''Plasmodium falciparum'' cell biology
Plasmodium falciparum has been the focus of much research due to it being the causative agent of malaria. This article describes some of the recent findings surrounding the unique biology of this organism.
|This article may be too long to read and navigate comfortably. (December 2012)|
|It has been suggested that this article be split into multiple articles. (Discuss) Proposed since December 2012.|
The nucleus, mitochondrion, apicoplast and the microtubules of Plasmodium sporozoites are linked to the parasite pellicle via long tethering proteins. The tethers originate from the inner membrane complex and are arranged in a periodic fashion following a 32 nanometer repeat. The tethers pass through a subpellicular structure that encompasses the entire parasite, probably as a network of membrane associated filaments.
The pellicle is a structure unique to the Apicomplexa made up of four components: the plasma membrane, the inner membrane complex, the subpellicular network and the subpellicular microtubules. The subpellicular network consists of a two-dimensional network of intermediate filaments located on the cytoplasmic side of the inner membrane complex and acts as a membrane skeleton. The proteins - the inner membrane complex proteins (IMCs) - that compose this structure are functional homologs of the articulins, the membrane skeleton proteins of free-living protists.
Cell division occurs through a process known as schizogony. This is a type of mitotic division in which multiple rounds of nuclear divisions occur before the cytoplasm segments.
DNA synthesis begins in the relatively small trophozoites but nuclear subdivision, which leads to the formation of multinucleate cells, occurs only during schizogony. Whether or not any gap phases exist between each round of DNA synthesis and mitosis is unknown. Eventually, a schizont composed of 8–32 nuclei undergoes segmentation, which culminates with the formation of individual merozoites that burst from the erythrocyte into the blood stream.
Invasion of the hepatocytes appears to involve at least 2 proteins: sporozoite invasion-associated proteins (SIAP)-1 and -2. These proteins bind heparin sulfate and chondroitin sulfate type membrane receptors on host cells.
Latency of sporozoites is controlled by the eIF2 alpha kinase IK2, a general inhibitor of protein synthesis. Puf2 participates in the regulation of IK2 and inhibits premature sporozoite transformation. In contrast Puf1 appears to be dispensable.
The RNA binding protein family PUF member Pumilio-2 (Puf2) appears to be involved in transformation of sporozoites into the hepatic stage of the life cycle. Knock out mutants of this gene exhibit genome wide transcriptional changes resulting in loss of gliding motility, cell traversal ability, reduction in infectivity and trigger metamorphosis typical of early Plasmodium intra-hepatic development.
The division of the liver stages into thousands of merozoites is a complex process. In parallel with nuclear division, the apicoplast and mitochondrion become two extensively branched and intertwining structures. The organelles subsequently undergo morphological and positional changes prior to cell division. Finally to form merozoites, the parasite undergoes cytokinesis.
During this stage of development the sporozoite selectively discards organelles unnecessary for growth at this stage of the life cycle. Among these are the micronemes and the inner membrane complex.
The host iron regulatory hormone hepcidin which is synthesised in the liver and spleen, appears to be able to inhibit growth of the liver stages. Levels of this hormone are elevated during infection and seem to correlate with the anaemia often found in malaria. Erythrocytic parasitaemia, above a minimum threshold, impairs the growth of subsequent liver cell sporozoite infection. The production of hepcidin leads to the redistributes iron away from hepatocytes thus slowing the development of the iron dependent liver stage.
Liver hepcidin expression is upregulated and downregulated during the early and late stages of malaria infection respectively. Inflammation and erythropoietin, rather than the iron sensing pathway, are involved in the regulation of hepcidin expression. Treatment of malaria infected mice with anti hepcidin neutralizing antibodies increased parasitemia and mortality rates. Overexpression of hepcidin improves the outcome.
Lipocalin 2, a host protein that sequesters iron, is upregulated during infection and appears to be involved in the host response. This protein increases both host macrophage function and granulocyte recruitment and decreases reticulocytosis.
Expression of the iron sequestering protein ferritin (ferritin H chain in mice) is associated with decreased tissue damage. The mechanism appears to be via prevention of activation of the proapoptotic c-Jun N-terminal kinase.
Invasion of the hepatocyte seems to require the RON4 protease.
Within the liver actin reorganization is a dynamic process in part controlled by the actin severing and capping protein - gelsolin. The hepatocyte cytoskeleton may contribute to parasite elimination.
In Plasmodium bergei a protein - liver specific protein 2 (LISP2) - is expressed 24 hours after infection and rapidly increases during the liver stage schizogony. LISP2 is carried first to the parasitophorous vacuole and subsequently transported to the cytoplasm and nucleus of host hepatocytes. Mutations in this gene result in arrested development of the merozoites.
Two other proteins (p52 and p36)in Plasmodium bergei appear to be important in the formation of the parasitophorous vacuole membrane in the liver.
This is a complex and poorly understood process. The merozoite initially contacts the erythrocyte and rotates until the rhoptery containing part is adjacent to the erythrocyte membrane. A tight contact is then established and the parasite enters the erythrocyte. This happens within seconds making the invasion process difficult to analyse.
- Initial adhesion
Two families of proteins are known to be involved in this process: the reticulocyte binding-like homologues (PfRh or PfRBP) and erythrocyte binding-like (EBL) proteins. The EBL family are principally located in the micronemes and the Reticulocyte binding Homolog (PfRH) family are principally located in the rhopteries. Ligands from the EBL family largely govern the sialic acid dependent pathways of invasion and the RH family ligands (except for RH1) mediate sialic acid independent invasion.
The PfRh family consists of five proteins and a pseudogene: PfRh1, PfRh2a, PfRh2b, PfRh3, PfRh4 and PfRh5. PfRh3 is a transcribed pseudogene in all strains examined to date. All the other members of this family bind to erythrocyes and antibodies to them inhibit invasion. PfRh5 is located within the rhoptries and appears to be an essential gene.
Reticulocyte binding like protein homologue 2a (PfRH2a) is processed both in the schizont as well as during invasion resulting in proteins with different erythrocyte binding properties. It also moves from the rhoptry neck to the moving junction during merozoite invasion. PfRh2a undergoes a cleavage event in the transmembrane region during invasion consistent with activity of the membrane associated PfROM4 protease. Both PfRh2a and PfRh2b bind to red blood cells. The erythrocyte-binding domain lies within a 15 kDa region at the N-terminus of each protein.
PfRh4 binds to a second protein P. falciparum Rh5 interacting protein (PfRipr). PfRipr has a molecular weight of 123 kiloDaltons with 10 epidermal growth factor-like domains and 87 cysteine residues distributed along the protein.
The receptor for the PfRh5 protein appears to be the Ok blood group antigen, basigin. Blocking access to this protein on the erythrocyte surface appears to inhibit erythrocyte invasion completely. Binding of the Rh5 protein appears to be critically dependent on a single residue within the Rh5 protein.
The EBL family of proteins includes EBA-175, EBA-181 (also known as JESEBL), EBA-140 (also known as BAEBL) and EBL-1. Whilst these parasite ligands function in merozoite invasion by binding to specific receptors on the erythrocyte, they appear also to have a central role in activation of the invasion process. Binding of EBA-175 to its receptor, glycophorin A, restores the basal cytosolic calcium levels after interaction of the merozoite with the erythrocyte and triggers the release of rhoptry proteins.
These proteins have several domains. Region II which is responsible for ligand-erythrocyte interaction during invasion, consists of two homologous F1 and F2 domains.
A member of the EBL family of proteins (maebl) has been shown to be present in Plasmodium gallinaceum. This protein is now known to be conserved in the primate, rodent and avian infecting species suggesting that it may play an important role in erythrocyte invasion.
The EBL proteins have a Duffy like binding domain (DBL) unique to Plasmodium species. The crystal structure of EBA-140 has been solved. This protein binds glycophorin C on the host cell membrane. The two domain binding region is present as a monomer. Both domains are required for binding to occur. Its electrostatic surface has a basic patch spanning both DBL domains that is important in the binding mechanism.
There seems to be some overlap between the functions of these proteins. Loss of EBA-175 can be compensated by increased expression of PfRh4.
Another family of proteins involved in the invasion process are the thrombospondin related anonymous protein (TRAP) family. These proteins are type I cell surface proteins with one or more extracellular thrombospondin type-I repeats (TSR) domains and/or von Willebrand factor like (vWF) A domain(s) and an acidic cytoplasmic tail with a subterminal tryptophan residue. The cytoplasmic tails of TRAP, CTRP, TLP and MTRAP interact with the enzyme aldolase.
The motile forms have their own stage specific cell surface TRAP family member: TRAP and S6 (also known as TREP) occur on the sporozoites; CTRP is found on the ookinetes; MTRAP is expressed in the merozoites; and TLP is present on both sporozoites and merozoites. Other members of this family are the proteins CSP, SPATR, TRSP, WARP and PTRAMP. Roles for several of these proteins has been discovered: TRAP is critical for sporozoite invasion of the mosquito salivary glands, infection of mammalian liver and sporozoite gliding motility; CTRP is required for invasion of the mosquito midgut; and S6 is important for both sporozoite gliding motility and invasion of mosquito salivary glands. TLP has a role in sporozoite cell traversal. The cytoplasmic tail of TRAP is essential for gliding motility and invasion of the mosquito's salivary glands. Both the TSR and A-domains of TRAP are required for the invasion of the mosquito salivary glands. Penetration of the mammalian hepatocytes however requires the TSR, the A-domain and the cytoplasmic tail. In contrast only the A-domains of CTRP are essential for infectivity by the ookinete.
Another protein thought to be involved in the invasion process is the merozoite-specific thrombospondin related anonymous protein homolog (MTRAP). The receptor for this protein has been identified as the GPI-linked protein semaphorin-7A (CD108). The MTRAP monomers interact via their tandem TSR domains with the Sema domains of a Semaphorin-7A homodimer.
A GPI-anchored micronemal antigen (GAMA) also appears to be essential in the process of erythrocyte invasion.
Merozoite proteins 8 and 10 which are thought to be involved in the invasion process appear to be under purifying selection.
A double C2 domain (DOC2) protein appears to be involved in the invasion of the erythrocyte. DOC2 proteins recruit the membrane fusion machinery an essential part of the Ca2+-dependent exocytosis mechanism. These proteins have a Munc13-interacting domain and tandem C2s (designated C2A and C2B) which are connected by a short polar linker. The C2 domains bind phospholipids in a Ca2+-dependent manner. Elucidating their precise role in erythrocyte invasion requires further work.
In Plasmodium vivax a number of tryptophan rich antigens are involved in erythrocyte invasion. Homologs of these proteins are found in P. falciparum - tryptophan-threonine rich antigen (PfTryThrA) and merozoite associated tryptophan rich antigen (PfMaTrA) and Plasmodium yoelii. These proteins also seem to be involved in the invasion process.
The invasion process appears to be ATP dependent and may involve a purogenic signalling pathway.
