A protein interaction network of the malaria parasite Plasmodium falciparum

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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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.

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Correspondence to Stanley Fields or Robert E. Hughes.

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

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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