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Assembly reflects evolution of protein complexes

Nature volume 453, pages 1262–1265 (2008)Cite this article

Abstract

A homomer is formed by self-interacting copies of a protein unit. This is functionally important1,2, as in allostery3,4,5, and structurally crucial because mis-assembly of homomers is implicated in disease6,7. Homomers are widespread, with 50–70% of proteins with a known quaternary state assembling into such structures8,9. Despite their prevalence, their role in the evolution of cellular machinery10,11 and the potential for their use in the design of new molecular machines12,13, little is known about the mechanisms that drive formation of homomers at the level of evolution and assembly in the cell9,14. Here we present an analysis of over 5,000 unique atomic structures and show that the quaternary structure of homomers is conserved in over 70% of protein pairs sharing as little as 30% sequence identity. Where quaternary structure is not conserved among the members of a protein family, a detailed investigation revealed well-defined evolutionary pathways by which proteins transit between different quaternary structure types. Furthermore, we show by perturbing subunit interfaces within complexes and by mass spectrometry analysis15, that the (dis)assembly pathway mimics the evolutionary pathway. These data represent a molecular analogy to Haeckel’s evolutionary paradigm of embryonic development, where an intermediate in the assembly of a complex represents a form that appeared in its own evolutionary history. Our model of self-assembly allows reliable prediction of evolution and assembly of a complex solely from its crystal structure.

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Figure 1: Abundance and properties of cyclic and dihedral symmetries.
Figure 2: Routes for homomer evolution.
Figure 3: Prediction of evolutionary routes and link with (dis)assembly in solution.
Figure 4: (Dis)assembly pathways in 16 complexes.

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References

  1. Cabezon, E. et al. Homologous and heterologous inhibitory effects of ATPase inhibitor proteins on F-ATPases. J. Biol. Chem. 277, 41334–41341 (2002)

    Article  CAS  PubMed  Google Scholar 

  2. Hardy, L. W. et al. Atomic structure of thymidylate synthase: target for rational drug design. Science 235, 448–455 (1987)

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Iber, D., Clarkson, J., Yudkin, M. D. & Campbell, I. D. The mechanism of cell differentiation in Bacillus subtilis . Nature 441, 371–374 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Marianayagam, N. J., Sunde, M. & Matthews, J. M. The power of two: protein dimerization in biology. Trends Biochem. Sci. 29, 618–625 (2004)

    Article  CAS  PubMed  Google Scholar 

  5. Monod, J., Wyman, J. & Changeux, J. P. On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12, 88–118 (1965)

    Article  CAS  PubMed  Google Scholar 

  6. Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Hayouka, Z. et al. Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium. Proc. Natl Acad. Sci. USA 104, 8316–8321 (2007)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Levy, E. D., Pereira-Leal, J. B., Chothia, C. & Teichmann, S. A. 3D complex: a structural classification of protein complexes. PLoS Comput. Biol. 2, e155 (2006)

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  9. Goodsell, D. S. & Olson, A. J. Structural symmetry and protein function. Annu. Rev. Biophys. Biomol. Struct. 29, 105–153 (2000)

    Article  CAS  PubMed  Google Scholar 

  10. Ispolatov, I., Yuryev, A., Mazo, I. & Maslov, S. Binding properties and evolution of homodimers in protein–protein interaction networks. Nucleic Acids Res. 33, 3629–3635 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pereira-Leal, J. B., Levy, E. D., Kamp, C. & Teichmann, S. A. Evolution of protein complexes by duplication of homomeric interactions. Genome Biol. 8, R51 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  12. Grueninger, D. et al. Designed protein–protein association. Science 319, 206–209 (2008)

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Janin, J. Biochemistry. Dicey assemblies. Science 319, 165–166 (2008)

    Article  CAS  PubMed  Google Scholar 

  14. Blundell, T. L. & Srinivasan, N. Symmetry, stability, and dynamics of multidomain and multicomponent protein systems. Proc. Natl Acad. Sci. USA 93, 14243–14248 (1996)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hernandez, H. et al. Subunit architecture of multimeric complexes isolated directly from cells. EMBO Rep. 7, 605–610 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Brinda, K. V. & Vishveshwara, S. Oligomeric protein structure networks: insights into protein–protein interactions. BMC Bioinformatics 6, 296 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Monod, J. Nobel Symposium 11: Symmetry and Function of Biological Systems at the Macromolecular Level (Almqvist & Wiksell, Stockholm, 1968)

