The uptake of nutrients, expulsion of metabolic wastes and maintenance of ion homeostasis by the intraerythrocytic malaria parasite is mediated by membrane transport proteins. Proteins of this type are also implicated in the phenomenon of antimalarial drug resistance (e.g. PfCRT). Yet the original annotation of the malaria parasite genome (Gardner et al. Nature 2002; 419:498-511) reported that the parasite has ‘a very limited repertoire of membrane transporters’. We have undertaken a comprehensive bioinformatic analysis of membrane transport proteins in the malaria parasite genome (Martin et al., 2005), the outcome of which was a doubling in the number of parasite-encoded transport proteins, as well as the assignment of putative substrate specificities and/or transport mechanisms to all of those proteins previously lacking this information. Moreover, we have subsequently uncovered additional candidate transport proteins (Martin, Ginsburg and Kirk, 2009).
A central theme of our research is to characterise the function of a selection of these transport proteins, with the aim of gaining important insights into key aspects of both the biology and pharmacology of the malaria parasite. The activity of a transport protein is best dissected in a heterologous expression system, and to date the most successful system for the functional expression of malaria parasite transport proteins has been the oocyte of the Xenopus laevis frog.
Nevertheless, achieving functional expression of a foreign transport protein in a host cell can be challenging. For example, the successful expression of PfCRT at the surface of the oocyte required the removal of a number of putative ‘intracellular retention signals’ from its amino acid sequence (PfCRT normally resides at the membrane of an internal organelle within the parasite). We are investigating the roles played by these signals in the localization and functional expression of PfCRT in the Xenopus system, and in the trafficking of the protein in the parasite. This work, which is being carried out in collaboration with Professor Geoff McFadden at the University of Melbourne, will provide valuable insights into the factors determining the successful expression of parasite proteins in heterologous systems, a field that has achieved only limited success to date.
Recent papers from this project:
- Marchetti RV, Lehane AM, Shafik SH, Winterberg M, Martin RE and Kirk K (2015). A lactate and formate transporter in the intraerythrocytic malaria parasite, Plasmodium falciparum. Nature Communications, 6: Article 6721. Open access
- Kirk K and Martin RE (2015). Membrane transport in the malaria parasite, in the Encyclopedia of Malaria (P Kremsner & M Hommel chief eds), Springer, pp 1-11.
- Cobbold SA, Martin RE and Kirk K (2011). Methionine transport in the malaria parasite, Plasmodium falciparum. International Journal of Parasitology, 41: 125-135.
- Martin RE, Ginsburg H and Kirk K (2009). Membrane transport proteins of the malaria parasite. Molecular Microbiology, 74: 519-528.
- Martin RE and Kirk K (2007). Transport of the essential nutrient isoleucine in human erythrocytes infected with the malaria parasite Plasmodium falciparum. Blood, 109: 2217-24.
- Saliba KJ1, Martin RE1, Bröer A, Henry RI, McCarthy CS, Downie MJ, Allen RJW, Mullin KA, McFadden GI, Bröer S2, and Kirk K2 (2006). Na+-dependent uptake of an essential nutrient by the intracellular malaria parasite. Nature, 443: 582-85. [1, 2: Equal contributions] Commentary: Merzendorfer H. (2007) J Exp Biol, 210: v-vi.
- Martin RE, Henry RI, Abbey JL, Clements JD, and Kirk K (2005). The ‘permeome’ of the malaria parasite: an overview of the membrane transport proteins of Plasmodium falciparum. Genome Biology, 6: R26. Open access
- Clements JD and Martin RE (2002). Identification of novel membrane proteins by searching for patterns in hydropathy profiles. FEBS Journal, 269: 2101-07.
- Malaria Discovery. ‘News Scan’ article by The Sydney Morning Herald.
- Malaria's taste for salt. Danielle Cronin, The Canberra Times.