relationship.

References

  1. Blobel, G. & Sabatini, D. D. in Biomembranes Vol. 2 (ed. Manson, L. A.) 193–195 (Plenum Publishing Corporation, New York, 1971).

    Book  Google Scholar 

  2. Blobel, G. & Dobberstein, B. Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma. J. Cell Biol. 67, 835–851 (1975).

    Article  CAS  Google Scholar 

  3. Blobel, G. & Dobberstein, B. Transfer of protein across membranes. II. Reconstitution of functional rough microsomes from heterologous components. J. Cell Biol. 67, 852–862 (1975).

    Article  CAS  Google Scholar 

  4. Devillers-Thiery, A., Kindt, T., Scheele, G. & Blobel, G. Homology in amino-terminal sequence of precursors to pancreatic secretory proteins. Proc. Natl Acad. Sci. USA 72, 5016–5020 (1975).

    Article  CAS  Google Scholar 

  5. Blobel, G. Intracellular protein topogenesis. Proc. Natl Acad. Sci. USA 77, 1496–1500 (1980).

    Article  CAS  Google Scholar 

  6. Dobberstein, B., Blobel, G. & Chua, N. H. In vitro synthesis and processing of a putative precursor for the small subunit of ribulose-1,5-bisphosphate carboxylase of Chlamydomonas reinhardtii. Proc. Natl Acad. Sci. USA 74, 1082–1085 (1977).

    Article  CAS  Google Scholar 

  7. Jackson, R. C. & Blobel, G. Post-translational cleavage of presecretory proteins with an extract of rough microsomes from dog pancreas containing signal peptidase activity. Proc. Natl Acad. Sci. USA 74, 5598–5602 (1977).

    Article  CAS  Google Scholar 

  8. Katz, F. N., Rothman, J. E., Lingappa, V. R., Blobel, G. & Lodish, H. F. Membrane assembly in vitro: synthesis, glycosylation, and asymmetric insertion of a transmembrane protein. Proc. Natl Acad. Sci. USA 74, 3278–3282 (1977).

    Article  CAS  Google Scholar 

  9. Goldman, B. M. & Blobel, G. Biogenesis of peroxisomes: intracellular site of synthesis of catalase and uricase. Proc. Natl Acad. Sci. USA 75, 5066–5070 (1978).

    Article  CAS  Google Scholar 

  10. Erickson, A. H. & Blobel, G. Early events in the biosynthesis of the lysosomal enzyme cathepsin D. J. Biol. Chem. 254, 11771–11774 (1979).

    CAS  PubMed  Google Scholar 

  11. Maccecchini, M. L., Rudin, Y., Blobel, G. & Schatz, G. Import of proteins into mitochondria: precursor forms of the extramitochondrially made F1-ATPase subunits in yeast. Proc. Natl Acad. Sci. USA 76, 343–347 (1979).

    Article  CAS  Google Scholar 

  12. Ahmed, S. et al. DNA zip codes control an ancient mechanism for gene targeting to the nuclear periphery. Nature Cell Biol. 12, 111–118 (2010).

    Article  CAS  Google Scholar 

  13. Bechtel, W. Discovering Cell Mechanisms: The Creation of Modern Cell Biology (Cambridge Univ. Press, Cambridge, UK, 2006).

    Google Scholar 

  14. Carnoy, J. B. La Biologie Cellulaire: Étude Comparée De La Cellule Dans Les Deux Règnes (J. Van In, Paris, 1884).

    Google Scholar 

  15. Porter, K. R., Claude, A. & Fullam, E. F. A study of tissue culture cells by electron microscopy: methods and preliminary observations. J. Exp. Med. 81, 233–246 (1945).

    Article  CAS  Google Scholar 

  16. Palade, G. E. & Porter, K. R. Studies on the endoplasmic reticulum. I. Its identification in cells in situ. J. Exp. Med. 100, 641–656 (1954).

    Article  CAS  Google Scholar 

  17. Palade, G. E. Studies on the endoplasmic reticulum. II. Simple dispositions in cells in situ. J. Biophys. Biochem. Cytol. 1, 567–582 (1955).

