Skip to main content

Thank you for visiting 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.

Oxygen content of transmembrane proteins over macroevolutionary time scales

This article has been updated


We observe that the time of appearance of cellular compartmentalization correlates with atmospheric oxygen concentration. To explore this correlation, we predict and characterize the topology of all transmembrane proteins in 19 taxa and correlate differences in topology with historical atmospheric oxygen concentrations. Here we show that transmembrane proteins, individually and as a group, were probably selectively excluding oxygen in ancient ancestral taxa, and that this constraint decreased over time when atmospheric oxygen levels rose. As this constraint decreased, the size and number of communication-related transmembrane proteins increased. We suggest the hypothesis that atmospheric oxygen concentrations affected the timing of the evolution of cellular compartmentalization by constraining the size of domains necessary for communication across membranes.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Figure 1: Oxygen content density functions on full proteome, transmembrane and non-transmembrane protein sets.
Figure 2: Ternary diagrams of compositional data for transmembrane, extracellular and intracellular domains for the entire predicted transmembrane protein set.
Figure 3: Mean domain length versus time of appearance of class.
Figure 4: Inside, outside and transmembrane domain oxygen content versus time of appearance of class.
Figure 5: Mean proteome oxygen content.

Change history

  • 31 January 2008

    The institute in address 2 should have been listed as 'Institute of Molecular Biology and Bioinformatics' and not 'Institute of Molecular Biology and Biochemistry'. This was corrected in the HTML on 31 January 2008.


  1. Han, T. M. & Runnegar, B. Macroscopic eukaryotic algae from the 2.1-billion-year-old Negaunee iron-formation, Michigan. Science 257, 232–235 (1992)

    Article  ADS  CAS  Google Scholar 

  2. Schopf, J. W. & Klein, C. (eds) The Proterozoic Biosphere: a Multidisciplinary Study (Cambridge Univ. Press, New York, 1992)

    Book  Google Scholar 

  3. Knoll, A. H. Proterozoic and early Cambrian protists: evidence for accelerating evolutionary tempo. Proc. Natl Acad. Sci. USA. 91, 6743–6750 (1994)

    Article  ADS  CAS  Google Scholar 

  4. Ren, Q. & Paulsen, Q. T. Comparative analyses of fundamental differences in membrane transport capabilities in prokaryotes and eukaryotes. PLoS Comp.Biol. 1, e27 (2005)

    Article  ADS  Google Scholar 

  5. Kyte, J. & Doolittle, R. F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 157, 105–132 (1982)

    Article  CAS  Google Scholar 

  6. von Heijne, G. Net N–C charge imbalance may be important for signal sequence function in bacteria. J. Mol. Biol. 192, 287–290 (1986)

    Article  CAS  Google Scholar 

  7. Sipos, L. & von Heijne, G. Predicting the topology of eukaryotic membrane proteins. Eur. J. Biochem. 213, 1333–1340 (1993)

    Article  CAS  Google Scholar 

  8. von Heijne, G. Membrane protein structure prediction. Hydrophobicity analysis and the positive-inside rules. J. Mol. Biol. 225, 487–494 (1992)

    Article  CAS  Google Scholar 

  9. Tourasse, N. J. & Li, W. H. Selective constraints, amino acid composition, and the rate of protein evolution. Mol. Biol. Evol. 17, 656–664 (2000)

    Article  CAS  Google Scholar 

  10. Mazel, D. & Marlière, P. Adaptive eradication of methionine and cysteine from cyanobacterial light-harvesting proteins. Nature 341, 245–248 (1989)

    Article  ADS  CAS  Google Scholar 

  11. Baudouin-Cornu, P., Surdin-Kerjan, Y., Marlière, P. & Thomas, D. Molecular evolution of protein atomic composition. Science 293, 297–300 (2001)

    Article  CAS  Google Scholar 

  12. Baudouin-Cornu, P., Schuerer, K., Marlière, P. & Thomas, D. Intimate evolution of Proteins. Proteome atomic content correlates with genome base composition. J. Biol. Chem. 279, 5421–5428 (2004)

    Article  CAS  Google Scholar 

  13. Elser, J. J., Fagan, W. F., Subramanian, S. & Kumar, S. Signatures of ecological resource availability in the animal and plant proteomes. Mol. Biol. Evol. 23, 1946–1951 (2006)

    Article  CAS  Google Scholar 

  14. Elser, J. J. et al. Biological stoichiometry from genes to ecosystems. Ecol. Lett. 3, 540–550 (2000)

    Article  Google Scholar 

  15. Kay, A. D. et al. Toward a stoichiometric framework for evolutionary biology. Oikos 109, 6–17 (2005)

    Article  Google Scholar 

  16. Hasenfuss, I. A possible evolutionary pathway to insect flight starting from lepismatid organization. J. Zool. Syst. Evol. Res. 40, 65–81 (2002)

