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.

A newly discovered protein export machine in malaria parasites

https://www.cell.com/cell/pdf/S0092-8674(10)01004-4.pdf

External Lipid PI3P Mediates Entry of Eukaryotic Pathogen Effectors into Plant and Animal Host Cells

The var gene encoded hyper-variable Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediates cytoadhesion of infected erythrocytes to human endothelium. Antibodies blocking cytoadhesion are important mediators of malaria immunity acquired by endemic populations. The development of a PfEMP1 based vaccine mimicking natural acquired immunity depends on a thorough understanding of the evolved PfEMP1 diversity, balancing antigenic variation against conserved receptor binding affinities. This study redefines and reclassifies the domains of PfEMP1 from seven genomes. Analysis of domains in 399 different PfEMP1 sequences allowed identification of several novel domain classes, and a high degree of PfEMP1 domain compositional order, including conserved domain cassettes not always associated with the established group A–E division of PfEMP1. A novel iterative homology block (HB) detection method was applied, allowing identification of 628 conserved minimal PfEMP1 building blocks, describing on average 83% of a PfEMP1 sequence. Using the HBs, similarities between domain classes were determined, and Duffy binding-like (DBL) domain subclasses were found in many cases to be hybrids of major domain classes. Related to this, a recombination hotspot was uncovered between DBL subdomains S2 and S3. The VarDom server is introduced, from which information on domain classes and homology blocks can be retrieved, and new sequences can be classified. Several conserved sequence elements were found, including: (1) residues conserved in all DBL domains predicted to interact and hold together the three DBL subdomains, (2) potential integrin binding sites in DBLα domains, (3) an acylation motif conserved in group A var genes suggesting N-terminal N-myristoylation, (4) PfEMP1 inter-domain regions proposed to be elastic disordered structures, and (5) several conserved predicted phosphorylation sites. Ideally, this comprehensive categorization of PfEMP1 will provide a platform for future studies on var/PfEMP1 expression and function.

/pdf/plasmodium-falciparum-erythrocyte-membrane-protein-1-4e0wef96i6.pdf

Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes - divide and conquer

Plasmodium falciparum causes the virulent form of malaria and disease manifestations are linked to growth inside infected erythrocytes. To survive and evade host responses the parasite remodels the erythrocyte by exporting several hundred effector proteins beyond the surrounding parasitophorous vacuole membrane. A feature of exported proteins is a pentameric motif (RxLxE/Q/D) that is a substrate for an unknown protease. Here we show that the protein responsible for cleavage of this motif is plasmepsin V (PMV), an aspartic acid protease located in the endoplasmic reticulum. PMV cleavage reveals the export signal (xE/Q/D) at the amino terminus of cargo proteins. Expression of an identical mature protein with xQ at the N terminus generated by signal peptidase was not exported, demonstrating that PMV activity is essential and linked with other key export events. Identification of the protease responsible for export into erythrocytes provides a novel target for therapeutic intervention against this devastating disease.

/pdf/an-aspartyl-protease-directs-malaria-effector-proteins-to-22bv1piqfv.pdf

An aspartyl protease directs malaria effector proteins to the host cell

During their intraerythrocytic development, malaria parasites export hundreds of proteins to remodel their host cell. Nutrient acquisition, cytoadherence and antigenic variation are among the key virulence functions effected by this erythrocyte takeover. Proteins destined for export are synthesized in the endoplasmic reticulum (ER) and cleaved at a conserved (PEXEL) motif, which allows translocation into the host cell via an ATP-driven translocon called the PTEX complex. We report that plasmepsin V, an ER aspartic protease with distant homology to the mammalian processing enzyme BACE, recognizes the PEXEL motif and cleaves it at the correct site. This enzyme is essential for parasite viability and ER residence is essential for its function. We propose that plasmepsin V is the PEXEL protease and is an attractive enzyme for antimalarial drug development.

/pdf/plasmepsin-v-licenses-plasmodium-proteins-for-export-into-219jfo0sif.pdf

Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte

http://derisilab.ucsf.edu/pdfs/HenryPEXEL-1.pdf

N-terminal processing of proteins exported by malaria parasites

The self-association of the tranquilizer chlorpromazine hydrochloride in aqueous solution was studied. Using isothermal titration calorimetry, the critical micelle concentration and solvent−micelle interactions were evaluated as a function of temperature, ionic strength, and pH. The enthalpy of demicellization, ΔHdemic, was directly measured from the experimental enthalpy values, which showed that the spontaneous demicellization of chlorpromazine hydrochloride is a highly endothermic process under all experimental conditions studied. The thermodynamic parameters were subsequently calculated from the temperature dependent thermograms. At 25 °C, the critical micelle concentration was determined to be 3.2 mM at pH 6.5 with a ΔHdemic of 12.5 kJ/mol, a ΔGdemic of 24.3 kJ/mol, and a TΔSdemic of −10.1 kJ/mol. Our results suggest that the enthalpy−entropy compensation theory may be applied to these micelles. In addition, using differential scanning calorimetry, a broad endothermic demicellization peak was observe...

Calorimetry studies of chlorpromazine hydrochloride in solution

It is known that when bilayers of some saturated phosphatidylcholines are stored for 3 or more days at approximately 0 degrees C, a lamellar subgel (Lc) phase is detected at temperatures below the pretransition by differential scanning calorimetry (DSC). However, the subgel (Lc) phase and the corresponding subtransition (Lc--> Lbeta') for dimyristoylphosphatidylcholine (DMPC) has not been clearly characterized. In this study, using the temperature jump protocol first developed by Tristram-Nagle et al. for the dipalmitoylphosphatidylcholine (DPPC) system, new and accurate data characterizing the subgel formation and subtransition of DMPC were obtained through DSC and fluorescence spectroscopy with 1,6-diphenyl-1,3,5-hexatriene (DPH). It was discovered that the formation of the DMPC subgel phase requires incubation at temperatures of -5 degrees C or lower for 2 h or more. Kinetics of the subgel formation indicate that it is a very complex process and demonstrates that the planar gel phase is merely metastable below the subtransition, and not the thermodynamically stable phase. The subgel growth of DMPC is proven to be the dehydration of the headgroup region, and the subtransition is a process in which poorly hydrated DMPC becomes hydrated.

Subgel Studies of Dimyristoylphosphatidylcholine Bilayers.

Insights into the dynamics of DMSO in phosphatidylcholine bilayers.

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N-terminal processing of proteins exported by malaria parasites

Calorimetry studies of chlorpromazine hydrochloride in solution

Subgel Studies of Dimyristoylphosphatidylcholine Bilayers.

Insights into the dynamics of DMSO in phosphatidylcholine bilayers.