    Article  CAS  Google Scholar 

  18. Palade, G. E. A small particulate component of the cytoplasm. J. Biophys. Biochem. Cytol. 1, 59–68 (1955).

    Article  CAS  Google Scholar 

  19. Rheinberger, H.-J. Toward a History of Epistemic Things (Stanford Univ. Press, California, 1997).

    Google Scholar 

  20. Siekevitz, P. & Palade, G. E. A cytochemical study on the pancreas of the guinea pig. V. In vivo incorporation of leucine-1-C14 into the chymotrypsinogen of various cell fractions. J. Biophys. Biochem. Cytol. 7, 619–630 (1960).

    Article  CAS  Google Scholar 

  21. Gazzinelli, G. & Dickman, S. R. Incorporation of amino acids into protein by beef-pancreas ribosomes. Biochim. Biophys. Acta 61, 980–982 (1962).

    CAS  PubMed  Google Scholar 

  22. Redman, C. M., Siekevitz, P. & Palade, G. E. Synthesis and transfer of amylase in pigeon pancreatic micromosomes. J. Biol. Chem. 241, 1150–1158 (1966).

    CAS  PubMed  Google Scholar 

  23. Redman, C. M. & Sabatini, D. D. Vectorial discharge of peptides released by puromycin from attached ribosomes. Proc. Natl Acad. Sci. USA 56, 608–615 (1966).

    Article  CAS  Google Scholar 

  24. Sabatini, D. D., Tashiro, Y. & Palade, G. E. On the attachment of ribosomes to microsomal membranes. J. Mol. Biol. 19, 503–524 (1966).

    Article  CAS  Google Scholar 

  25. Sabatini, D. D. In awe of subcellular complexity: 50 years of trespassing boundaries within the cell. Annu. Rev. Cell Dev. Biol. 21, 1–33 (2005).

    Article  CAS  Google Scholar 

  26. Harrison, T. M. Messenger Ribonucleic Acid and Polysomes in a Mouse Plasmacytoma. Thesis, Univ. Cambridge (1972).

    Google Scholar 

  27. Milstein, C., Brownlee, G. G., Harrison, T. M. & Mathews, M. B. A possible precursor of immunoglobulin light chains. Nature New Biol. 239, 117–120 (1972).

    Article  CAS  Google Scholar 

  28. Blobel, G. & Sabatini, D. D. Controlled proteolysis of nascent polypeptides in rat liver cell fractions. I. Location of the polypeptides within ribosomes. J. Cell Biol. 45, 130–145 (1970).

    Article  CAS  Google Scholar 

  29. Sabatini, D. D. & Blobel, G. Controlled proteolysis of nascent polypeptides in rat liver cell fractions. II. Location of the polypeptides in rough microsomes. J. Cell Biol. 45, 146–157 (1970).

    Article  CAS  Google Scholar 

  30. Lingappa, V. R., Devillers-Thiery, A. & Blobel, G. Nascent prehormones are intermediates in the biosynthesis of authentic bovine pituitary growth hormone and prolactin. Proc. Natl Acad. Sci. USA 74, 2432–2436 (1977).

    Article  CAS  Google Scholar 

  31. Shields, D. & Blobel, G. Cell-free synthesis of fish preproinsulin, and processing by heterologous mammalian microsomal membranes. Proc. Natl Acad. Sci. USA 74, 2059–2063 (1977).

    Article  CAS  Google Scholar 

  32. Chang, C. N., Blobel, G. & Model, P. Detection of prokaryotic signal peptidase in an Escherichia coli membrane fraction: endoproteolytic cleavage of nascent f1 pre-coat protein. Proc. Natl Acad. Sci. USA 75, 361–365 (1978).

    Article  CAS  Google Scholar 

  33. Walter, P., Jackson, R. C., Marcus, M. M., Lingappa, V. R. & Blobel, G. Tryptic dissection and reconstitution of translocation activity for nascent presecretory proteins across microsomal membranes. Proc. Natl Acad. Sci. USA 76, 1795–1799 (1979).

