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A newly discovered protein export machine in malaria parasites

Abstract

Several hundred malaria parasite proteins are exported beyond an encasing vacuole and into the cytosol of the host erythrocyte, a process that is central to the virulence and viability of the causative Plasmodium species. The trafficking machinery responsible for this export is unknown. Here we identify in Plasmodium falciparum a translocon of exported proteins (PTEX), which is located in the vacuole membrane. The PTEX complex is ATP-powered, and comprises heat shock protein 101 (HSP101; a ClpA/B-like ATPase from the AAA+ superfamily, of a type commonly associated with protein translocons), a novel protein termed PTEX150 and a known parasite protein, exported protein 2 (EXP2). EXP2 is the potential channel, as it is the membrane-associated component of the core PTEX complex. Two other proteins, a new protein PTEX88 and thioredoxin 2 (TRX2), were also identified as PTEX components. As a common portal for numerous crucial processes, this translocon offers a new avenue for therapeutic intervention.

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Figure 1: HSP101 and PTEX150 co-localize and have dual apical merozoite and PVM localization.
Figure 2: Isolation of a five-member PTEX complex.
Figure 3: The PTEX complex interacts with PEXEL proteins.
Figure 4: Model for PTEX function.

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Acknowledgements

We thank the Australian Red Cross Blood Bank for the provision of human blood and serum. We thank J. McBride, A. Lupas, A. Diemand, M. T. O’Neill, M. Brown, P. Cannon, S. Charnaud, R. Moritz, S. Haase, R. Waller, G. McFadden, G. Cantin and J. Yates for provision of reagents and/or other assistance with some aspects of this study. We are especially grateful to S. Muller for sharing unpublished images and data. This work was supported by NHMRC, by a grant from the NIH (RO1 AI44008) and by infrastructure support from NHMRC IRIISS (361646 and 361637) and Victorian State Government OIS grants. J.A.B. is an NHMRC Peter Doherty postdoctoral fellow, A.G.M. is an ARC Research fellow and A.F.C. is an International Research Scholar of the Howard Hughes Medical Institute.

Author Contributions T.F.d.K.-W. and P.R.G. designed, performed and interpreted much of the experimental work, while B.S.C. designed and interpreted the work and, with T.F.d.K.-W., wrote the manuscript. J.A.B., M.R., P.R.S. and R.J.L. performed experiments and provided intellectual insight in aspects of this study. B.J.S. and A.T.P. contributed the EXP2 molecular modelling and phylogenetic analysis, respectively. A.G.M. and A.F.C. provided novel reagents and mutants, while A.F.C. also provided considerable input into study design and data interpretation. All authors commented on the manuscript.

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Correspondence to Brendan S. Crabb.

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de Koning-Ward, T., Gilson, P., Boddey, J. et al. A newly discovered protein export machine in malaria parasites. Nature 459, 945–949 (2009). https://doi.org/10.1038/nature08104

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