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A protein interaction network of the malaria parasite Plasmodium falciparum

Nature volume 438, pages 103–107 (2005)Cite this article

Abstract

Plasmodium falciparum causes the most severe form of malaria and kills up to 2.7 million people annually1. Despite the global importance of P. falciparum, the vast majority of its proteins have not been characterized experimentally. Here we identify P. falciparum protein–protein interactions using a high-throughput version of the yeast two-hybrid assay that circumvents the difficulties in expressing P. falciparum proteins in Saccharomyces cerevisiae. From more than 32,000 yeast two-hybrid screens with P. falciparum protein fragments, we identified 2,846 unique interactions, most of which include at least one previously uncharacterized protein. Informatic analyses of network connectivity, coexpression of the genes encoding interacting fragments, and enrichment of specific protein domains or Gene Ontology annotations2 were used to identify groups of interacting proteins, including one implicated in chromatin modification, transcription, messenger RNA stability and ubiquitination, and another implicated in the invasion of host cells. These data constitute the first extensive description of the protein interaction network for this important human pathogen.

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Figure 1: Connectivity analysis.
Figure 2: Interactions between uncharacterized P. falciparum proteins and proteins involved in the invasion of host cells.
Figure 3: Subnetworks with shared protein domains and GO annotations.

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References

  1. Breman, J. G. The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden. Am. J. Trop. Med. Hyg. 64, 1–11 (2001)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Sibley, C. H. et al. Yeast as a model system to study drugs effective against apicomplexan proteins. Methods 13, 190–207 (1997)

    Article  CAS  Google Scholar 

  5. Formstecher, E. et al. Protein interaction mapping: a Drosophila case study. Genome Res. 15, 376–384 (2005)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Rives, A. W. & Galitski, T. Modular organization of cellular networks. Proc. Natl Acad. Sci. USA 100, 1128–1133 (2003)

    Article  ADS  CAS  Google Scholar 

  9. Bader, G. D. & Hogue, C. W. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 4, 2 (2003)

    Article  Google Scholar 

  10. Fan, Q., An, L. & Cui, L. Plasmodium falciparum histone acetyltransferase, a yeast GCN5 homologue involved in chromatin remodeling. Eukaryot. Cell 3, 264–276 (2004)

    Article  CAS  Google Scholar 

  11. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000)

    Article  ADS  CAS  Google Scholar 

  12. Ragvin, A. et al. Nucleosome binding by the bromodomain and PHD finger of the transcriptional cofactor p300. J. Mol. Biol. 337, 773–788 (2004)

    Article  CAS  Google Scholar 

  13. Li, L., Stoeckert, C. J. Jr & Roos, D. S. OrthoMCL: identification of ortholog groups for eukaryotic genomes. Genome Res. 13, 2178–2189 (2003)

    Article  CAS  Google Scholar 

  14. Iida, T. & Araki, H. Noncompetitive counteractions of DNA polymerase epsilon and ISW2/yCHRAC for epigenetic inheritance of telomere position effect in Saccharomyces cerevisiae. Mol. Cell. Biol. 24, 217–227 (2004)

    Article  CAS  Google Scholar 

  15. Huynh, K. D. & Bardwell, V. J. The BCL-6 POZ domain and other POZ domains interact with the co-repressors N-CoR and SMRT. Oncogene 17, 2473–2484 (1998)

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  18. Coulson, R. M., Hall, N. & Ouzounis, C. A. Comparative genomics of transcriptional control in the human malaria parasite Plasmodium falciparum. Genome Res. 14, 1548–1554 (2004)

    Article  CAS  Google Scholar 

  19. Aravind, L., Iyer, L. M., Wellems, T. E. & Miller, L. H. Plasmodium biology: genomic gleanings. Cell 115, 771–785 (2003)

    Article  CAS  Google Scholar 

  20. Daniel, J. A. et al. Deubiquitination of histone H2B by a yeast acetyltransferase complex regulates transcription. J. Biol. Chem. 279, 1867–1871 (2004)