    Article  CAS  Google Scholar 

  34. Walter, P. & Blobel, G. Purification of a membrane-associated protein complex required for protein translocation across the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 77, 7112–7116 (1980).

    Article  CAS  Google Scholar 

  35. Walter, P. & Blobel, G. Translocation of proteins across the endoplasmic reticulum III. Signal recognition protein (SRP) causes signal sequence-dependent and site-specific arrest of chain elongation that is released by microsomal membranes. J. Cell Biol. 91, 557–561 (1981).

    Article  CAS  Google Scholar 

  36. Walter, P. & Blobel, G. Translocation of proteins across the endoplasmic reticulum. II. Signal recognition protein (SRP) mediates the selective binding to microsomal membranes of in-vitro-assembled polysomes synthesizing secretory protein. J. Cell Biol. 91, 551–556 (1981).

    Article  CAS  Google Scholar 

  37. Walter, P., Ibrahimi, I. & Blobel, G. Translocation of proteins across the endoplasmic reticulum. I. Signal recognition protein (SRP) binds to in-vitro-assembled polysomes synthesizing secretory protein. J. Cell Biol. 91, 545–550 (1981).

    Article  CAS  Google Scholar 

  38. Gilmore, R., Blobel, G. & Walter, P. Protein translocation across the endoplasmic reticulum. I. Detection in the microsomal membrane of a receptor for the signal recognition particle. J. Cell Biol. 95, 463–469 (1982).

    Article  CAS  Google Scholar 

  39. Gilmore, R., Walter, P. & Blobel, G. Protein translocation across the endoplasmic reticulum. II. Isolation and characterization of the signal recognition particle receptor. J. Cell Biol. 95, 470–477 (1982).

    Article  CAS  Google Scholar 

  40. Meyer, D. I., Krause, E. & Dobberstein, B. Secretory protein translocation across membranes-the role of the 'docking protein'. Nature 297, 647–650 (1982).

    Article  CAS  Google Scholar 

  41. Meyer, D. I., Louvard, D. & Dobberstein, B. Characterization of molecules involved in protein translocation using a specific antibody. J. Cell Biol. 92, 579–583 (1982).

    Article  CAS  Google Scholar 

  42. Walter, P. & Blobel, G. Signal recognition particle contains a 7S RNA essential for protein translocation across the endoplasmic reticulum. Nature 299, 691–698 (1982).

    Article  CAS  Google Scholar 

  43. Walter, P. & Blobel, G. Subcellular distribution of signal recognition particle and 7SL-RNA determined with polypeptide-specific antibodies and complementary DNA probe. J. Cell Biol. 97, 1693–1699 (1983).

    Article  CAS  Google Scholar 

  44. Walter, P. & Blobel, G. Disassembly and reconstitution of signal recognition particle. Cell 34, 525–533 (1983).

    Article  CAS  Google Scholar 

  45. Evans, E. A., Gilmore, R. & Blobel, G. Purification of microsomal signal peptidase as a complex. Proc. Natl Acad. Sci. USA 83, 581–585 (1986).

    Article  CAS  Google Scholar 

  46. Schatz, G. & Dobberstein, B. Common principles of protein translocation across membranes. Science 271, 1519–1526 (1996).

    Article  CAS  Google Scholar 

  47. Harmey, M. A., Hallermayer, G., Korb, H. & Neupert, W. Transport of cytoplasmically synthesized proteins into the mitochondria in a cell free system from Neurospora crassa. Eur. J. Biochem. 81, 533–544 (1977).

    Article  CAS  Google Scholar 

  48. Chua, N. H. & Schmidt, G. W. Post-translational transport into intact chloroplasts of a precursor to the small subunit of ribulose-1,5-bisphosphate carboxylase. Proc. Natl Acad. Sci. USA 75, 6110–6114 (1978).

    Article  CAS  Google Scholar 

  49. Highfield, P. E. & Ellis, R. J. Synthesis and transport of the small subunit of chloroplast ribulose bisphosphate carboxylase. Nature 271, 420–424 (1978).