The invasion process requires a coupling of the actin-myosin motor to the surface receptors. The myosin molecule involved belongs to the single-headed class XIV myosin. For the thromobospondin related anonymous protein on the sporozoites, aldolase which can bind actin forms this connection. This connection requires tryptophan and negatively charged amino acids in the ligand's cytoplasmic tail. PfRH2b also binds aldolase with its cytoplasmic tail. This binning requires an aromatic amino acid (phenylalanine or tyrosine) rather than tryptophan again also in the context of negatively charged amino acids. PfLRH2a does not bind aldolase. A second protein glyceraldehyde-3-phosphate dehydrogenase can also bind actin. It is capable of biding the cytoplasmic tails of some of the PfRh and Duffy biding ligands ligands in an aromatic amino acid dependent manner.
The motor behind the invasion process is an actinomyosin motor complex that is assembled below the parasite's plasma membrane. This complex includes myosin, myosin tail domain interacting protein and glideosome associated proteins 45 and 50. It is anchored on the inner membrane complex which underlies the cell membrane. Myosin, myosin tail domain interacting protein and GAP45 first form a complex that then associates with GAP50. GAP45 is phosphorylated by calcium dependent protein kinase 1 on a number of serine residues. Removal of these residues does not appear to affect the assembly of this complex. This complex may have other function in addition to its role erythrocyte invasion.
GAP45 is phosphorylated in response to Phospholipase C and calcium signaling. It is phosphorylated by the P. falciparum kinases Protein kinase B and Calcium dependent protein kinase 1, both of which are calcium dependent enzymes, at Serine89, Serine103 and Serine149. Phosphorylation of these sites is differentially regulated during parasite development.
Some details of the invasion process are known. The rhoptery protein RON2 is inserted into the erythrocyte membrane. The protein AMA1 secreted from microneme then binds to RON2. RON2 forms part of a macromolecular complex which includes RON2, RON 4, RON5 and RON8.
The calcium dependent protein kinase 1 appears to play a role in micronene discharge. The drug purfalcamine is a specific inhibitor of this kinase and it also inhibits micronene discharge and erythrocyte invasion. These kinases typically have an N terminal kinase domain and C terminal calmodulin like domain with calcium binding EF hands. The N and C terminals are joined by a junction domain. The C terminal appears to interact with the junction domain in the process of binding calcium.
The rhopteries appear to have subcompartments allowing for differential secretion during the life cycle. Two of these are known as the neck and the bulb. A number of rhoptry neck proteins are conserved between apicomplexan species and are involved in host cell invasion. Bulb proteins in contrast are less well conserved between the apicomplexa and most likely evolved for a particular lifestyle. In In the majority of species studied to date, rhoptry content is involved in formation and maintenance of the parasitophorous vacuole.
The rhoptery neck proteins (RONs) along with the micronemal AMA1 protein are important in the penetration of the erythrocyte. These form part of the moving junction which initially binds to the erythrocyte surface and is involved in the entry of the parasite into the erythrocyte cytoplasm. The mechanisms involved in this process are still being elucidated. The protein RON8 appears to be central to the binding of parasite to the erythrocyte surface. Apical Sushi Protein and Rhoptry Neck protein 2 are released early following the formation of the tight junction between the merozoite and the erythrocyte. The rhoptry protein PFF0645c is released only after invasion is complete.
The rhoptry protein 2 of Plasmodium vivax has been cloned. The 1,369 amino acid protein is encoded PVX_099930 gene. The gene has nine introns and the protein contains a signal peptide at its N-terminus and 12 cysteines predominantly in its C-terminal half. It is localized in one of the apical organelles of the merozoite, the rhoptry, and the localization pattern is similar to its homolog in P. falciparum.
Apical membrane antigen-1 (AMA-1) - the product of the Pfama1 gene - is a surface exposed protein that plays a role in erythrocyte invasion. It is shed from the parasite surface predominantly via the action of the protease Sub2 Sub2 is released from the micronemes and can also act on the MSP1/6/7 complex and PTRAMP - another micronemal protein. Sub2 appears to be an essential gene.
The residues of the RON2 protein binds to the AMA-1 protein have been identified. It also appears that the formation of the junction and parasitophorous vacuole are molecularly distinct steps in the invasion process. Positive diversifying selection appears to have acted in the RON2 protein of Plasmodium vivax.
The receptor binding site of AMA-1 comprises the hydrophobic groove and a region that becomes exposed by displacement of the flexible domain II loop.
Several proteins are involved in the binding of the sporozoite to the various tissues it attaches to. TRAP, S6 and TLP have been implicated in these processes. Heparin like molecules bound to the surface of the erythrocyte appear to be important in this process which involves the merozoite surface protein 1.
In 1902 the German physician Georg Maurer discovered an unusual staining pattern in the cytoplasm of erythrocytes infected with P. falciparum. These structures were subsequently named Maurer's clefts. These consist of a convoluted set of membranes that lie within the erythrocyte's cytoplasm and appear to be involved in secrection from the erythrocyte. They are known to have proteins of parasite origin within them including the Maurer's cleft two transmembrane proteins (PfMC-2TM) The clefts appear to originate from vacuoles budding off them the parasitophorous vacuole membrane which then diffuse within the erythrocyte cytoplasm before taking up residence at the cell periphery.
Another protein associated with these structure is skeleton-binding protein 1 (SBP1). This protein is involved in transport of the var gene protein, pfEMP1 (erythrocyte membrane protein 1) to the erythrocyte surface.
Mutations in the ring exported protein 1 (Rex 1), a protein normally found in Maurer's clefts, reduces transport of the var gene products to the erythrocyte surface.
The parasite generates a host derived actin cytoskeleton within the cytoplasm of the erythrocytes that connects the Maurer's clefts with the host cell membrane and to which transport vesicles are attached. Hemoglobin oxidation products which are enriched in hemoglobin S and C containing erythrocytes inhibit actin polymerization. This may account for their protective role in malaria.
The protein trophozoite exported protein 1 (PFF0165c) is located within the clefts. The protein's N-terminal region is intrinsically unstructured but it also has a coiled coil domain. It appears to lack export motifs such as PEXEL, signal sequence/anchor or a transmembrane domain. Transport of this protein to the clefts is sensitive to inhibition by Brefeldin A. This is normally associated with proteins that are have co-translation translocation into the endoplasmic reticulum or posttranslational insertion into the endoplasmic reticulum followed by vesicular transport from the endoplasmic reticulum via Golgi apperatus to the cell surface.
The 700 kiloDalton protein Pf332 is the largest known exported asexual malaria protein. The protein has three parts: an N-terminal Duffy binding like domain followed by a putative transmembrane region and a large number of negatively charged repeats that are not identical but have the consensus (X)3-EE-(X)2-EE-(X)2–3 where E is glutamic acid and X is a hydrophobic amino acid. The repeat portion of the protein consititue more than 90% of the protein. The protein has a predicted isoelectric point (pI) of 3.8. It is known to associate with the erythrocyte plasma membrane.
The Pf332 protein can first be detected within the parasite at 20–24 hours post invasion, after which it translocates across the parasitotopherous vacuole membrane into the host cell cytosol. It is initially synthesised in the endoplasmic reticulum and eported to the host cytosol. From there it is trafficked as part of a multimeric protein complex to Maurer's clefts. It may interact with two chaperone proteins - PF14_0700 (a hypothetical protein with a J domain) and PFB0595w (a heat shock protein 40). It is associated with the cytoplasmic side of Maurer's clefts in a peripheral manner throughout trophozoite maturation and schizogony. In the clefts both the N and C-termini are localised to the erythocyte cytosol. Export of Pf332 is sensitive to treatment with Brefeldin A The export signal appears to be encoded in the N terminal domain
Within a red blood cell, P. falciparum resides inside the parasitophorous vacuole. This is formed during erythrocyte invasion.
The proteins originating in the parasite pass through the membrane of the parasitophorous vacuole and are transported to the cytoplasm or membrane of the erythrocyte. Although this transport mechanism is largely unknown some details have been elucidated. Ingestion of the erythrocyte cytoplasm begins in mid-ring-stage parasites. Host cytoplasm is internalised via cytostome-derived invaginations and then concentrated into several acidified peripheral structures. Haemoglobin digestion and haemozoin formation occur within these vesicles. The ring-stage parasites can adopt a deeply invaginated cup shape, but they do not take up haemoglobin via macropinocytosis. As the parasite matures the haemozoin containing compartments coalesce to form a single acidic digestive vacuole (pH 4.5 - 5.5) that is then fed by haemoglobin containing vesicles. Some haemoglobin degradation also occurs in compartments outside the digestive vacuole.
The enzyme phosphatidyl-inositol-3-kinase (PI3K) has been implicated in this process. PI3K is located in vesicular compartments near the membrane and in the digestive vacuole and is involved in endocytosis from the host and trafficking of hemoglobin in the parasite. Its inhibition with wortmannin or LY294002 results in entrapment of hemoglobin in vesicles within the parasite cytoplasm preventing its transport to the digestive vacuole.
The pH of the digestive vacuole is maintained by a V-type H(+)-ATPase.
A signal sequence at the N terminal of proteins targeted to the arasitophorous vacuole has been identified. The signal appears to reside in the 55 amino acids of the N terminal of the protein. There may be a retention signal at the C terminal.
Plasmodium falciparum, and most other members of the phylum Apicomplexa, contain an organelle termed an apicoplast. The apicoplast is an essential plastid, homologous to a chloroplast, although the apicoplast itself lacks any photosynthetic function. Evolutionarily it is thought to have been derived through secondary endosymbiosis. As humans do not harbor apicoplasts, this organelle and its constituents are seen as a possible target for antimalarial drugs.
It contains a 35-kb genome, which encodes for 30 proteins. The genome of this organelle has now been sequenced for several species. It appears to be conserved and to encode ~30 genes in all species examined.
The plastid genome replicates at the late trophozoite stage of the parasite intraerythocytic cycle. It proceeds predominantly via a D-loop/bi-directional ori mechanism with replication ori localized within the inverted repeat region. The process of replication involves a nuclear-encoded DnaJ homolog that binds to the ori site.
The DNA polymerase involved in the replication of its genome is Pfprex (Klenow-like polymerase). This enzyme has been cloned, expressed and purified. The enzymes is relatively error prone and shows a bias toward T->C mutations.
Other nuclear encoded proteins are transported into the apicoplast. Transport into the apicoplast are not well understood. These proteins has a signal in the N terminal but unlike many other organisms this appears to be a disordered chain rather than a conserved sequence. It was thought that a specific signal peptide was responsible for this targeting  and it was estimated that 551, or roughly 10%, of the predicted nuclear-encoded proteins are targeted to the apicoplast. This hypothesis now appears to be incorrect. It appears that a relative enrichment within the protein of positively charged amino acid residues (Arginine, Histidine, Lysine) particularly at the N terminal of the protein may be sufficient to target the protein to the apicomplast.
The biosynthesis of this organelle is not well understood. Phosphatidylinositol 3-monophosphate has been shown to be involved in its biosynthesis in the apicomplexian Toxoplasma gondii. It seems likely that this enzyme is involved in the formation of this organelle in the Plasmodium species also.
This organelle appears to be essential in the liver stages.
