The Plasmodium protein network diverges from those of other eukaryotes

Abstract

Plasmodium falciparum is the pathogen responsible for over 90% of human deaths from malaria1. Therefore, it has been the focus of a considerable research initiative, involving the complete DNA sequencing of the genome2, large-scale expression analyses3,4, and protein characterization of its life-cycle stages5. The Plasmodium genome sequence is relatively distant from those of most other eukaryotes, with more than 60% of the 5,334 encoded proteins lacking any notable sequence similarity to other organisms2. To systematically elucidate functional relationships among these proteins, a large two-hybrid study has recently mapped a network of 2,846 interactions involving 1,312 proteins within Plasmodium6. This network adds to a growing collection of available interaction maps for a number of different organisms, and raises questions about whether the divergence of Plasmodium at the sequence level is reflected in the configuration of its protein network. Here we examine the degree of conservation between the Plasmodium protein network and those of model organisms. Although we find 29 highly connected protein complexes specific to the network of the pathogen, we find very little conservation with complexes observed in other organisms (three in yeast, none in the others). Overall, the patterns of protein interaction in Plasmodium, like its genome sequence, set it apart from other species.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Conserved and distinct complexes within P. falciparum.
Figure 2: Network similarity across the five organisms.
Figure 3: Number of interactions per protein and the signal-to-noise ratio of protein complexes.
Figure 4: Functional roles within the Plasmodium protein network.

References

  1. 1

    Miller, L. H., Baruch, D. I., Marsh, K. & Doumbo, O. K. The pathogenic basis of malaria. Nature 415, 673–679 (2002)

  2. 2

    Gardner, M. J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498–511 (2002)

  3. 3

    Bozdech, Z. et al. The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol. 1, E5 (2003)

  4. 4

    Le Roch, K. G. et al. Discovery of gene function by expression profiling of the malaria parasite life cycle. Science 301, 1503–1508 (2003)

  5. 5

    Florens, L. et al. A proteomic view of the Plasmodium falciparum life cycle. Nature 419, 520–526 (2002)

  6. 6

    LaCount, D. J. et al. A protein interaction network of the malaria parasite Plasmodium falciparum. Nature doi:10.1038/nature04104 (this issue)

  7. 7

    Conant, G. C. & Wagner, A. Convergent evolution of gene circuits. Nature Genet. 34, 264–266 (2003)

  8. 8

    Yu, H. et al. Annotation transfer between genomes: protein–protein interologs and protein–DNA regulogs. Genome Res. 14, 1107–1118 (2004)

  9. 9

    Sharan, R. et al. Conserved patterns of protein interaction in multiple species. Proc. Natl Acad. Sci. USA 102, 1974–1979 (2005)

  10. 10

    Kelley, B. P. et al. Conserved pathways within bacteria and yeast as revealed by global protein network alignment. Proc. Natl Acad. Sci. USA 100, 11394–11399 (2003)

  11. 11

    Xenarios, I. et al. DIP, the Database of Interacting Proteins: a research tool for studying cellular networks of protein interactions. Nucleic Acids Res. 30, 303–305 (2002)

  12. 12

    Li, S. et al. A map of the interactome network of the metazoan C. elegans. Science 303, 540–543 (2004)

  13. 13

    Giot, L. et al. A protein interaction map of Drosophila melanogaster. Science 302, 1727–1736 (2003)

  14. 14

    Rain, J. C. et al. The protein–protein interaction map of Helicobacter pylori. Nature 409, 211–215 (2001)

  15. 15

    Felsenstein, J. PHYLIP—phylogeny inference package (version 3.2). Cladistics 5, 164–166 (1989)

  16. 16

    Barabasi, A. L. & Oltvai, Z. N. Network biology: understanding the cell's functional organization. Nature Rev. Genet. 5, 101–113 (2004)

  17. 17

    Shanmugam, K. S. Digital and Analog Communication Systems (Wiley, New York, 1979)

  18. 18

    Gagny, B. et al. A novel EH domain protein of Saccharomyces cerevisiae, Ede1p, involved in endocytosis. J. Cell Sci. 113, 3309–3319 (2000)

  19. 19

    Engqvist-Goldstein, A. E. & Drubin, D. G. Actin assembly and endocytosis: from yeast to mammals. Annu. Rev. Cell Dev. Biol. 19, 287–332 (2003)

  20. 20

    Goodson, H. V., Anderson, B. L., Warrick, H. M., Pon, L. A. & Spudich, J. A. Synthetic lethality screen identifies a novel yeast myosin I gene (MYO5): myosin I proteins are required for polarization of the actin cytoskeleton. J. Cell Biol. 133, 1277–1291 (1996)

  21. 21

    Salisbury, J. L., Condeelis, J. S., Maihle, N. J. & Satir, P. Calmodulin localization during capping and receptor-mediated endocytosis. Nature 294, 163–166 (1981)

  22. 22

    Scheibel, L. W. et al. Calcium and calmodulin antagonists inhibit human malaria parasites (Plasmodium falciparum): implications for drug design. Proc. Natl Acad. Sci. USA 84, 7310–7314 (1987)

  23. 23

    Sanchez, C. P., McLean, J. E., Stein, W. & Lanzer, M. Evidence for a substrate specific and inhibitable drug efflux system in chloroquine resistant Plasmodium falciparum strains. Biochemistry 43, 16365–16373 (2004)

  24. 24

    Hoppe, H. C. et al. Antimalarial quinolines and artemisinin inhibit endocytosis in Plasmodium falciparum. Antimicrob. Agents Chemother. 48, 2370–2378 (2004)

  25. 25

    Langst, G. & Becker, P. B. Nucleosome mobilization and positioning by ISWI-containing chromatin-remodeling factors. J. Cell Sci. 114, 2561–2568 (2001)

  26. 26

    Sollars, V. et al. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nature Genet. 33, 70–74 (2003)

  27. 27

    Gavin, A. C. et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141–147 (2002)

  28. 28

    Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature Genet. 25, 25–29 (2000)

  29. 29

    Uetz, P. et al. A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae. Nature 403, 623–627 (2000)

  30. 30

    Mewes, H. W. et al. MIPS: analysis and annotation of proteins from whole genomes. Nucleic Acids Res. 32, D41–D44 (2004)

Download references

Acknowledgements

We are indebted to M. Vignali, D. LaCount and S. Fields at the University of Washington, and B. Hughes and S. Sahasrabudhe at Prolexys, for providing us with advance access to the Plasmodium interaction data and for suggestions on our manuscript. We also thank E. Winzeler and J. Vinetz for advice on Plasmodium protein function, R. Sharan for help with the PathBLAST algorithm, and V. Bafna for assistance with the false-positive analysis. Finally, we acknowledge the following funding support: the National Science Foundation (S.S.); the National Institute of General Medical Sciences (T.I.); a David and Lucille Packard Fellowship award (T.I.); the Howard Hughes Medical Institute (T.S.); and Unilever (T.S.). Author Contributions S.S. and T.S. contributed equally to this work. All authors discussed the results and wrote the paper.

Author information

Correspondence to Silpa Suthram.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains the Supplementary Methods, Supplementary Figures 1–3 and Supplementary Tables 1–7. (DOC 1636 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Suthram, S., Sittler, T. & Ideker, T. The Plasmodium protein network diverges from those of other eukaryotes. Nature 438, 108–112 (2005). https://doi.org/10.1038/nature04135

Download citation

Further reading

Comments

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.