Medical Biology - Research Publications

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Type: Journal Article × Author: Papenfuss, Anthony × Author: Crabb, Brendan × Start date: 2006 × End date: 2009 ×

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    A newly discovered protein export machine in malaria parasites
    de Koning-Ward, TF ; Gilson, PR ; Boddey, JA ; Rug, M ; Smith, BJ ; Papenfuss, AT ; Sanders, PR ; Lundie, RJ ; Maier, AG ; Cowman, AF ; Crabb, BS (NATURE PORTFOLIO, 2009-06-18)
    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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    Molecular genetics and comparative genomics reveal RNAi is not functional in malaria parasites
    Baum, J ; Papenfuss, AT ; Mair, GR ; Janse, CJ ; Vlachou, D ; Waters, AP ; Cowman, AF ; Crabb, BS ; de Koning-Ward, TF (OXFORD UNIV PRESS, 2009-06)
    Techniques for targeted genetic disruption in Plasmodium, the causative agent of malaria, are currently intractable for those genes that are essential for blood stage development. The ability to use RNA interference (RNAi) to silence gene expression would provide a powerful means to gain valuable insight into the pathogenic blood stages but its functionality in Plasmodium remains controversial. Here we have used various RNA-based gene silencing approaches to test the utility of RNAi in malaria parasites and have undertaken an extensive comparative genomics search using profile hidden Markov models to clarify whether RNAi machinery exists in malaria. These investigative approaches revealed that Plasmodium lacks the enzymology required for RNAi-based ablation of gene expression and indeed no experimental evidence for RNAi was observed. In its absence, the most likely explanations for previously reported RNAi-mediated knockdown are either the general toxicity of introduced RNA (with global down-regulation of gene expression) or a specific antisense effect mechanistically distinct from RNAi, which will need systematic analysis if it is to be of use as a molecular genetic tool for malaria parasites.