    Article  CAS  Google Scholar 

  21. Collart, M. A. Global control of gene expression in yeast by the Ccr4-Not complex. Gene 313, 1–16 (2003)

    Article  CAS  Google Scholar 

  22. Ge, H., Walhout, A. J. & Vidal, M. Integrating ‘omic’ information: a bridge between genomics and systems biology. Trends Genet. 19, 551–560 (2003)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  24. Le Roch, K. G. et al. Global analysis of transcript and protein levels across the Plasmodium falciparum life cycle. Genome Res. 14, 2308–2318 (2004)

    Article  CAS  Google Scholar 

  25. Li, X. et al. A co-ligand complex anchors Plasmodium falciparum merozoites to the erythrocyte invasion receptor band 3. J. Biol. Chem. 279, 5765–5771 (2004)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  27. Kissinger, J. C. et al. The Plasmodium genome database. Nature 419, 490–492 (2002)

    Article  ADS  CAS  Google Scholar 

  28. Cooke, B. M., Lingelbach, K., Bannister, L. H. & Tilley, L. Protein trafficking in Plasmodium falciparum-infected red blood cells. Trends Parasitol. 20, 581–589 (2004)

    Article  CAS  Google Scholar 

  29. Hiller, N. L. et al. A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306, 1934–1937 (2004)

    Article  ADS  CAS  Google Scholar 

  30. Marti, M., Good, R. T., Rug, M., Knuepfer, E. & Cowman, A. F. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306, 1930–1933 (2004)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. Duffy, J. Feagin and C. H. Sibley for reading the manuscript critically, A. Gauntlett for technical assistance, and W. Hol for helpful discussions. This work was supported by a grant from the NIH. J.R.H. was supported by an NIH Kirschstein NRSA post-doctoral fellowship. S.F. is an Investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Robert E. Hughes

    Present address: Buck Institute, Novato, California, 94945, USA

  2. Douglas J. LaCount and Marissa Vignali: *These authors contributed equally to this work

Authors and Affiliations

  1. Howard Hughes Medical Institute,

    Douglas J. LaCount, Lori W. Schoenfeld & Stanley Fields

  2. Departments of Genome Sciences and Medicine, University of Washington, Box 357730, Washington, 98195, Seattle, USA

    Douglas J. LaCount, Marissa Vignali, Jay R. Hesselberth, Lori W. Schoenfeld & Stanley Fields

  3. Prolexys Pharmaceuticals, Inc., 2150 West Dauntless Avenue, Utah, 84111, Salt Lake City, USA

    Rakesh Chettier, Amit Phansalkar, Russell Bell, Irene Ota, Sudhir Sahasrabudhe, Cornelia Kurschner & Robert E. Hughes

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Correspondence to Stanley Fields or Robert E. Hughes.

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Supplementary information

Supplementary Methods

Additional details of methods used in this study. (PDF 115 kb)

Supplementary Notes

This file contains additional references. (PDF 89 kb)

Supplementary Figures

This file contains Supplementary Figure 1–7. (PDF 5747 kb)

Supplementary Table 1

Plasmodium falciparum yeast two-hybrid search statistics (PDF 37 kb)

Supplementary Table 2

Promiscuous protein fragments (PDF 40 kb)

Supplementary Table 3

Core Dataset (TXT 294 kb)

Supplementary Table 4

Previously identified Plasmodium protein-protein interactions and interactions observed between orthologous proteins (PDF 64 kb)

Supplementary Table 5

Subnetworks with significantly higher than expected level of interconnectivity (TXT 5 kb)

Supplementary Table 6

Subnetworks with significantly higher than expected correlation among mRNA expression profiles (TXT 6 kb)

Supplementary Table 7

Interactions among proteins found in LeRoch et al. 1 Cluster 15. (PDF 41 kb)

Supplementary Table 8

Subnetworks associated with protein domains (TXT 31 kb)

Supplementary Table 9

Subnetworks associated with GO annotations (TXT 120 kb)

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LaCount, D., Vignali, M., Chettier, R. et al. A protein interaction network of the malaria parasite Plasmodium falciparum. Nature 438, 103–107 (2005). https://doi.org/10.1038/nature04104

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