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.

  • Letter
  • Published:

Robust signals of coevolution of interacting residues in mammalian proteomes identified by phylogeny-aided structural analysis

Abstract

The structure of a protein depends critically on the complex interactions among its amino acid residues. It has long been hypothesized that interacting residues might tend to coevolve, but it is not known whether such coevolution is a general phenomenon across the proteome. Here, we describe a novel methodology called phylogeny-aided structural analysis, which uncovers robust signals of interacting-residue coevolution in mammalian proteomes. Furthermore, this new method allows the magnitude of coevolution to be quantified. Finally, it facilitates a comprehensive evaluation of various factors that affect interacting-residue coevolution, such as the physicochemical properties of the interactions between residues, solvent accessibility of the residues and their secondary structure context.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Examples of different types of DRIPs.
Figure 2: Phylogenetic relationship of the species used in the study.
Figure 3: Significant excess of coupled DRIPs (rat-human-dog data).
Figure 4: Comparison of the observed frequency of coupled DRIPs with chance expectation for different classes of interacting residues.

Similar content being viewed by others

References

  1. Gutell, R.R., Larsen, N. & Woese, C.R. Lessons from an evolving rRNA: 16S and 23S rRNA structures from a comparative perspective. Microbiol. Rev. 58, 10–26 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Haas, E.S., Brown, J.W., Pitulle, C. & Pace, N.R. Further perspective on the catalytic core and secondary structure of ribonuclease P RNA. Proc. Natl. Acad. Sci. USA 91, 2527–2531 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Chen, Y. et al. RNA secondary structure and compensatory evolution. Genes Genet. Syst. 74, 271–286 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Kern, A.D. & Kondrashov, F.A. Mechanisms and convergence of compensatory evolution in mammalian mitochondrial tRNAs. Nat. Genet. 36, 1207–1212 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Kimura, M. The role of compensatory neutral mutations in molecular evolution. J. Genet. 64, 7–19 (1985).

    Article  CAS  Google Scholar 

  6. Yanofsky, C., Horn, V. & Thorpe, D. Protein structure relationships revealed by mutational analysis. Science 146, 1593–1594 (1964).

    Article  CAS  PubMed  Google Scholar 

  7. Malcolm, B.A., Wilson, K.P., Matthews, B.W., Kirsch, J.F. & Wilson, A.C. Ancestral lysozymes reconstructed, neutrality tested, and thermostability linked to hydrocarbon packing. Nature 345, 86–89 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Zhang, J. & Rosenberg, H.F. Complementary advantageous substitutions in the evolution of an antiviral RNase of higher primates. Proc. Natl. Acad. Sci. USA 99, 5486–5491 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Gillespie, J.H. The molecular clock may be an episodic clock. Proc. Natl. Acad. Sci. USA 81, 8009–8013 (1984).

    Article  CAS  PubMed  Google Scholar 

  10. Kondrashov, A.S., Sunyaev, S. & Kondrashov, F.A. Dobzhansky-Muller incompatibilities in protein evolution. Proc. Natl. Acad. Sci. USA 99, 14878–14883 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Gao, L. & Zhang, J. Why are some human disease-associated mutations fixed in mice? Trends Genet. 19, 678–681 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Gobel, U., Sander, C., Schneider, R. & Valencia, A. Correlated mutations and residue contacts in proteins. Proteins 18, 309–317 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Neher, E. How frequent are correlated changes in families of protein sequences? Proc. Natl. Acad. Sci. USA 91, 98–102 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Shindyalov, I.N., Kolchanov, N.A. & Sander, C. Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations? Protein Eng. 7, 349–358 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Taylor, W.R. & Hatrick, K. Compensating changes in protein multiple sequence alignments. Protein Eng. 7, 341–348 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Ortiz, A.R. & Skolnick, J. Sequence evolution and the mechanism of protein folding. Biophys. J. 79, 1787–1799 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fukami-Kobayashi, K., Schreiber, D.R. & Benner, S.A. Detecting compensatory covariation signals in protein evolution using reconstructed ancestral sequences. J. Mol. Biol. 319, 729–743 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Pollock, D.D. & Taylor, W.R. Effectiveness of correlation analysis in identifying protein residues undergoing correlated evolution. Protein Eng. 10, 647–657 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Tuff, P. & Darlu, P. Exploring a phylogenetic approach for the detection of correlated substitutions in proteins. Mol. Biol. Evol. 17, 1753–1759 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Springer, M.S., Murphy, W.J., Eizirik, E. & O'Brien, S.J. Placental mammal diversification and the Cretaceous-Tertiary boundary. Proc. Natl. Acad. Sci. USA 100, 1056–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Tramontano, A., Leplae, R. & Morea, V. Analysis and assessment of comparative modeling predictions in CASP4. Proteins (Suppl.) 5, 22–38 (2001).

    Google Scholar 

  22. Fitch, W.M. Toward defining the course of evolution: minimum change for a specific tree topology. Syst. Zool. 20, 406–416 (1971).

    Article  Google Scholar 

  23. Westbrook, J., Feng, Z., Chen, L., Yang, H. & Berman, H.M. The Protein Data Bank and structural genomics. Nucleic Acids Res. 31, 489–491 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Baker, D. & Sali, A. Protein structure prediction and structural genomics. Science 294, 93–96 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Baudry, J., Li, W., Pan, L., Berenbaum, M.R. & Schuler, M.A. Molecular docking of substrates and inhibitors in the catalytic site of CYP6B1, an insect cytochrome p450 monooxygenase. Protein Eng. 16, 577–587 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Mackerell, A.D., Jr. Empirical force fields for biological macromolecules: overview and issues. J. Comput. Chem. 25, 1584–1604 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Stickle, D.F., Presta, L.G., Dill, K.A. & Rose, G.D. Hydrogen bonding in globular proteins. J. Mol. Biol. 226, 1143–1159 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. Kabsch, W. & Sander, C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22, 2577–2637 (1983).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C.M. Malcom, P.A. Rice, T.R. Sosnick, E.J. Vallender, G.J. Wyckoff and X. Yang for technical help, discussions and comments on the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bruce T Lahn.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Declining signal of coevolution as the sequence identity between the modeled protein and the template declines. (PDF 11 kb)

Supplementary Table 1

Proteins in the rat-human-dog data set. (PDF 31 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shim Choi, S., Li, W. & Lahn, B. Robust signals of coevolution of interacting residues in mammalian proteomes identified by phylogeny-aided structural analysis. Nat Genet 37, 1367–1371 (2005). https://doi.org/10.1038/ng1685

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1685

This article is cited by

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