The functions of this organelle remains to be fully determined but it appears to be involved in the metabolism of fatty acids, isoprenoids and heme. There are two pathways for protein lipoylation in Plasmodium - one in the mitochondrion and the other in the apicoplast. The apicoplast pathway is not found in the vertebrate host and relies on de novo lipoic acid synthesis.
The role of the apicoplast in the blood stages has been clarified. Inhibition of isoprenoid precursor biosynthesis with the antibiotic fosmidomycin (an inhibitor of the enzyme DOXP reductoisomerase) causes delayed death in this parasite. This effect can be overcome with the addition of isopentenyl pyrophosphate (IPP) to the culture medium. Continued culture in the presence of this agent leads to the loss of the apicoplast genome and these mutants fail to process or localize organelle proteins. These auxotrophs can be grown indefinitely in asexual blood stage culture but are entirely dependent on exogenous IPP for survival.
Iron-sulphur prosthetic groups are assembled in this organelle. One component (SufB) is encoded in the apicoplast genome and a second (SufC) is encoded in the nucleus. SufB also exhibits ATPase activity. Other pathways that have been linked to this organelle include biosynthesis of isoprenoid precursors, fatty acids, heme and lipoic acid.
A gene ''Plasmodium''-specific Apicoplast protein for Liver Merozoite formation (PALM) has been shown to be important for merozoite formation. Knock out mutants are unable to release merozoites into the blood from the liver stages. Mutants lacking this gene appear to be able to elicit at least temporary immunity.
Falcilysin a zinc metalloprotease is found in the apicoplast. It is a member of the M16 protease group and has maximal activity at neutral pH. It appears to be an essential gene. Its function in this organelle is not quite clear but it appears to be involved in the degradation of transit peptides.
Two C3 sugar phosphate transporter are present in the membrane of the apicoplast of Plasmodium berghei - triose phosphate transporter and phosphoenolpyruvate transporter. Knock out mutants of the triose phosphate transporter fail to survive. Phosphoenolpyruvate transporter knock out mutants survive in the blood stages but suffer defects during maturation. These latter mutants also do not survive in the liver or mosquito stages.
An ATP dependent caseinolytic protease (ClpP) is present in the apicomplast. Its function is currently unknown.
Plasmodium lacks mitochondrial pyruvate dehydrogenase and the hydrogen ion translocating NADH dehydrogenase (Complex I, NDH1). The mitochondrion contains a minimal DNA genome (~6 kilobases) and carries out oxidative phosphorylation in the insect vector stages by using 2-oxoglutarate as an alternative means of entry into the tricarboxylic acid cycle and a single-subunit flavoprotein as an alternative NADH dehydrogenase (NDH2). In the blood stages mitochondrial enzymes are down regulated and parasite energy metabolism relies mainly on glycolysis. The enzyme malate quinone oxidoreductase was acquired from an epsilon proteobacteria via lateral gene transfer. This transfer occurred in an ancestor of the Apicomplexa.
The ATP synthase is localised to the mitochondrion, is assembled as a large dimeric complex and appears to be essential for in the blood stages of the life cycle. Its function in these stages is not yet clear.
The sulfhydryl:cytochrome c oxidoreductase Erv1/ALR/GFER/HSS (Essential for Respiration and Vegatative growth/Augmenter of Liver Regeneration/Growth Factor Erv1-like/Hepatic regenerative Stimulation Substance/hepatopoietin) is an essential sulfhydryl oxidase for required oxidative protein import into the mitochondrial intermembrane space. It is one of several enzymes involved in electron transferase activity. It is encoded by all eukaryotes and cytoplasmic DNA viruses sequenced to date. The enzyme from P. falciparum differs significantly from that found in yeast and humans with altered cysteine motifs and intermolecular disulfide bonds. Despite successful cloning and expression in yeast, the parasite enzyme fails to function in yeast. A second related enzyme - Mia40 - does not appear to be present in P. falciparum.
Deletion of the gene in the rodent parasite Plasmodium berghei for the flavoprotein subunit of succinate dehydrogenase - part of the complex II - showed impairment of ookinete function and oocyst formation.
The gene for the flavoprotein subunit of succinate dehydrogenase can be disrupted in the parasite. Its disruption causes growth retardation of the intraerythrocytic forms. It appears that complex II functions as a quinol-fumarate reductase to form succinate from fumarate in the intraerythrocytic parasite.
The dicarboxylate-tricarboxylate carrier homolog has been cloned from P. falciparum. This protein may mediate the oxoglutarate-malate exchange across the inner mitochondrial membrane required for the branched pathway of tricarboxylic acid metabolism.
The ClpQ protease and ClpY ATPase have been cloned. ClpQY function disruption caused hindrance in the parasite growth and maturation of asexual stages of parasites. Features of apoptosis like cell death are also found.
The mitochondrial pathway of protein lipoylation relies on scavenging from the host and can be inhibited with the lipoic acid analog 8-bromo-octanoic acid. Use of this agent inhibits growth and significantly reduces merosome formation. Schizogony is the phase most affected by this inhibition.
Atovaquone, a 2-hydroxynaphthoquinone, is a competitive inhibitor of the quinol oxidation site of the mitochondrial cytochrome bc1 complex and is used as an antimalaria agent. Inhibition of this enzyme leads to the collapse of the mitochondrial membrane potential and disruption of pyrimidine biosynthesis. These effects are lethal to the parasite.
The mitochondrial RNA polymerase appears to be an essential gene for the erythrocytic stages.
Over half the genome of the mitochondrion encodes the genes for three classic mitochondrial proteins: cytochrome oxidase subunits I and III and apocytochrome b. The remainder encodes 34 RNA genes of which 27 have been assigned to ribosomal RNA (12 to the small subunit and 15 to the large subunit). These genes are fragmented and are encoded on both strands.
During growth of the parasite and as part of its digestion of the erythrocyte's haemoglobin, fusion of digestive vesicles occurs and gives rise to a large digestive vacuole. This vacuole the interior of which is maintained at a low pH (pH 4.5 - 5.5), processes 60-80% of the ingested hemoglobin and provides a pool of amino acids that is crucial for parasite growth and development. The membrane contains ion pumps and transporters that maintain its low pH. During haemoglobin digestion the heme is released from hemoglobin. Haem is toxic to the parasite and is detoxified by biocrystallization to hemozoin within the vacuole. Quinoline drugs, including chloroquine, act by binding to heme and thus prevent its sequestration into hemozoin.
It has been shown that micromolar concentrations of chloroquine partially permeabilized the parasite's digestive vacuole membrane and that this event appears to precede mitochondrial dysfunction.
Quinine has been shown localise to a non acidic compartment within the digestive vacuole. It may colocate with haemozoin. It's localisation within the parasite is not altered by the presence or absence of a functional multidrug resistance gene.
The digestive vacuole is able to activate both the alternative complement and the intrinsic clotting pathway. The digestive vacuole membrane has the capacity to assemble prothrombinase, a key enzyme of the intrinsic clotting pathway. The capacity of this membrane to activate both complement and coagulation can be suppressed by low molecular weight dextran sulfate. Phagocytosis of these membranes drives the polymorphonucleocytes into a state of functional exhaustion.
Two multi-spanning digestive vacuole membrane proteins are known: the multidrug resistance protein 1 and Chloroquine Resistance Transporter (CRT). The CRT protein moves from the endoplasmic reticulum to the Golgi apparatus before becoming associated with the digestive vacuole. The digestive vacuole forms in the ring stages of the parasites life cycle. Chloroquine sensitivity is not influenced by the absence of CRT from the digestive vacuole bringing into question its relationship (if any) to chloroquine resistance. Mutations in the CRT gene have been associated with sensitivity and resistance to quinolines. In particular a lysine to isoleucine at codon 76 (Adenosine -> Thymine at base 227) mutation and a valine to phenylalanine (Guanine -> Thymine at base 1108) mutation have been associated with changes in drug sensitivity.
The digestion of haemoglobin produces large quantities of ferriprotoporphyrin IX which it unable to digest and is potentially toxic to the parasite. To avoid the toxicity the ferriprotoporphyrin is converted to haemozoin. Chloroquine inhibits this process. The mechanisms behind this process are still unclear. In vitro conversion of ferriprotoporphyrin to haemazoin is enhanced at a temperature of 41C when compared to its conversion at 37C. It is possible that the rise in temperature that occurs in malaria may be part of a strategy to enhance this reaction at the later stages of growth when the ferriprotoporphyrin concentration is likely to be high.
This forms a set of reticular structures adjacent to the nuclear regions during the trophozoite and schizont stages. In the late schizont stage it forms globular structures surrounding each budding merozoite.
Unlike other eukaryotes studied to date Plasmodium species have two or three distinct SSU rRNA (18S rRNA) molecules encoded within the genome. These have been divided into types A, S and O. Type A is expressed in the asexual stages; type S in the sexual and type O only in the oocyte. Type O is only known to occur in Plasmodium vivax at present. The reason for this gene duplication is not known but presumably reflects an adaption to the different environments the parasite lives within.
The Asian simian Plasmodium species - Plasmodium coatneyi, Plasmodium cynomolgi, Plasmodium fragile, Plasmodium inui, Plasmodium fieldi, Plasmodium hylobati and Plasmodium simiovale - have a single single S-type-like gene and several A-type-like genes. Phylogenetic analyses has shown that gene duplication events giving rise to A- and S-type-like sequences took place independently at least three times in the Plasmodium evolution.
The phosphoprotein P0 occurs as a complex with two other small acidic ribosomal proteins (P1 and P2). A pentameric complex [(P1–P2) P0 (P1–P2)] form the stalk of the large ribosomal subunit, which seems to play a role in the GTPase elongation centre of the ribosome.
The P2 protein is exported to the infected erythrocyte surface at 30 hrs post merozoite invasion, concomitant with extensive oligomerization. It is largely largely composed of alpha helical and random coil domains.
FACT (facilitates chromatin transcription) is a dimeric complex of two proteins - SPT16 and SSRP1 - which acts as a histone chaperone in the (dis)assembly of nucleosome (and chromatin) structure during transcription and DNA replication. It is an essential gene in Plasmodium. Changing its promoter to one expressed only in the blood stages leads to changes in the male gametocytes. The mutant gametocytes have delayed DNA replication and gametocyte formation. Male gamete fertility is strongly reduced. Female gametocytes appear to be normal. When successful fertilization is achieved, the ookinetes generate oocysts that arrest early in development and fail to enter sporogony.
The proteins cell division cycle protein 20 and its homologue, CDC20 homologue 1 are central to the cell cycle activating the anaphase-promoting complex/cyclosome (APC/C) in mitosis and facilitating degradation of mitotic APC/C substrates. A single homolog of this gene has been identified in Plasmodium berghei. It appears to be essential in male gametogensis but not for asexual reproduction. Blockage occurs at the nuclear spindle/kinetochore stage.
A gametocyte development 1 gene (Gdv1) which encodes a perinuclear protein has been identified. Its mechanism of action is not known. Homologues of this gene have been found in Plasmodium vivax, Plasmodium knowlesi and Plasmodium gallinaceum.