    Article  Google Scholar 

  17. Elser, J. J., Watts, J., Schampel, J. H. & Farmer, J. Early Cambrian food webs on a trophic knife-edge? A hypothesis and preliminary data from a modern stromatolite-based ecosystem. Ecol. Lett. 9, 295–303 (2006)

    Article  Google Scholar 

  18. Knoll, A. H. Life on a Young Planet: The First Three Billion Years of Evolution on Earth (Princeton Univ. Press, Princeton and Oxford, 2003)

    Google Scholar 

  19. Berner, R. A. Atmospheric oxygen over Phanerozoic time. Proc. Natl Acad. Sci. USA. 96, 10955–10957 (1999)

    Article  ADS  CAS  Google Scholar 

  20. Krogh, A., Larsson, B., von Heijne, G. & Sonnhammer, E. L. Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J. Mol. Biol. 305, 567–580 (2001)

    Article  CAS  Google Scholar 

  21. Stevens, T. J. & Arkin, I. T. Do more complex organisms have a greater proportion of membrane proteins in their genomes?. Proteins 39, 417–420 (2000)

    Article  CAS  Google Scholar 

  22. Wallin, E. & von Heijne, G. Genome-wide analysis of integral membrane proteins from eubacterial, archaean, and eukaryotic organisms. Protein Sci. 7, 1029–1038 (1998)

    Article  CAS  Google Scholar 

  23. Liò, P. & Vannucci, M. Investigating the evolution and structure of chemokine receptors. Gene 317, 29–37 (2003)

    Article  Google Scholar 

  24. Aitchison, J. The Statistical Analysis of Compositional Data 154–155 (Chapman and Hall, London, 1986)

    Book  Google Scholar 

  25. Tamames, J., Ouzounis, C., Sander, C. & Valencia, A. Genomes with distinct function composition. FEBS Lett. 389, 96–101 (1996)

    Article  CAS  Google Scholar 

  26. Liu, J. & Rost, B. Comparing function and structure between entire proteomes. Protein Sci. 10, 1970–1979 (2001)

    Article  CAS  Google Scholar 

  27. Akashi, H. & Gojobori, T. Metabolic efficiency and amino acid composition in the proteomes of Escherichia coli and Bacillus subtilis.. Proc. Natl Acad. Sci. USA. 99, 3695–3700 (2002)

    Article  ADS  CAS  Google Scholar 

  28. Raymond, J. & Segre, D. The effect of oxygen on biochemical networks and the evolution of complex life. Science 311, 1764–1767 (2006)

    Article  ADS  CAS  Google Scholar 

  29. Hedges, S. B., Blair, J. E., Venturi, M. L. & Shoe, J. L. A molecular timescale of eukaryote evolution and the rise of complex multicellular life. BMC Evol. Biol. 4, 2 (2004)

    Article  Google Scholar 

  30. Martin, W. et al. Early cell evolution, eukaryotes, anoxia, sulfide, oxygen, fungi first (?), and a tree of genomes revisited. IUBMB Life 55, 193–204 (2003)

    Article  CAS  Google Scholar 

  31. Douzery, E. J. P., Snell, E. A., Bapteste, E., Delsuc, F. & Philippe, H. The timing of eukaryotic evolution: does a relaxed molecular clock reconcile proteins and fossils?. Proc. Natl Acad. Sci. USA. 101, 15386–15391 (2004)

    Article  ADS  CAS  Google Scholar 

  32. Sheridan, P. P., Freeman, K. H. & Brenchley, J. E. Estimated minimal divergence times of the major bacterial and archaeal phyla. Geomicrobiol. J. 20, 1–14 (2003)

    Article  CAS  Google Scholar 

  33. Hedges, S. B. The origin and evolution of model organisms. Nature Rev. Genet. 3, 838–849 (2002)

    Article  CAS  Google Scholar 

  34. Anderson, J. S. & Sues, H.-D. (eds) Major Transitions in Vertebrate Evolution (Indiana Univ. Press, Bloomington and Indianapolis, in the press).

Download references


The authors would like to thank J. Anderson for help with the estimates of the time of appearance of the organisms used for this study, and D. Schomburg, R. Wünschiers, D. Bauer, A. Scialpi, M. Koornneef, H. Hillebrand, A. M. Tarchi, P. Bruni, T. Wiehe, B. Haubold and T. Rothery for valuable discussions. Author Contributions C.A. initiated and devised the project; C.A., S.C. and J.K. analysed the data; and S.C. and C.A. wrote the manuscript.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Claudia Acquisti.

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Table showing organisms names and data sets sample sizes and Supplementary Figures 1- 7 with legends. (PDF 2115 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Acquisti, C., Kleffe, J. & Collins, S. Oxygen content of transmembrane proteins over macroevolutionary time scales. Nature 445, 47–52 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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