Article

A protein interaction network of the malaria parasite Plasmodium falciparum.

Howard Hughes Medical Institute, University of Washington, Box 357730, Seattle, Washington 98195, USA.
Nature (Impact Factor: 42.35). 12/2005; 438(7064):103-7. DOI: 10.1038/nature04104
Source: PubMed

ABSTRACT Plasmodium falciparum causes the most severe form of malaria and kills up to 2.7 million people annually. 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 annotations 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.

Download full-text

Full-text

Available from: Sudhir Sahasrabudhe, Jun 17, 2015
0 Followers
 · 
265 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Since the functional state of a protein-protein interaction network depends on gene expression, a fundamental question is what relationships exist between protein interaction network and gene regulation. In particular, microRNAs have recently emerged as a major class of post-transcriptional regulators that influences a large proportion of genes in higher eukaryotes. Here we show that protein connectivity in the human protein-protein interaction network is positively correlated with the number of microRNA target-site types in the 3' untranslated regions of the gene encoding the protein and that interacting proteins tend to share more microRNA target-site types than random pairs. Moreover, our results demonstrate that microRNA targeting propensity for genes in different biological processes can be largely explained by their protein connectivity. Finally, we show that for hub proteins, microRNA regulation complexity is negatively correlated with clustering coefficient, suggesting that microRNA regulation is more important to inter-modular hubs than to intramodular ones. Taken together, our study provides the first evidence for global correlation between microRNA repression and protein-protein interactions.
    RNA 10/2007; 13(9):1402-8. DOI:10.1261/rna.634607 · 4.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Apicomplexa have developed distinctive adaptations for invading and surviving within animal cells. Here a synthetic overview of the diversity and evolutionary history of cell membrane-associated, -secreted, and -exported proteins related to apicomplexan parasitism is presented. A notable feature in this regard was the early acquisition of adhesion protein domains and glycosylation systems through lateral transfer from animals. These were utilized in multiple contexts, including invasion of host cells and parasite-specific developmental processes. Apicomplexans possess a specialized version of the ancestral alveolate extrusion machinery, the rhoptries and micronemes, which are deployed in invasion and delivery of proteins into host cells. Each apicomplexan lineage has evolved a unique spectrum of extruded proteins that modify host molecules in diverse ways. Hematozoans, in particular, appear to have evolved novel systems for export of proteins into the host organelles and cell membrane during intracellular development. These exported proteins are an important aspect of the pathogenesis of Plasmodium and Theileria, being involved in response to fever and in leukocyte proliferation respectively. The complement of apicomplexan surface proteins has primarily diversified via massive lineage-specific expansions of certain protein families, which are often coded by subtelomeric gene arrays. Many of these families have been found to be central to immune evasion. Domain shuffling and accretion have resulted in adhesins with new domain architectures. In terms of individual genes, constant selective pressures from the host immune response has resulted in extensive protein polymorphisms and gene losses. Apicomplexans have also evolved complex regulatory mechanisms controlling expression and maturation of surface proteins at the chromatin, transcriptional, posttranscriptional, and posttranslational levels. Evolutionary reconstruction suggests that the ancestral apicomplexan had thrombospondin and EGF domain adhesins, which were linked to the parasite cytoskeleton, and played a central role in invasion through formation of the moving junction. It also suggests that the ancestral parasite had O-linked glycosylation of surface proteins which was partially or entirely lost in hematozoan lineages.
    International Review of Cytology 02/2007; 262:1-74. DOI:10.1016/S0074-7696(07)62001-4 · 9.00 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Malaria is a global problem that affects millions of people annually. A relatively poor understanding of the malaria parasite biology has hindered vaccine and drug development against this disease. Robust methods for genetic analyses in Plasmodium have been lacking due to the difficulties in its genetic manipulation. Introduction of transfection technologies laid the foundation for genetic dissection of Plasmodium and recent years have seen the development of novel tools for genetic manipulation that will help us delineate the intriguing biology of this parasite. This review focuses on such recent advances in transfection technologies for Plasmodium that have improved our ability to carry out more thorough genetic analyses of the biology of the malaria parasite.
    International Journal for Parasitology 02/2007; 37(1):1-10. DOI:10.1016/j.ijpara.2006.10.001 · 3.40 Impact Factor