Egress from the erythrocyte
This is an essential step in the life cycle. The calcium dependent protein kinase PfCDPK5 which is expressed in the merozoite is essential for this process. Deletion mutations of this gene result in cell arrest in the late schizont stages. Merozoites released from these schizonts are capable of invasion.
Large holes appear in the cytoskeleton ~35 hours post invasion. This occurs at the same time as the loss of cytoskeletal adaptor proteins that are part of the junctional complex, including α/β-adducin and tropomyosin. This is followed by the proteolysis of many cytoskeletal proteins during egress at ~48 hours post infection. This later proteolysis is mediated by the erythrocyte's own calpain-1.
Along with the release from the erythrocyte of the merozoites, the now functionless digestive vacuole is also released. These are can active complement and are rapidly taken up by the polymorphs. On ingestion the digestive vacuoles induce a vigorous respiratory burst which drives the cells into a state of functional exhaustion, blunting production of reactive oxygen species and microbicidal activity upon challenge with bacterial pathogens.
The serine repeat antigen (SERA) multigene family encode a series of proteins with a putative papain-like cysteine protease motif. One of these SERA5 (120 kiloDaltons) is produced at the late trophozoite/schizont stage. It is secreted together with other SERAs into the parasitophorous vacuole in an infected erythrocyte where it is cleaved into three fragments: an N-terminal domain (47 kDa), a central domain containing putative papain-like cysteine protease motifs (56 kDa) and a C-terminal domain (18 kDa). This N-terminal fragment is then cleaved in turn into two 25 kDa fragments. These fragments become covalently linked to the C-terminal 18 kDa fragment via disulfide bonding and attach to the merozoite surface. The central fragment is further cleaved to 50 kDa and 6 kDa fragments before being shed to the medium. These proteolytic cleavages are carried out by a subtilisin-like serine protease called PfSUB1 and the inhibition of this processing, likewise, results in blockade of merozoite release. SERA6 may also be involved in schizont rupture and merozoite release from the erythrocyte. Both SERA5 and SERA6 are essential for blood stage parasite viability. SERA6 is found in parasitophorous vacuole where it is activated by cleavage by the serine protease PfSUB1 just prior to egress. The release of PfSUB1 may be controlled by a calcium flux within the exomemes of the merozoites. The release may be under the control of a phopholipase C.
A protein - gamete egress and sporozoite traversal - has been identified that appears to be involved in the egress of male and female gametes from the erythrocyte. It is also involved in sporozoite migration.
Although several kinases are known in P. falciparum (~90) very little is known about them. Several are cyclin dependent kinase kinase like kinases (CLK): of these two - the Lammer kinase homologue PfCLK-1 and PfCLK-2 have been cloned. CLKs in other eukaryotes are involved in the regulation of mRNA splicing through phosphorylation of serine/arginine-rich proteins. Both are transcribed throughout the asexual blood stages and in gametocytes. PfCLK-1/Lammer possesses two nuclear localization signal sites while PfCLK-2 possesses one of these signal sites upstream of the C-terminal catalytic domains. The two PfCLKs form complexes with proteins with predicted nuclease, phosphatase or helicase functions.
Although the kinases are primarily localized in the parasite nucleus, PfCLK-2 is also present in the cytoplasm. They are important for completion of the asexual replication cycle. Substrates phosphorylated by the PfCLKs include the Sky1p substrate, splicing factor Npl3p, and the plasmodial alternative splicing factor PfASF-1.
Within the genome is a family of four protein kinases (Pfnek-1 to -4) that are related to the NIMA (never-in-mitosis/Aspergillus) family of kinases. The members of this latter family play important roles in mitosis and meiosis. Pfnek-1 (PFL1370w) is expressed in asexual parasites and male gametocytes. It is an essential gene for completion of the asexual cycle. The other three - Pfnek-2 (PFE1290w), -3 (PFL0080c) and -4 (MAL7P1.100) - are expressed predominantly in gametocytes.
Pfnek-2 is predominantly expressed in gametocytes and is required for DNA replication during meiosis and ookinete development.
A mitogen activated protein kinase (MAP kinase) gene is located on is located on chromosome 14. It is predominantly expressed in gametocytes and gametes/zygotes. The protein has 882 amino acid residues and possesses a TDY dual phosphorylation site upstream of the highly conserved VATRWYRAPE sequence within subdomain VIII. Within the carboxyl-terminal segment the protein contains an unusually large and highly charged domain. This region includes two repetitive sequences of either a tetrapeptide or octapeptide motif.
A subgroup of cyclin-dependent kinases (CDK) including crk-5 have an activation loop that contains a novel Proline-Threonine-x-Cytosine motif which is absent from all known CDKs outside the Apicomplexa.
The protein PFD0975w appears to be homologous with the right open reading frame 2 kinase RIO-2, a kinase involved in ribosome biogenesis and other cell cycle events. This enzyme is unique among the kinases in the genome because along with the kinase domain, it also has a highly conserved N-terminal winged helix domain.
The right open reading frame 2 protein kinase may be a potential drug target.
The protein kinase CK2, a serine/threonine protein kinase, has one catalytic subunit (PfCK2) and two regulatory ones (PfCK2beta1 and PfCK2beta2). This enzyme is found both in the cytoplasm and the nucleus. Substrates include the nucleosome assembly proteins (Naps), histones and two members of the Alba family. Both of the two regulatory subunits are required for completion of the asexual erythrocytic cycle.
There are at least three adenylate kinases (AK) encoded in the genome - PfAK1, PfAK2 and a GTP:AMP phosphotransferase (PfGAK). There are two additional adenylate kinase-like proteins - PfAKLP1 (which is homologous to human AK6) and PfAKLP2. PfAK1, PfAKLP1, and PfAKLP2 are found in the cytosol. PfGAK is located in the mitochondrion. PfAK2 is located at the parasitophorous vacuole membrane and this localization is driven by N-myristoylation.
The calcium dependent protein kinases (CDPK) are part of a superfamily found in plants, ciliates and some apicomplexa. They are not present in fungi or animals. They have three domains: a variable N-terminal region involved in substrate recognition and protein interaction, a kinase catalytic domain and a regulatory domain. The regulatory domain has two subdomains - an autoinhibitory junction domain and a calmodulin like domain. The calmodulin domain has four EF hands. These hands, upon binding calcium, undergo a structural change that moves the junction domain from its autoinhibitory interaction with the substrate binding site of the kinase domain which in turn activates kinase domain catalytic activity.
In P. falciparum CDPK5 controls parasite egress from host cells. In P. bergei CDPK3 is essential for the ookinete to traverse the mosquito midgut epithelium and CDPK4 is involved in development of the male gametocyte.
The homolog of calcium dependent protein kinase 1 (CDPK1) in Toxoplasma gondii is calcium dependent protein kinase 3 (TgCDPK3). This protein in Toxoplasma is localised to the inner membrane and is not an essential gene. It is involved in Ca(2+) ionophore control and host cell egress. The role of this protein in Plasmodium is not currently known. It is however expressed and localises with proteins at the perifery of the schizonts and merozoites involved in gliding motility and can can phosphorylate these proteins. Inhibition of CDPK 1 is associated with a block in development at the schizont level. In P bergei CDPK1 regulates transcription of stored mRNA during ookinete development in the mosquito midgut.
The cyclic guanine monophosphate dependent protein kinase is essential for the initiation of gametogenesis and for blood stage schizont rupture and may also be involved in ookinete differentiation and motility and liver stage schizont development.
There are 27 putative protein phosphatases in the genome. These can be classed into groups: phosphoprotein phosphatases, metallo-dependent protein phosphatases, protein tyrosine phosphatases and NLI interacting factor-like phosphatases.
A number of cysteine proteases have been identified this organism including four falcipains, serine repeat antigens (SERA), dipeptidyl aminopeptidase 1, dipeptidyl aminopeptidase 3 and a calpain homolog. The falcipains belong to the papain family of enzymes (clan CA).
Falcipain-1 appears to be important in the development of the oocysts in the mosquito.
Falcipain-2 is involved in the hydrolysis of haemoglobin and appears to be a non essential gene. It also promotes host cell rupture by cleaving the skeletal proteins of the erythrocyte membrane.
Falcipain-3 appears to be an essential gene but its function has yet to be firmly established.
Dipeptidyl aminopeptidase 1 is found in the digestive vacuole and is also an essential gene.
Dipeptidyl aminopeptidase 3 appears to be involved in the release of the merozoites from the erythrocyte.
Although most SERAs are cysteine proteases some have serine at the active site. SERA-5 and SERA-6 appear to be essential genes: SERA-5 also seems to be involved with egress of the merozoites.
There is at least one M1 family aminopeptidase in the genome (PfA-M1). This is a zinc binding metalopeptidase with optimal activity at pH 7.4, and remains at least 40% active between pH 5.8-8.6. Immunofluorescence studies have shown that in trophozoites that it diffusely found in the parasite cytoplasm with accumulations outside the digestive vacuole while in schizonts it is progressively located to a vesicle like pattern ending as a single location in released merozoites. It exists as two major isoforms, a nuclear 120 kDa species and a processed species consisting of a complex of 68 and 35 kDa fragments.
There are at least 2 essential metallopeptidases encoded in the genome - PfA-M1 and Pf-LAP. Specific inhibition of PfA-M1 causes swelling of the parasite digestive vacuole and prevented proteolysis of haemoglobin derived oligopeptides. This inhibition is lethal to the parasite probably by starvation. Inhibition of Pf-LAP is lethal to parasites early in the life cycle, prior to the onset of haemoglobin degradation suggesting a different role for this enzyme.
Falcilysin a zinc metalloprotease found in the apicoplast. It is a member of the M16 protease group and has maximal activity at neutral pH. It appears to be an essential gene. Its function in this organelle is not quite clear but it appears to be involved in the degradation of transit peptides.
M18 AAP is a metallo-aminopeptidase that has a highly restricted specificity for peptides with an N-terminal glutamine or asparagine residue.
The histo-aspartic protease (HAP) has been crystallised. This protein has high sequence similarity to pepsin-like aspartic proteases, but one of the two catalytic aspartates, Asp32, is replaced in this enzyme by a histidine residue. The propeptide interacts with the C-terminal domain of the enzyme, forcing the N- and C- terminal domains apart. This mechanically separates His32 and Asp215 and prevents formation of the mature active site. This mechanism is similar to those of other proplasmepsins. The enzyme has a number of unique features and may be a useful drug target.
There are at least 10 aspartic proteases encoded within the genome. Plasmepsins I, II, IV and histo-aspartic protease are known to be involved in the digestion of haemoglobin. These four enzymes share 50-79% amino acid sequence identity and are located on chromosome 14 (gene identifiers PF14_0076, PF14_0077, PF14_0078, and PF14_0075 respectively). Plasmepsins I and II are present in the food vacuole and make the initial cleavages in the hemoglobin molecule. The proplasmepsins I and II are both type II integral membrane proteins that are transported through the secretory pathway before cleavage to the soluble form. This reaction occurs within the food vacuole and the cleavage occurs immediately after a conserved Leucine-Glycine dipeptidyl motif. This reaction may be blocked calpain inhibitors. It appears that plasmepsin II and IV are capable of autoactivation as well as activation each other's inactive form. These two proteins are not glycosylated. Plasmepsin I is synthesized and processed to the mature form soon after the parasite invades the red blood cell, while plasmepsin II synthesis is delayed until later in development.
