Walking a thousand miles starts with one step

Malaria is a debilitating and sometimes fatal illness that is caused by infection with Plasmodium parasites and is passed between people by mosquitoes. Credit: Jim Gathany

11 September 2012

Written by Matthew Jones

3.3 billion people, over half of the world’s population, are at risk of malaria infection caused by the Plasmodium parasite. For those living in sub-Saharan Africa there is the added risk of severe disease and death because the most virulent Plasmodium species, Plasmodium falciparum, is the primary cause of disease. Adding to the severity of this public health problem is the continuing emergence of drug resistance—chloroquine, a cheap antimalarial used for decades to great effect is now mostly useless, and resistance to artemisinin, the now frontline defense against disease, is beginning to emerge. These factors combine to create an urgent need for a deeper understanding of Plasmodium parasites on many levels, from a practical level focused on finding new compounds that can be used as drugs, to a basic level focused on biological questions that will allow a deeper understanding of how these parasites cause disease.

The Malaria Programme at the Wellcome Trust Sanger Institute is carrying out research addressing questions both practical and fundamental, and as part of this programme, I have been working with the Institute’s Mass Spectrometry team to perform a large-scale analysis of protein palmitoylation in P. falciparum (http://dx.doi.org/10.1016/j.chom.2012.06.005). Protein palmitoylation is a tool that cells use to control specific protein-membrane interactions, and knowing which proteins in a cell are palmitoylated can give important clues about their regulation or function—clues that can be used to piece together new ideas about how cells work. In order to identify P. falciparum’s complement of palmitoylated proteins, we used a combination of palmitoyl-protein purification techniques and the latest in quantitative mass spectrometry techniques so that we could probe protein palmitoylation in great depth and with as much accuracy as is technically possible. In the end, this combination of techniques allowed us to identify more than 450 new palmitoyl-proteins—a significant achievement considering that before this work only 3 had been identified!

This new catalogue of P. falciparum palmitoyl-proteins is important for many reasons. For example, P. falciparum, especially when compared to laboratory model systems like yeast (which have a comparable number of genes), is an enigma; it’s proteome, the set of proteins expressed by its genome, is full of proteins with no known function, and large-scale studies like the one we have performed can shed light on processes that we currently know little or nothing about—a little like connecting pieces at the edge of a puzzle. To give a specific example, P. falciparum causes fatal disease largely because it is able to make infected red blood cells stick to blood-vessel walls. This ability depends on the parasite-driven wholesale reorganization of red blood cell structure, which P. falciparum is able to perform by exporting its own proteins into the red cell interior. What we have discovered, as a result of our analysis, is that P. falciparum palmitoylates a surprising number of the proteins that it exports. This is important because in most cases we don’t know what these exported proteins do, and we now have important clues about their function and regulation and can start to build hypotheses that probe an important disease-causing feature of P. falciparum biology.

To wrap up, on a basic level this work is important and will drive future research because the identification of 450-plus palmitoylated proteins immediately creates 450-plus specific questions (how does palmitoylation affect this specific protein?), but this work also brings up a number of related questions that deal with the means by which palmitoylation is accomplished, and how the proteins we have identified fit into their larger context to support parasite development. These questions will take years to address, but if walking a thousand miles starts with one step, then figuring out how P. falciparum works starts with one new experiment.

Matthew Jones is a Postdoctoral Fellow in Julian Rayner’s team, which is part of the Malaria Programme at the Wellcome Trust Sanger Institute more…

Review Article:

Matthew L. Jones, Mark O. Collins, David Goulding et al (2012) ‘Analysis of Protein Palmitoylation Reveals a Pervasive Role in Plasmodium Development and Pathogenesis’ Cell Host & Microbe, 12:246–258 http://dx.doi.org/10.1016/j.chom.2012.06.005

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