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The multiprotein complex PTEX enables malaria-causing parasites to survive inside red blood cells. Studies reveal how PTEX assembles, and identify a function for one of the complex's proteins, EXP2.Structural analysis reveals how the PTEX complex assembles., Author(s): Tania F. de Koning-WardAuthor Affiliations:Spotlight on proteins that aid malaria PTEX consists of five proteins[sup.3] : HSP101, PTEX150, EXP2, PTEX88 and TRX2. Multiple HSP101, PTEX150 and EXP2 molecules assemble [...]

To mediate its survival and virulence, the malaria parasite Plasmodium falciparum exports hundreds of proteins into the host erythrocyte (1). To enter the host cell, exported proteins must cross the parasitophorous vacuolar membrane (PVM) within which the parasite resides, but the mechanism remains unclear. A putative Plasmodium translocon of exported proteins (PTEX) has been suggested to be involved for at least one class of exported proteins; however, direct functional evidence for this has been elusive (2-4). Here we show that export across the PVM requires heat shock protein 101 (HSP101), a ClpB-like AAA+ ATPase component of PTEX. Using a chaperone auto-inhibition strategy, we achieved rapid, reversible ablation of HSP101 function, resulting in a nearly complete block in export with substrates accumulating in the vacuole in both asexual and sexual parasites. Surprisingly, this block extended to all classes of exported proteins, revealing HSP101-dependent translocation across the PVM as a convergent step in the multi-pathway export process. Under export-blocked conditions, association between HSP101 and other components of the PTEX complex was lost, indicating that the integrity of the complex is required for efficient protein export. Our results demonstrate an essential and universal role for HSP101 in protein export and provide strong evidence for PTEX function in protein translocation into the host cell., PTEX is a protein complex found in the PVM, where a translocon responsible for export into the host erythrocyte is expected (2). The timing of its synthesis is appropriate for [...]

During the blood stages of malaria, several hundred parasite-encoded proteins are exported beyond the double-membrane barrier that separates the parasite from the host cell cytosol (1-6). These proteins have a variety of roles that are essential to virulence or parasite growth (7). There is keen interest in understanding how proteins are exported and whether common machineries are involved in trafficking the different classes of exported proteins (8,9). One potential trafficking machine is a protein complex known as the Plasmodium translocon of exported proteins (PTEX) (10). Although PTEX has been linked to the export of one class of exported proteins (10,11), there has been no direct evidence for its role and scope in protein translocation. Here we show, through the generation of two parasite lines defective for essential PTEX components (HSP101 or PTEX150), and analysis of a line lacking the non-essential component TRX2 (ref. 12), greatly reduced trafficking of all classes of exported proteins beyond the double membrane barrier enveloping the parasite. This includes proteins containing the PEXEL motif (RxLxE/Q/D) (1,2) and PEXEL-negative exported proteins (PNEPs) (6). Moreover, the export of proteins destined for expression on the infected erythrocyte surface, including the major virulence factor PfEMP1 in Plasmodium falciparum, was significantly reduced in PTEX knockdown parasites. PTEX function was also essential for blood-stage growth, because even a modest knockdown of PTEX components had a strong effect on the parasite's capacity to complete the erythrocytic cycle both in vitro and in vivo. Hence, as the only known nexus for protein export in Plasmodium parasites, and an essential enzymic machine, PTEX is a prime drug target., To address the role of PTEX in protein export directly, we examined parasite lines defective in PTEX components for their capacity to translocate exported proteins. Two PTEX components, TRX2 and [...]

A central hub of carbon metabolism is the tricarboxylic acid cycle (1), which serves to connect the processes of glycolysis, gluconeogenesis, respiration, amino acid synthesis and other biosynthetic pathways. The protozoan intracellular malaria parasites (Plasmodium spp.), however, have long been suspected of possessing a significantly streamlined carbon metabolic network in which tricarboxylic acid metabolism plays a minor role (2). Blood-stage Plasmodium parasites rely almost entirely on glucose fermentation for energy and consume minimal amounts of oxygen (3), yet the parasite genome encodes all of the enzymes necessary for a complete tricarboxylic acid cycle (4). Here, by tracing [sup.13]C-labelled compounds using mass spectrometry (5), we show that tricarboxylic acid metabolism in the human malaria parasite Plasmodium falciparum is largely disconnected from glycolysis and is organized along a fundamentally different architecture from the canonical textbook pathway. We find that this pathway is not cyclic, but rather is a branched structure in which the major carbon sources are the amino acids glutamate and glutamine. As a consequence of this branched architecture, several reactions must run in the reverse of the standard direction, thereby generating two-carbon units in the form of acetyl-coenzyme A. We further show that glutamine-derived acetyl-coenzyme A is used for histone acetylation, whereas glucose-derived acetyl-coenzyme A is used to acetylate amino sugars. Thus, the parasite has evolved two independent production mechanisms for acetyl-coenzyme A with different biological functions. These results significantly clarify our understanding of the Plasmodium metabolic network and highlight the ability of altered variants of central carbon metabolism to arise in response to unique environments., The mitochondrion of P. falciparum contains the smallest genome sequenced to date, and seems to have evolved reduced functional roles compared with other eukaryotic organisms (6). Moreover, the limited number [...]

Two studies provide evidence that the protein complex PTEX is needed for export of malaria-parasite proteins into the cytoplasm of infected cells, and that such export is essential for parasite [...]

Charles Darwin, the man of 'enlarged curiosity', was particularly curious about sex. He wondered, for example, why males and females are equally abundant in so many species in which males [...]

Conserved Repetitive Epitope Recognized by [CD4.sup.4] Clones from a Malaria-Immunized Volunteer IMMUNIZATION BY EXPOSURE TO THE bites of irradiated malaria-infected mosquitoes induces protective anti-sporozoite immunity in rodents, monkeys, and human [...]