Plasmepsin V, an integral membrane protein, is located within the endoplasmic reticulum but not in the Golgi apperatus. The gene is expressed over the course of asexual intraerythrocytic development. The amount of the protein in the parasite is lowest in the ring stage and increases steadily through schizogony. It appears to be involved in the export of proteins to the erythrocyte.
There are at least 3 subtilisin like proteases encoded in the genome. These are serine proteases. One of these (PfSUB3) is expressed at late asexual blood stages. In the merozoites SUB2 has been implicated in shedding of adhesins at a juxtamembrane position.
Erythrocyte proteins taken up
A small number of erythrocytic proteins are taken up by the parasite during the course of its life cycle. The role these play is not clear. Among these proteins is dematin which interacts with the parasite's 14-3-3 protein.
The parasite is capable of making use of the erythrocyte's own enzymes. The enzymes PAK1 and MEK1 neither of which are encoded in the Plasmodium genome have been shown to be phosphorylated and activated during the course of infection' In vitro work has shown that inhibition of these enzymes is fatal to the parasite.
The uninfected erythrocyte lacks a regulated transport system. Vesicular transport within both the parasite and the infected erythrocyte cytoplasm must be provided by the parasite itself.
Both the cytoplasmic pH (7.3) and the inside-negative plasma membrane potential (-95mV) are kept fairly constant during the intra erythrocytic cycle. This is due to the action of a V-type H(+)-ATPase which is also responsible for the pH of the digestive vacuole.
The intracellular concentration of chloride ions has been estimated to be 48 milliMolar. It appears to actively import using ATP both hydrogen ions and chloride ions in a linked fashion via a DIDS sensitive transporter in the cytoplasmic membrane.
One difficulty the parasite has in acquiring nutrients from the cytoplasm is the presence of phosphate groups on these molecules. It appears to have overcome this by secreting an acid phosphatase (glideosome-associated protein 50 - GAP50 ) into the cytoplasm that is then taken up into the digestive vacuole.
The parasite has an absolute requirement for isoleucine - an amino acid absent from human haemoglobin. A saturable neutral amino acid (methionine, leucine, isoleucine) transporter appears to be encoded by the parasite and this protein functions in the infected erythrocyte membrane.
Two folate transporters (PfFT1 and PfTF2) have been cloned. Substrates include folic acid, folinic acid, the folate precursor pABA and the human folate catabolite pABAG(n). 5-methyl tetrahydofolate is not transported by PfFT1 and only poorly by PfFT2. The activity of both transporters may be inhibited by probenecid or methotrexate.
Within the genome are encoded 11 Rab GTPases. These proteins are typically involved in vesicle transport. Casein kinase-1 has been shown to interact with Rab5B and the catalytic subunit of cAMP-dependent protein kinase A interacts with Rab5A and Rab7.
The parasite possesses its own equilibrative nucleoside transporter 1. All members of this protein family have 11 transmembrane segments. The gene product is located in the parasite's plasma membrane and knock out mutants have shown that this is an essential gene at least at physiological concentrations. In the 11th transmembrane segment two mutations have been shown to affect its activity: a phenylalanine (Phe) to leucine (Leu) at residue 394 (F394L) via cytosine (C) or uracil (U) to adenosine (A) or guanine (G) at the third codon position and a cysteine (Cys) to glycine (Gly) mutation at either glycine in a conserved glycine-X-X-glycine motif (where X is any amino acid) via a cytosine to uracil at the second codon position. Additional work suggests that the 11th transmembrane segment is largely alpha helical. It has been suggested that this transmembrane segment may be the actual purine transport channel.
Within the genome there are encoded four equilibrative nucleoside transporters (ENTs). ENT 1 is the major route of purine nucleoside/nucleobase transport in the erythrocytic stages. Knock out mutants have been generated that can survive. ENT4 has been cloned and expressed. It does not appear to transport either hypoxanthine or adenine monophosphate but does transport adenine and 2'-deoxyadenosine. It is inhibited by dipyridamole.
The parasite is unable to synthesize purines (including adenosine, hypoxanthine and adenine) and must take these up from the host. Three purine transporters have been studied: the human equilibrative nucleoside transporter (hENT1), the human facilitative nucleobase transporter (hFNT1) and the parasite-induced new permeation pathway (NPP). The bulk of transport is facilitated by host's own transporters rather than through the NPP. Hypoxanthine and adenine were transported mainly through the hFNT1 pathway whereas adenosine entered predominantly through the hENT1 system. The rate of purine uptake in infected cells was approximately twice that of uninfected erythrocytes. The rate of adenosine uptake was greater than the rate of hypoxanthine uptake in infected human red blood cells. Furosemide inhibits the transport of purine bases through the hFNT1.
The clag3 genes on chromosome 3 appear to be involved in anion transport rather than in cell adherence as originally thought.
The clag3 gene family encode a parasite ion channel known as the plasmodial surface anion channel. Its activation appears to involve an intracellular domain.
At least two of the clag3 genes appear to be involved in the surface anion channel which functions in nutrient uptake.
An ATP-binding cassette (ABC) transporter encoded by the gene Pf14_0244 (PfABCG2) on chromosome 14 appears to have some role in the asexual stages, gametocyte stages and in the oocyst.
A copper transport protein (PF14_0369) has been identified This protein is expressed in early ring stage and translocating from the erythrocyte plasma membrane to a parasite membrane as the parasites developed to schizonts. Inhibition of copper uptake with neocuproine inhibits the ring to trophozoite transition.
There is at least one protein export system in the parasite. Several proteins are known to be involved in this process: HSP101 (a AAA+ ATPase), a protein of no known function termed PTEX150, and the apparent membrane component EXP2 - all of which are located within the dense granules of the merozoites.
For proteins destined for the erythrocyte a motif is known - RxLxE/D/Q Arginine - any amino acid - Leucine - any amino acid - Aspartic acid / Glutamic acid / Glutamine. Proteins with this motif bind to the lipid phosphatidylinositol 3-phosphate within the endoplasmic reticulum (ER). Cleavage of the motif results in the release of the protein from the ER membrane. Cleavage within the ER is carried out by the aspartyl protease plasmepsin V. The peptide chain is cleaved between the RxL and xE/Q/D submotifs. The xE/Q/D submotif then acts as an export signal to the erythrocyte. Mutation of the arginine to alanine results in the loss of binding to phosphatidylinositol 3-phosphate and an approximately threefold reduction in the export rate of the protein to the erythrocyte.
Protein export appears to be complex. It has been thought that protein export depended at least in part on the presence of a Plasmodium export element (PEXEL) within the protein. This does not actually appear to be the case.
Within the genome are encoded two forms of the protein actin - I and II. The first form (I) is present in significantly greater quantities. Actin II appears to be essential for the process of exflagellation. Deletion of this gene results in viable asexual stages. During the formation of the male gametes actin I is found initially in both the nucleus and the cytoplasm. After activation it is found only in the cytoplasm. In actin II deletion mutants actin I remains in both the nucleus and the cytoplasm after activation. Morphologically in the actin II mutants male gametocyte DNA was replicates normally and axonemes are assembled but egress from the host cell is inhibited and axoneme motility is abolished.
Two proteins P. falciparum actin-depolymerizing factor 1 (PfADF1) and P. falciparum actin-depolymerizing factor 2 (PfADF2) are involved in the polymerisation of actin. PfADF1 has ben crystallised and despite having significant differences from other proteins with similar function it is capable of severing actin filaments. PfADF2, like canonical ADF proteins but unlike ADF1, binds to both globular and filamentous actin, severing the filaments and inducing nucleotide exchange on the actin monomer. The crystal structure of PfADF1 shows major differences from the ADF consensus, explaining the lack of F-actin binding. PfADF2 structurally resembles the canonical members of the ADF/cofilin family.
The actins found In Plasmodium and in Toxoplasma are divergent both in sequence and function and only form short, unstable filaments in contrast to the stability of conventional actin filaments. This inherent instability of parasite's actin filaments is a critical adaptation for their gliding motility.
Actin is involved in the expression of the var genes. The var introns interact with an 18 base pair nuclear protein binding element which recruits actin and repositions the var DNA from a transcriptionally repressive to a transcriptionally active perinuclear compartment.
There are two formin genes encoded in the genome. These associate with and nucleate both mammalian and Plasmodium actin filaments. Another gene profilin - also encoded in the genome but only as a single copy - sequesters actin monomers preventing their polymerisation.
Several hemoglobinopathies that protect carriers from severe malaria may do so by interfering with host actin reorganization.
The cyclase associated proteins are among the most highly conserved regulators of actin dynamics. They catalyze nucleotide exchange on actin monomers from ADP to ATP and recycle actin monomers from ADF/cofilin for new rounds of filament assembly. The Plasmodium falciparum cyclase associated protein is entirely composed of β-sheet domains and efficiently promotes nucleotide exchange on actin monomers.
Thrombospondin Related Anonymous Protein (TRAP) is a type I transmembrane proteins which has several extracellular adhesive domains and a cytoplasmic domain that recruits the glycolytic enzyme aldolase. Normally only small amount of TRAP found on the sporozoite surface. TRAP is involved in cell motility.
Its' tandem von Willebrand factor A and thrombospondin type I repeat domains connect through the proline rich stalk, transmembrane and cytoplasmic domains to the parasite's actin dependent motility apparatus. Binding is dependent on the presence of a metal ion. The protein is capable of considerable conformational changes.
The cytoplasmic domain binds to F-actin which connects to myosin A. Within the transmembrane domain it has a canonical rhomboid cleavage site (Ala-Gly-Gly-Ile-Ile-Gly-Gly). Rhomboid proteases are a family of serine proteases that require helical instability in the transmembrane domain and have specific residue requirements in their P1, P4 and P2′ positions. These proteases are responsible for intramembraneous cleavage.
TRAP binds to receptors on the host and is translocated posteriorly by the actomyosin motor. It is then normally cleaved by a calcium independent serine protease. Removal of the cytoplasmic domain abolish the motility of the parasite. Mutations in the rhomboid cleavage site are defective in TRAP shedding and display slow, staccato motility and reduced infectivity. The reduction in infectivity is particularly marked if the sporozoites are inoculated intradermally rather than intravascularly. Prevention of cleavage of the TRAP protein entirely renders the sporozoites uninfectious and immobile. The rhomboid protease normally involved in TRAP cleavage appears to be the ROM4 protease. This protease is found across the entire sporozoite surface suggesting it has functions in addition to TRAP cleavage.
The circumsporozoite- and thrombospondin-related adhesive protein (CTRP) is a modular multidomain protein containing six tandem von Willebrand factor A like domains and seven tandem thrombospondin type I repeat-like domains. The A domains of CTRP are critical for ookinete gliding motility and oocyst formation. The thrombospondin domains are fully redundant.