    Google Scholar 

  18. Lukatsky, D. B., Shakhnovich, B. E., Mintseris, J. & Shakhnovich, E. I. Structural similarity enhances interaction propensity of proteins. J. Mol. Biol. 365, 1596–1606 (2007)

    Article  CAS  PubMed  Google Scholar 

  19. Claverie, P., Hofnung, M. & Monod, J. Sur certaines implications de l'hypothèse d'équivalence stricte entre les protomères des protéines oligomériques. C. R. Séanc. Acad. Sci. 266, 1616–1618 (1968)

    CAS  Google Scholar 

  20. DePristo, M. A., Weinreich, D. M. & Hartl, D. L. Missense meanderings in sequence space: a biophysical view of protein evolution. Nature Rev. Genet. 6, 678–687 (2005)

    Article  CAS  PubMed  Google Scholar 

  21. Bahadur, R. P., Rodier, F. & Janin, J. A dissection of the protein-protein interfaces in icosahedral virus capsids. J. Mol. Biol. 367, 574–590 (2007)

    Article  CAS  PubMed  Google Scholar 

  22. Powers, E. T. & Powers, D. L. A perspective on mechanisms of protein tetramer formation. Biophys. J. 85, 3587–3599 (2003)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Luke, K. & Wittung-Stafshede, P. Folding and assembly pathways of co-chaperonin proteins 10: Origin of bacterial thermostability. Arch. Biochem. Biophys. 456, 8–18 (2006)

    Article  CAS  PubMed  Google Scholar 

  24. Cheesman, C., Ruddock, L. W. & Freedman, R. B. The refolding and reassembly of Escherichia coli heat-labile enterotoxin B-subunit: analysis of reassembly-competent and reassembly-incompetent unfolded states. Biochemistry 43, 1609–1617 (2004)

    Article  CAS  PubMed  Google Scholar 

  25. Kress, W., Mutschler, H. & Weber-Ban, E. Assembly pathway of an AAA+ protein: tracking ClpA and ClpAP complex formation in real time. Biochemistry 46, 6183–6193 (2007)

    Article  CAS  PubMed  Google Scholar 

  26. Levy, E. D. PiQSi: Protein quaternary structure investigation. Structure 15, 1364–1367 (2007)

    Article  CAS  PubMed  Google Scholar 

  27. Sobott, F. et al. A tandem mass spectrometer for improved transmission and analysis of large macromolecular assemblies. Anal. Chem. 74, 1402–1407 (2002)

    Article  CAS  PubMed  Google Scholar 

  28. Hernandez, H. & Robinson, C. V. Determining the stoichiometry and interactions of macromolecular assemblies from mass spectrometry. Nature Protocols 2, 715–726 (2007)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the collaborators listed in Supplementary Table 2 for supplying the different complexes and acknowledge H. Hernandez, J. Freeke and L. Lane for assistance with mass spectrometry. We also thank C. Chothia, J. Clark and M. Babu for discussions. This work was supported by the Medical Research Council, the EMBO Young Investigators Programme, the Royal Society and the Waters Kundert Trust.

Author Contributions E.D.L., E.B.E., C.V.R. and S.A.T. designed the experiments and wrote the manuscript; E.D.L. and E.B.E. performed the bioinformatics and mass spectrometry experiments, respectively.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK ,

    Emmanuel D. Levy & Sarah A. Teichmann

  2. Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK

    Elisabetta Boeri Erba & Carol V. Robinson

Authors
  1. Emmanuel D. Levy
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  2. Elisabetta Boeri Erba
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Corresponding authors

Correspondence to Emmanuel D. Levy, Carol V. Robinson or Sarah A. Teichmann.

Supplementary information

Supplementary Information

The file contains Supplementary Discussions 1-2; Supplementary Figures 1-4 and Supplementary Tables 1-3. This file contains discussions on the hierarchy in interface size, and on membrane proteins; figures on conservation of QS and transitions between them, on our model of QS evolution, and on the MS protocol used for disassembly. Tables list complexes used for the evolutionary and MS analyses, and those from the literature. (PDF 818 kb)

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Levy, E., Erba, E., Robinson, C. et al. Assembly reflects evolution of protein complexes. Nature 453, 1262–1265 (2008). https://doi.org/10.1038/nature06942

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