    Article  CAS  Google Scholar 

  50. Randall, L. L., Hardy, S. J. & Josefsson, L. G. Precursors of three exported proteins in Escherichia coli. Proc. Natl Acad. Sci. USA 75, 1209–1212 (1978).

    Article  CAS  Google Scholar 

  51. Ito, K., Mandel, G. & Wickner, W. Soluble precursor of an integral membrane protein: synthesis of procoat protein in Escherichia coli infected with bacteriophage M13. Proc. Natl Acad. Sci. USA 76, 1199–1203 (1979).

    Article  CAS  Google Scholar 

  52. Date, T. & Wickner, W. T. Procoat, the precursor of M13 coat protein, inserts post-translationally into the membrane of cells infected by wild-type virus. J. Virol. 37, 1087–1089 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Josefsson, L. G. & Randall, L. L. Processing in vivo of precursor maltose-binding protein in Escherichia coli occurs post-translationally as well as co-translationally. J. Biol. Chem. 256, 2504–2507 (1981).

    CAS  PubMed  Google Scholar 

  54. Date, T., Goodman, J. M. & Wickner, W. T. Procoat, the precursor of M13 coat protein, requires an electrochemical potential for membrane insertion. Proc. Natl Acad. Sci. USA 77, 4669–4673 (1980).

    Article  CAS  Google Scholar 

  55. Deshaies, R. J. & Schekman, R. A yeast mutant defective at an early stage in import of secretory protein precursors into the endoplasmic reticulum. J. Cell Biol. 105, 633–645 (1987).

    Article  CAS  Google Scholar 

  56. Simon, S. M. & Blobel, G. A protein-conducting channel in the endoplasmic reticulum. Cell 65, 371–380 (1991).

    Article  CAS  Google Scholar 

  57. Gorlich, D., Prehn, S., Hartmann, E., Kalies, K. U. & Rapoport, T. A. A mammalian homolog of SEC61p and SECYp is associated with ribosomes and nascent polypeptides during translocation. Cell 71, 489–503, (1992).

    Article  CAS  Google Scholar 

  58. Crowley, K. S., Liao, S., Worrell, V. E., Reinhart, G. D. & Johnson, A. E. Secretory proteins move through the endoplasmic reticulum membrane via an aqueous, gated pore. Cell 78, 461–471 (1994).

    Article  CAS  Google Scholar 

  59. Gorlich, D. & Rapoport, T. A. Protein translocation into proteoliposomes reconstituted from purified components of the endoplasmic reticulum membrane. Cell 75, 615–630 (1993).

    Article  CAS  Google Scholar 

  60. Nakai, K. Protein sorting signals and prediction of subcellular localization. Adv. Protein Chem. 54, 277–344 (2000).

    Article  CAS  Google Scholar 

  61. Nakai, K. & Horton, P. Computational prediction of subcellular localization. Methods Mol. Biol. 390, 429–466 (2007).

    Article  CAS  Google Scholar 

  62. Kerr, S. C. & Corbett, A. H. Should INO stay or should INO go: a DNA “zip code” mediates gene retention at the nuclear pore. Mol. Cell 40, 3–5 (2010).

    Article  CAS  Google Scholar 

  63. Rothman, J. E. & Lodish, H. F. Synchronised transmembrane insertion and glycosylation of a nascent membrane protein. Nature 269, 775–780 (1977).

    Article  CAS  Google Scholar 

  64. Goldman, B. M. & Blobel, G. In vitro biosynthesis, core glycosylation, and membrane integration of opsin. J. Cell Biol. 90, 236–242 (1981).

    Article  CAS  Google Scholar 

  65. Audigier, Y., Friedlander, M. & Blobel, G. Multiple topogenic sequences in bovine opsin. Proc. Natl Acad. Sci. USA 84, 5783–5787 (1987).

    Article  CAS  Google Scholar 

  66. Kevles, D. J. & Hood, L. The Code of Codes: Scientific and Social Issues of the Human Genome Project (Harvard Univ. Press, Massachusetts,1992).