The cell-traversal protein for ookinetes and sporozoites (CelTOS) is a protein involved in the invasion of both vertebrate and insect host cells.
The C-terminal tail of myosin A (MyoA) and its light chain, myosin A tail domain interacting protein (MTIP) are essential parts of the gliding motility apperatus.
Surface exposed proteins
Enolase is bound to the surface of P. falciparum and several other pathogens. In this location it binds plasminogen which is thought to function in the degradation of the extracellular matrix surrounding the targeted host cell, thereby facilitating pathogen invasion.
The ETRAMP family is characterized by a predicted signal peptide, a short lysine rich stretch, an internal transmembrane domain and a highly charged C-terminal region of variable length. The highly charged terminal region appears to be involved in protein-protein interactions. The gene ETRAMP 10.3 has been shown to be expressed in the liver, sporozoites and blood stages. Within the liver and blood stages it is localized to the parasitophorous vacuole membrane. It is also exported to the erythrocyte during the blood stages. It appears to be an essential gene in the blood stages.
Merozoite surface protein 7 appears to enhance the virulence of the parasite at least in the rodent.
The mature parasite-infected erythrocyte surface antigen (MESA) is exported to the erythrocyte cytoplasm where it binds to the N-terminal 30 kiloDalton domain of the erythrocyte protein 4.1R via a 19-residue sequence. This sequence is also found in a number of other proteins in the parasite. Their role in remodeling of the erythrocyte are still under investigation.
The proteins Pf12, Pf34, Pf92 and Pf38 are associated with detergent resistant membrane microdomains through glycosylphosphatidylinositol anchor sequences. These microdomains are considered organizing centers for the assembly of molecules implicated in cell signaling.
Positive diversifying selection is present in clag2, clag8 and clag9 but not in clag3.1 and clag3.2.
A protein PfMSPDBL1 (encoded by PF10_0348 gene) that is a member of the MSP3 family and has both Duffy binding-like (DBL) domain and secreted polymorphic antigen associated with merozoites (SPAM) domain appears to be critical for erythrocyte invasion.
The cleavage of MSP 1 appears to involve a purinergic signalling pathway.
The MSP1 protein binds the pro inflammatory protein S100P. This binding appears to prevent the usual NFκB activation in monocytes and chemotaxis in neutrophils. S100P appears to be able to bind to at least 2 alleles of MSP1 which are separated by at least 27 million years of evolution suggesting that this inhibition mechanism may also be of considerable age.
The merozoite specific thrombospondin related anonymous protein (MTRAP) is thought to be released from the micronemes during merozoite invasion and mediates motility and host cell invasion through an interaction with aldolase. MTRAP is a highly extended bifunctional protein that binds to an erythrocyte receptor and the merozoite motor. MTRAP specific antibodies fail to inhibit parasite development in vitro.
Thrombospondin related apical membrane protein (PTRAMP) is a surface exposed protein whose function is currently unknown.
The gene PFE0565w is transcribed in both the erythrocytic and sporozoite stages. The protein is only expressed in the salivary gland sporozoite stage.
The circumsporozoite protein has been shown to be an inhibitor of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Its nuclear localization signal alone is sufficient to block NF-κB activation.
A group of proteins known as the 6-cys domain proteins - so called because they contain modules with six characteristic cysteines forming three intra-molecular disulphide bonds between C1 and C2, C3 and C6, and C4 and C5 - are surface exposed proteins. The first P12 - named after the clone it was isolated from - was described in 1990. There are at least nine members of the 6-cys family. Most family members contain two 6-cys modules, but up to seven modules can be found in a single protein, in addition to incomplete modules containing fewer cysteine residues. About half of the 6-cys family members characterised to date possess glycosylphosphatidylinositol (GPI) moieties that anchor them to the outer leaflet of the plasma membrane, while those that lack GPI-anchors presumably remain associated with the parasite surface via interactions with other membrane proteins. Of this family P12, P38 and P41 are blood stage antigens. P230 and P48/45 - another two members of this family - are expressed on the surface of gametes.
There are a family of LCCL/lectin adhesive-like protein (LAP) proteins encoded in the genome. The six members are expressed in gametocytes and form a multi-protein complex.
The 60S stalk ribosomal acidic protein P2 (gene PFC0400w) as well as forming part of the ribosome complex is surface exposed where it forms homo-tetramers. This protein is exported to the erythrocyte surface 26-28 post invasion and persists there for 6–8 hours. Treatment with antiP2 antibodies causes mitotic arrest at the first nuclear division and disruption of the tubovesicular network which is set up during the trophozoite stages. Removal of the antibodies al lows the reformation of the tubovesicular network and mitotic division to continue.
The Ring-Infected Erythrocyte Surface Antigen (RESA/Pf155) protein appears to affect the mobility of the erythrocyte membrane.
The circumsporozoite protein forms a dense coat on the sporozoite's surface. It consists of approximately 400 amino acids organized into three domains: an N-terminal domain containing a conserved pentapeptide (region I), a highly repetitive species specific central domain and a C-terminal domain containing a second conserved sequence (region II). It is involved in invasion of the mosquito's salivary glands and the binding sporozoites to liver cells.
The addition of the small protein ubiquitin to other proteins as part of post translational processing is widespread in most eukaryotes. This is also the case with P. falciparum where this process occurs at all stages of the asexual life cycle. Ubiquitylation involves the covalent attachment of a ubiquitin moiety to lysine residues of protein substrates via the hierarchical intervention of an E1 ubiquitin activating enzyme, an E2 ubiquitin conjugating enzyme, and an E3 ubiquitin ligase that is usually involved in specific substrate recognition
Ubiquitylation is involved in removing misfolded proteins from the endoplasmic reticulum - a process known as Endoplasmic-reticulum-associated protein degradation. This process is a prerequisite for subsequent retro-translocation to the cytosol and destruction by the 26S proteasome. Aberrant proteins are recognized by endoplasmic reticulum luminal chaperone proteins and protein disulfide isomerases to help discriminate properly folded proteins from misfolded proteins. Misfolded proteins are shuttled to the DER1 translocon complex which forms a hydrophobic pore to allow the retro-translocation of proteins through the endoplasmic reticulum membrane. Several components of the system are known to be present in the parasite: HRD1 (E3 ubiquitin ligase), UBC (E2 ubiquitin conjugating enzyme) and UBA1 (E1 ubiquitin activating enzyme). HRD1 localizes to the endoplasmic reticulum membranes, while UBC and UBA1 localize to the cytosol. HRD1 interacts with membrane bound proteins needed for retro-translocation and helps form the hydrophobic pore complex. Another member of this pathway is the signal peptide peptidase.
The genes PFL1245w is the E1 ubiquitin activating enzyme, PFL0190w is the E2 ubiquitin conjugating enzyme and PF14_0215 is the E3 ubiquitin ligase. PFL1245w (E1) contains a ubiquitin activating enzyme active site, two ubiquitin like activating enzyme catalytic domains, two ThiF repeats and a catalytic cysteine at the N-terminal end. PFL0190w (E2) is 147 amino acid residues in length and contains an ubiquitin conjugating enzyme domain takes up almost its whole length. PF14_0215 (E3) has multiple transmembrane domains, an E3 RING zinc finger (zf-C3HC4) domain on its C-terminal half and a predicted signal peptide consistent with endoplasmic reticulum targeting. The presence of four transmembrane domains is compatible with a pore forming ability and to be able to participate in the recognition and translocation of misfolded proteins across the endoplasmic reticulum membrane.
CCR4-associated factor 1 is involved in the regulation more than 1000 genes during malaria parasite's intraerythrocytic stages. Mutations in this gene result in mistimed expression, aberrant accumulation and localization of proteins involved in parasite egress and invasion of new host cells. This leads to the premature release of predominantly half-finished merozoites in turn drastically reducing the intraerythrocytic growth rate of the parasite.
A homolog of the DEAD box (Asparagine-Glutamate-Alanine-Asparagine) RNA helicase DDX19 (Dbp5) has been cloned from the P. falciparum genome and has been termed PfD66. This protein has intrinsic nucleic acid dependent ATPase and RNA binding activities and ATP dependent bipolar DNA and RNA unwinding activity.
The protein PfMyb1 is a transcription factor belonging to the tryptophan cluster family. Inhibition of this gene reduces growth by ~40% with the mortality being concentrated at the trophozoite-schizont interface.
During the life cycle the telomeres and telomere associated repeat elements are transcribed as long non coding RNAs. They are transcribed by RNA polymerase II as single-stranded molecules. In the ring stage, these transcripts are located in a single perinuclear compartment that does not co-localize with any known nuclear subcompartment. During the schizont stage they are found at several nuclear foci. At least some of these can form stable and repetitive hairpin structure that is able to bind histones. Their function requires further elucidation.
Heat shock proteins
A number of heat shock proteins 40 (hsp40) have been predicted from the sequenced genome. Only one is predicted to be a cytosolic canonical Hsp40 capable of interacting with the major cytosolic Hsp70 an interaction that has been confirmed experimentally.
PfGECO is a type IV heat shock protein 40 expressed in gametocyte stages I to IV and is exported to the erythrocyte cytoplasm. This gene appears to be non essential.
Heat shock proteins Hsp70 and Hsp90 are both expressed in P. falciparum. They are linked by an essential adaptor protein known as the Hsp70-Hsp90 organising protein (Hop). This protein co-localises with PfHsp70 and PfHsp90 at the trophozoite stage and forms a complex with them.
Heat shock protein 20 has been shown to have a critical role in sporozoite motility. This role appears to be via substrate adhesion.
A Hsp40 class of chaperone (PFB0090c; PF3D7_0201800; KAHsp40) is located in a chromosomal cluster together with knob components KAHRP and PfEMP3. This protein has a PEXEL motif required for transport to the erythrocyte compartment. It occurs in punctuate spots in the erythrocyte periphery, distinctly from Maurer's clefts. These structures may be knobs particularly since it is found in a complex the known knob proteins KAHRP, PfEMP3 and Hsp101.
Polynucleotide kinase/phosphatase (PNKP) is a bifunctional enzyme that can phosphorylate the 5'-OH termini and dephosphorylate the 3'-phosphate termini of DNA. It is a DNA repair enzyme involved in the processing of strand break termini, which permits subsequent repair proteins to replace missing nucleotides and rejoin broken strands. A P. falciparum gene encoding a protein with 24% homology to human PNKP has been cloned. This enzyme dephosphorylates single-stranded substrates or double-stranded substrates with a short 3'-single-stranded overhang, but not double-stranded substrates that mimicked single-strand breaks.
Sir2A is a member of the sirtuin family of nicotinamide adenine dinucleotide dependent deacetylases. In P. falciparum it has been has been shown to regulate the expression of surface antigens to evade the detection by host immune surveillance. While it is a poor deacetylator of histones it also catalyzes the hydrolysis of medium and long chain fatty acyl groups from lysine residues. Proteins are present in P. falciparum with these modifications and these can be removed by can be removed by PfSir2A in vitro. This suggests that this may be its role rather than the deacetylation of histones.
