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Proteomics Taking aim at malaria, TB with protein interaction data

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Protein interaction networks may just help researchers tackle two diseases that continue to be the bane of humanity: malaria and tuberculosis. Researchers have recently finished the protein network for Plasmodium falciparum and are hard at work teasing out the protein circuitry of Mycobacterium tuberculosis.

“Most of the [protein] networks to date have been focused on model organisms,” says Stan Fields, a professor at the University of Washington who was involved with the malaria project.

In November, scientists at the Howard Hughes Medical Institute, University of Washington, and Prolexys Pharmaceuticals published the first extensive description of the protein interaction network for Plasmodium falciparum. The network, available through the Biomolecular Interaction Network Database, should help researchers devise novel prevention and treatment strategies.

Until now, techniques used for studying protein expression of other organisms have worked poorly for Plasmodium because 80 percent of its genome is comprised of AT-rich regions. The researchers modified techniques and created special culture conditions to study the parasite.

Using 32,000 yeast two-hybrid screens with P. falciparum protein fragments, the researchers identified 2,846 interactions involving 1,312 proteins. The collaborators used informatic analyses of network connectivity, co-expression of the genes encoding interacting fragments, and enrichment of specific protein domains or gene ontology annotations to identify groups of interacting proteins. This included one group implicated in chromatin modification, transcription, messenger RNA stability, and the kiss of death for proteins, ubiquitination. Another group of proteins was implicated in the parasite’s invasion strategy.

The scientific community is already starting to explore the map. Researchers from the University of California, San Diego, have focused on interacting proteins that have homologs in other species and found that malaria’s protein wiring differs markedly from several other higher organisms. Plasmodium has only three conserved complexes with Saccharomyces cerevisiae and no conserved complexes with C. elegans, Drosophila melanogaster, and the bacterial pathogen Helicobacter pylori.

“We’ve known since the Plasmodium genome was sequenced three years ago that 40 percent of its 5,300 proteins are significantly similar, or homologous, to proteins in other eukaryotes, but until now we didn’t know that the malaria parasite assembles those proteins so uniquely,” says Trey Ideker, a professor of bioengineering at UCSD.

Infectious disease researchers who keep score of successes in their field will soon have another tool to celebrate: Prolexys is currently tackling TB with a consortium of researchers.

“A year from now, we will have the protein-protein interaction of Mycobacterium tuberculosis elucidated,” says Sudhir Sahasrabudhe, chief scientific officer and director of Prolexys. The consortium will use the network to develop drugs that combat latent TB.

— Kate O’Rourke

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