    Google Scholar 

  67. Inouye, H. & Beckwith, J. Synthesis and processing of an Escherichia coli alkaline phosphatase precursor in vitro. Proc. Natl Acad. Sci. USA 74, 1440–1444 (1977).

    Article  CAS  Google Scholar 

  68. Silhavy, T. J., Shuman, H. A., Beckwith, J. & Schwartz, M. Use of gene fusions to study outer membrane protein localization in Escherichia coli. Proc. Natl Acad. Sci. USA 74, 5411–5415 (1977).

    Article  CAS  Google Scholar 

  69. Emr, S. D., Hanley-Way, S. & Silhavy, T. J. Suppressor mutations that restore export of a protein with a defective signal sequence. Cell 23, 79–88 (1981).

    Article  CAS  Google Scholar 

  70. Kalderon, D., Roberts, B. L., Richardson, W. D. & Smith, A. E. A short amino acid sequence able to specify nuclear location. Cell 39, 499–509 (1984).

    Article  CAS  Google Scholar 

  71. Friedlander, M. & Blobel, G. Bovine opsin has more than one signal sequence. Nature 318, 338–343 (1985).

    Article  CAS  Google Scholar 

  72. Wiedmann, M., Kurzchalia, T. V., Bielka, H. & Rapoport, T. A. Direct probing of the interaction between the signal sequence of nascent preprolactin and the signal recognition particle by specific cross-linking. J. Cell Biol. 104, 201–208 (1987).

    Article  CAS  Google Scholar 

  73. Gould, S. J., Keller, G. A., Hosken, N., Wilkinson, J. & Subramani, S. A conserved tripeptide sorts proteins to peroxisomes. J. Cell Biol. 108, 1657–1664 (1989).

    Article  CAS  Google Scholar 

  74. Casanova, J. E., Apodaca, G. & Mostov, K. E. An autonomous signal for basolateral sorting in the cytoplasmic domain of the polymeric immunoglobulin receptor. Cell 66, 65–75 (1991).

    Article  CAS  Google Scholar 

  75. Beckmann, R. et al. Alignment of conduits for the nascent polypeptide chain in the ribosome-Sec61 complex. Science 278, 2123–2126 (1997).

    Article  CAS  Google Scholar 

  76. von Heijne, G. Models for transmembrane translocation of proteins. Biochem. Soc. Symp. 46, 259–273 (1981).

    CAS  Google Scholar 

  77. Van den Berg, B. et al. X-ray structure of a protein-conducting channel. Nature 427, 36–44 (2004).

    Article  CAS  Google Scholar 

  78. Becker, T. et al. Structure of monomeric yeast and mammalian Sec61 complexes interacting with the translating ribosome. Science 326, 1369–1373 (2009).

    Article  CAS  Google Scholar 

  79. Rapoport, T. A. Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membrane. Nature 450, 663–669 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The author is grateful for support of this project from the US National Library of Medicine and the US National Institutes of Health (NIH), to W. Green, N. Matlin, A. Engelberg and J. Collier for review of the manuscript, and to members of the Committee on Conceptual and Historical Studies of Science at the University of Chicago, Illinois, USA, for stimulating discussions. Photographs in figure 2 were provided by the Laboratory of Molecular Biology at the University of Cambridge, UK, and by N. Dwyer, NIH, USA. The author thanks the many individuals who have provided information for this article through interviews.

Author information

Authors and Affiliations

  1. Karl S. Matlin is at Department of Surgery, The University of Chicago, 5841 South Maryland Avenue, MC 5032, SBRI J557, Chicago, Illinois 60637-1470, USA. kmatlin@uchicago.edu,

    Karl S. Matlin

Authors
  1. Karl S. Matlin
    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

DATABASES

PubMed

FURTHER INFORMATION

Karl S. Matlin's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matlin, K. Spatial expression of the genome: the signal hypothesis at forty. Nat Rev Mol Cell Biol 12, 333–340 (2011). https://doi.org/10.1038/nrm3105

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3105

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