The telomerase (tert) is a large protein (2518 codons) and has a predicted molecular weight of ~280 kiloDaltons. It has the usual telomerase specific motifs within the N-terminal half of the protein (GQ/N, CP, QFP and T) and reverse transcriptase (RT) specific motifs in the C-terminal half. The N-terminal half is required for efficient binding of the RNA template, defining the 5′ RNA template boundary, multimerization and interactions with associated proteins. The RT domain is essential for the catalytic activity. The protein contains several nuclear localization signals and is found in the nucleolus.
A histone deacetylase (HDAC1) has been cloned. The protein has 449 amino acid residues and localises to the nucleus. Its molecular weight is 50 kiloDaltons and it is predominantly expressed in mature asexual blood stages and in gametocytes.
A novel DNA/RNA binding protein PfAlba has been described. This protein is related to the archaeal protein Alba (Acetylation lowers binding affinity). There are at least four paralogs of the PfAlba gene and these proteins form a complex with the P. falciparum specific TARE6 (Telomere-Associated Repetitive Elements 6) subtelomeric regions. Also associated with the TARE6 regions are PfSir2 a histone deacetylase. In the early blood stages the PfAlba proteins are enriched at the nuclear periphery and associate with the PfSir2 proteins. When the parasite switches from trophozoite to the schizont stage the PfAlba proteins move to the cytoplasm. These proteins will also bind single stranded RNA but the reason for this binding is not known.
A number of novel DNA binding sites have been identified along the genome. Their function - if any - remains to be determined.
Aminoacyl-tRNA synthetases are required for protein synthesis. Alanine tRNA synthetase, Glycine tRNA synthetase and Threonine tRNA synthetase are dually localised to the cytosol and the apicoplast. These enzymes do not appear to be present in the mitochondrion.
Tyrosyl tRNA synthetase is secreted by the parasite into the cytoplasm of the infected erythrocyte. On lysis of the erythrocyte it is released into the blood stream where it is pro inflammatory. It is specifically bound by and taken up by host macrophages and leads to enhanced secretion of the cytokines tumor necrosis factor-alpha and interleukin 6. This interaction also increases the adherence linked host endothelial receptors ICAM-1 and VCAM-1.
The eukaryotic translation initiation factor 2α has a regulatory serine at position 51. This can be phosphorylated by several kinases. Three are known in P falciparum: IK1, IK2 and PK4. IK1 regulates stress response to amino acid starvation; IK2 inhibits development of malaria sporozoites present in the mosquito salivary glands; and PK4 is essential for the completion of the parasite's erythrocytic cycle.
The centromeres occupy a 4-4.5 kilobase region in each chromosome. The centromeres cluster to a single nuclear location prior to and during mitosis and cytokinesis but dissociate soon after invasion.
The single stranded DNA binding protein (SSB) plays an important role in all known organisms. A SSB protein is encoded in the genome and localises to the apicoplast. It forms a homo-tetramer alone and when bound to single stranded DNA. The protein binds 52-65 nucleotides/tetramer. While similar in its overall structure to that of the SSB of E. coli it differs at the carboxy terminal region. Although it binds single stranded DNA in a similar fashion to the SSB of E. coli it does so with the opposite polarity. There are a number of other functional differences between this protein and that of E. coli. The basis for these differences has yet to be determined.
The RuvB protein belongs to AAA+ family of enzymes which are involved in diverse cellular activities. There are at least 3 copies of this protein in the genome. RuvB3 possesses the Walker motif A, Walker motif B, sensor I and sensor II conserved motifs similar to yeast and human RuvB like proteins. It has single stranded DNA dependent ATPase activity. The protein is mainly expressed during intraerythrocytic schizont stages and localizes to the nuclear region. In the merozoite the protein relocalizes to the sub nuclear region.
A helicase - PfH45 - of 398 amino acid residues (molecular weight 45 kiloDaltons) is a unique bipolar helicase with both the 3' to 5' and 5' to 3' directional helicase activities. It is expressed in all the intraerythrocytic developmental stages and has a role in translation.
The transcription factor NF-YB is localised in the nucleus during the erythrocytic stages of the life cycle. Melatonin and cyclic adenosine monophosphate modulate the expression of NF-YB. NF-YB is also more ubiquitinated in the presence of melatonin.
SET is a conserved nuclear protein involved in chromatin dynamics. In P falciparum it is expressed in both asexual and sexual blood stages but strongly accumulates in male gametocytes. In P falciparum there are two distinct promoters upstream. he one active in all blood stage parasites while the other active only in gametocytes and in a fraction of schizonts possibly committed to sexual differentiation. In ookinetes both promoters exhibit a basal activity, while in the oocysts the gametocyte-specific promoter is silent and the reporter gene is only transcribed from the constitutive promoter.
A number of the DExD/DExH-box containing pre-mRNA processing proteins (Prps) - PfPrp2p, PfPrp5p, PfPrp16p, PfPrp22p, PfPrp28p, PfPrp43p and PfBrr2p - are present in the genome. PfPrp16p a helicase and a member of DEAH-box protein family with nine collinear sequence motifs has been cloned. It binds to RNA, hydrolyses ATP and appears to be involved in splicing.
A putative tyrosine site specific recombinase has been isolated. The N-terminus has the typical alpha helical bundle and potentially a mixed alpha-beta domain resembling that of λ-Int. The C-terminal domain has the putative tyrosine recombinase conserved active site residues Lysine-Histadine-Lysine-(Histadine/Tryptophan)-Tyrosine. The gene is expressed differentially during the erythrocytic stages being maximal in the schizont stage. The open reading frame encodes a ∼57 kiloDalton protein. Knockout mutants are viable and appear normal. DNA binding studies suggest a number of targets include the subtelomeric regions.
Apetala 2 (AP2) family proteins are transcription factors that have DNA-binding domains of ~60 amino acids called AP2 domains. 27 AP2-family genes have been identified in the Plasmodium falciparum genome. One of these proteins appears to play a critical role in the liver stage development of the parasite.
Several nucleic acid repair pathways are known. These include the nucleotide excision repair, the mismatch repair, the base excision repair, the double strand break repair and the cross link repair pathways. DNA replication errors - base substitution mismatches and insertion-deletion loops - are primarily corrected by the mismatch repair system.
The DNA helicase II (uvrD) is a superfamily 1A helicase which plays an essential role in the mismatch repair pathway. Homologues of UvrD include the proteins PcrA and Rep. These proteins have a two domain (1 and 2) structure with each domain made of two sub-domains (1A, 1B, 2A and 2B) and a C-terminal extension. They are DNA-dependent ATPases with 3′ to 5′ helicase activity. The helicase activity is located in the N terminal domain.
The UvrD protein of P. falciparum has been cloned. This gene (PFE0705c) is located on chromosome 5 and contains no introns. It is 4326 bases in length, encodes a protein of 1441 amino acids and has a predicted molecular weight of ~170 kiloDaltons. The two domains and their subdomains are present: The 1A domain is from amino acid 1–722; the 1B domain is from amino acid 150–464; the 2A domain is from amino acid 723–1441; and the 2B domain is from amino acid 896–1359. There is no C-terminal extension. The ATPase and helicase activty are confined to domain 1A and 1B (the N-terminal and first half of the C terminal). It is expressed in the schizont stages of intraerythrocytic development and it colocalizes with PfMLH, a protein involved in mismatch repair. Both PfDH60 - another helicase - and PfMLH are also expressed in schizont stages.
The proteins gamma-glutamylcysteine synthetase and glutathione synthetase which are involved in the synthesis of glutathione appear to be essential genes in P. falciparum. Inhibition of the glutathione biosynthesis by the parasite is lethal. Its levels appear to be tightly regulated. The enzyme glutathione reductase is highly specific for its substrate glutathione disulfide.
The thioredoxin system like the glutathione system is responsible for maintaining the redox balance in the cell. The thioredoxin reductase reduces thioredoxin and a number of other low molecular weight compounds. The other members of this system include five peroxiredoxins differentially located in the cytosol, apicoplast, mitochondria and nucleus with partially overlapping substrate preferences. It also includes members of the thioredoxin superfamily with three thioredoxins, two thioredoxin-like proteins, a dithiol and three monocysteine glutaredoxins and a redox-active plasmoredoxin being encoded in the genome.
The infected host cell is under considerable oxidative stress. Normal erythrocytes have a ratio of reduced (GSH) and oxidized glutathione (GSSG) of 321.6 while the GSH/GSSG ratio in infected cells is 26.7. The ratio in the parasite is 284.5. Efflux of GSSG from the intact infected cell is more than 60-fold higher than the rate observed in normal erythrocytes. This export process is mediated by permeability pathways that the parasite induces in the erythrocyte's membrane. Exogenous gamma-glutamylcysteine is not converted into GSH in the infected erythrocyte suggesting that the erythrocytes' own GSH synthetase may not be functional. This may be due to the lower levels of magnesium (Mg2+) in the infected erythrocyte (0.5 milliMolar) compared to the normal erythrocytes (1.5-3 mM). The lower level of results in cessation of gamma-glutamylcysteine synthesis and of GSH synthesis in the infected erythrocyte. The parasite maintains a level of 4 mM magnesium. The parasite membrane is impermeable to both gamma-glutamylcysteine and GSH.
Glutathione export from parasitized cells is inhibited partially by both the compound MK571 and by furosemide. These agents are inhibitors of the 'new permeability pathways' induced by the parasite in the host erythrocyte membrane.
Ferriprotoporphyrin IX is released inside the food vacuole of the malaria parasite during the digestion of host cell hemoglobin. Undegraded ferriprotoporphyrin IX accumulates in the membrane fraction and is degraded by reduced glutathione in a radical mediated mechanism.
The 1-Cys peroxiredoxin enzyme appears to be located in the cytoplasm.
Within the cytoplasm two peroxiredoxins - T peroxiredoxin-1 and 1-Cys peroxiredoxin - are produced at differing points in the life cycle. Disruption of the T peroxiredoxin-1 enzymes renders the parasite hypersensitive to heat stress. This does not occur with knock out mutants of 1-Cys peroxiredoxin suggesting that these enzymes have different roles in the life cycle.
Investigation of the liver stages of these enzymes in Plasmodium berghei has shown that both TPx-1 and 1-Cys Prx are present in the cytosol but differ in their expression patterns. TPx-1 is transcribed shortly after infection of the hepatocyte and expression continues until the schizont stage. Transcription of 1-Cys Prx starts after the parasite has developed into the schizont stage.
Polyamine biosynthesis in these parasites is controlled by a unique bifunctional S-adenosylmethionine decarboxylase/ornithine decarboxylase (PfAdoMetDC/ODC). On the secondary structure level PfAdoMetDC is similar to that of the human protein. This bifunctional enzyme ensure coordination decarboxylated AdoMet and putrescine for the subsequent synthesis of spermidine.
P. falciparum contains both cytosolic and mitochondrial serine hydroxymethyltransferase isoforms. This is a pyridoxal phosphate dependent enzyme which plays a vital role in the de novo pyrimidine biosynthesis pathway. Both genes are expressed throughout the erythrocytic stages. Both enzymes appear to be essential.
The first two reactions of the pentose phosphate pathway in P. falciparum are catalysed by a single bifunctional enzyme - glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase. This is distinct from the case in humans where the enzymes are separate. In animals this pathway is usually found in the cytosol while in plants it is found in the plastids. The location of this reaction is not currently known in P. falciparum.
Fusions between these two enzymes (glucose 6-phosphate dehydrogenase and 6-phosphogluconolactonase) have also been reported in chordates. The chordate fusion differs in its orientation to that in Plasmodium (in Plasmodium the 6-phosphogluconolactone is found at the N-terminus of the glucose 6-phosphate dehydrogenase protein), indicating that at least two separate fusion events have occurred. The metazoan fusion appears to have occurred near the bases of the metazoan and apicomplexan lineages. This fusion event was not found in any of the three sequenced Cryptosporidium genomes. It was not found in Perkinsus marinus or in either of the ciliate (Paramecium tetraurelia and Tetrahymena thermophila) genomes. More data will be needed to estimate the timing of this fusion event.
Only one of the two metazoan paralogs of glucose 6-phosphate dehydrogenase is fused, indicating that the fusion occurred after a duplication event. This duplication event occurred in an ancestor of the choanoflagellates and metazoans. Another fusion event between these enzymes occurred in an ancestor of the protozoan parasites Trichomonas and Giardia lamblia. In Giardia, the proteins are fused in opposite orientations. A third fusion event occurred between glucose 6-phosphate dehydrogenase with phosphogluconate dehydrogenase in a diatom species (Phaeodactylum tricornutum).
Phosphoinositide-specific phospholipase C (PI-PLC) is a major regulator of calcium-dependent signal transduction usually by liberation of calcium from intracellular stores through the action of its product, inositol-(1,4,5)-trisphosphate. These genes are found in P. falciparum and appear to be essential. The genes are twice as long as their mammalian counterparts and belong to the delta class of phospholipase C proteins.
The mechanism of action of the triose phosphate isomerase enzyme has been investigated in some detail. The conserved glutamic acid residue at position 97 is involved in the catalytic proton transfer. Modification of this residue may reduce the rate of catalysis by 9000 fold.
Chorismate synthase (CS) catalyses the seventh and final step of the shikimate pathway. P. falciparum chorismate synthase (PfCS) is unique in terms of enzymatic behavior, cellular localization and in having two additional amino acid inserts compared to any other CS.
Membrane biogenesis in this organism involves the enzyme phosphoethanolamine methyltransferase which catalyses the methylation of phosphoethanolamine to phosphocholine. This pathway is found in plants and nematodes but not in humans. The enzymes in P. falciparum is a multi-functional unlike that of plants and nematodes. The enzyme from P. falciparum has been cloned and its structure solved.
A homolog of the inhibitor of protein phosphatase 1 has been cloned. This gene is essential for survival and appears to be localised to the nucleus. A conserved 41- Lysine-Valine-Valine-Arginine-Tryptophan- 45 motif is essential for its inhibition activity.
The parasite actively synthesises pyridoxal-phosphate (vitamin B6). This process involves two sets of reactions: condensation of ribulose 5-phosphate, glyceraldehyde-3-phosphate and ammonia produced from glutamine. These actions are carried out by separate subunits. The synthase domain is known as Pdx1 and the glutaminase domain as Pdx2. In P. falciparum the core Pdx1 is a dodecamer and forms the core of the enzyme. There are up to 12 Pdx2 subunits surrounding the Pdx1 subunit. The majority of the synthesis is carried out by Pdx1. The pentose substrate is covalently attached through its C1 and forms a Schiff base with the Lysine 84 residue. The ammonia transfer between Pdx2 glutaminase and Pdx1 active sites is regulated by a transient tunnel.
At least one function of B6 in this parasite is as an antioxidant.
Orotate phosphoribosyltransferase catalyzes the magnesium dependent condensation of orotic acid with 5-α-D-phosphorylribose 1-diphosphate to yield diphosphate and the nucleotide orotidine 5'-monophosphate. This enzyme has been crystallised.
HMB-PP synthase (IspG), an iron-sulphur (4Fe4S) protein involved in isoprenoid biosynthesis, has two domains - a TIM barrel and a 4Fe4S domain - in bacteria. In plants and malaria parasites there is an additional large insert domain. This is a second TIM barrel that interacts with the other TIM barrel.
Adenylate kinases are phosphotransferases that catalyze the interconversion of adenine nucleotides. There are at least three adenylate kinases (PfAK1, PfAK2 and GTP:AMP phosphotransferase) encoded in the genome. PfAK1 and PfAK2 both catalyse the conversion of ATP and AMP to two molecules of ADP. PfGAK instead has a preference for GTP and AMP and does not accept ATP as a substrate.
Within the genome there are two adenylyl cyclases - ACα and ACβ. ACα contains six predicted transmembrane domains and a single carboxy-terminal catalytic domain homologous to sAC-like ACs. It is a predicted bifunctional protein comprising both a potassium channel and an AC that is conserved in the alveolates. It is expressed in the gametocytes. ACβ has no predicted transmembrane regions and possesses two AC catalytic domains. It has a marked pH dependence and is required for the erythrocytic stages.
Asymmetrical diadenosine 5',5″-P1,P4-tetraphosphate hydrolase (EC 220.127.116.11) catalyses the conversion of diadenosine 5',5″-P1,P4-tetraphosphate (Ap4A) to ATP and AMP and diadenosine 5',5″-P1,P5-pentaphosphate (Ap5A) to ATP and ADP. This enzyme from the parasite has been cloned and expressed.
A glycerophosphodiesterase has been cloned. This enzyme is found in the parasitophorous vacuole, food vacuole and cytosol. It appears to be an essential gene but its specific function is currently unclear.
In recently invaded erythrocytes the Ca2+ concentration increases about 10 fold. The Ca2+ content increases as the parasite matures. In infected erythrocytes, Ca2+ is almost exclusively localized in the parasite compartment and changes but little in the cytosol of the host cell.
Cytosolic calcium2+ increases evoked by extracellular stimuli are may be observed in the form of oscillating Ca2+ spikes in eukaryotic cells. Spontaneous spikes in the calcium levels have been observed in Plasmodium falciparum. The frequency of Ca2+ oscillations are higher in early ring forms than that in early trophozoites. Blockage of this oscillation results in the cessation of intraerythrocytic maturation and death of the parasite. This effect is maximal in the trophozoites.
- Kudryashev M, Lepper S, Stanway R, et al. (March 2010). "Positioning of large organelles by a membrane- associated cytoskeleton in Plasmodium sporozoites". Cell. Microbiol. 12 (3): 362–71. doi:10.1111/j.1462-5822.2009.01399.x. PMID 19863555.
- Tremp AZ, Khater EI, Dessens JT (2008) IMC1b is a putative membrane skeleton protein involved in cell shape, mechanical strength, motility, and infectivity of malaria ookinetes. J Biol Chem 283(41):27604-27611
- Arévalo-Pinzón G, Curtidor H, Muñoz M, Patarroyo MA, Patarroyo ME (2011). "Synthetic peptides from two Pf sporozoite invasion-associated proteins specifically interact with HeLa and HepG2 cells.". Peptides 32 (9): 1902–8. doi:10.1016/j.peptides.2011.08.008. PMID 21864602.
- Müller K, Matuschewski K, Silvie O (2011). Gruner, Anne Charlotte. ed. "The Puf-family RNA-binding protein Puf2 controls sporozoite conversion to liver stages in the malaria parasite". PLoS ONE 6 (5): e19860. doi:10.1371/journal.pone.0019860. PMID 21673790.
- Gomes-Santos CS, Braks J, Prudêncio M, Carret C, Gomes AR, Pain A, Feltwell T, Khan S et al. (2011). "Transition of Plasmodium sporozoites into liver stage-like forms is regulated by the RNA binding protein pumilio". PLoS Pathog 7 (5): e1002046. doi:10.1371/journal.ppat.1002046. PMC 3098293. PMID 21625527. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3098293/.
- Stanway RR, Mueller N, Zobiak B, et al. (November 2011). "Organelle segregation into Plasmodium liver stage merozoites". Cell. Microbiol. 13 (11): 1768–82. doi:10.1111/j.1462-5822.2011.01657.x. PMID 21801293.
- Yu M, Kumar T. R, Nkrumah L. J, Coppi A, Retzlaff S et al. (2008). "The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites". Cell Host & Microbe 4: 567–578. doi:10.1016/j.chom.2008.11.001. PMID 19064257.
- Coppens I (2011). "Metamorphoses of malaria: the role of autophagy in parasite differentiation". Essays Biochem. 51: 127–36. doi:10.1042/bse0510127. PMID 22023446.
- Portugal S, Carret C, Recker M, Armitage AE, Gonçalves LA, Epiphanio S, Sullivan D, Roy C et al. (2011). "Host-mediated regulation of superinfection in malaria". Nat Med 17 (6): 732–737. doi:10.1038/nm.2368. PMID 21572427.
- de Mast Q, Nadjm B, Reyburn H, et al. (January 2009). "Assessment of urinary concentrations of hepcidin provides novel insight into disturbances in iron homeostasis during malarial infection". J. Infect. Dis. 199 (2): 253–62. doi:10.1086/595790. PMID 19032104.
- Wang HZ, He YX, Yang CJ, Zhou W, Zou CG (2011). "Hepcidin is regulated during blood-stage malaria and plays a protective role in malaria infection.". J Immunol 187 (12): 6410–6. doi:10.4049/jimmunol.1101436. PMID 22084434.
- Zhao H, Konishi A, Fujita Y, Yagi M, Ohata K, Aoshi T, Itagaki S, Sato S, Narita H, Abdelgelil NH, Inoue M, Culleton R, Kaneko O, Nakagawa A, Horii T, Akira S, Ishii KJ, Coban C (2012) Lipocalin 2 bolsters innate and adaptive immune responses to blood-stage malaria infection by reinforcing host iron metabolism. Cell Host Microbe 12(5):705-16. doi: 10.1016/j.chom.2012.10.010
- Gozzelino R, Andrade BB, Larsen R, Luz NF, Vanoaica L, Seixas E, Coutinho A, Cardoso S, Rebelo S, Poli M, Barral-Netto M, Darshan D, Kühn LC, Soares MP (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12(5):693-704. doi: 10.1016/j.chom.2012.10.011
- Giovannini D, Späth S, Lacroix C, et al. (December 2011). "Independent roles of apical membrane antigen 1 and rhoptry neck proteins during host cell invasion by apicomplexa". Cell Host Microbe 10 (6): 591–602. doi:10.1016/j.chom.2011.10.012. PMID 22177563.
- Gomes-Santos CS, Itoe MA, Afonso C, et al. (2012). "Highly Dynamic Host Actin Reorganization around Developing Plasmodium Inside Hepatocytes". PLoS ONE 7 (1): e29408. doi:10.1371/journal.pone.0029408. PMC 3253080. PMID 22238609. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3253080/.
- Miller JL, Harupa A, Kappe SH, Mikolajczak SA (2012). "Plasmodium macrophage migration inhibitory factor is necessary for efficient liver stage development.". Infect Immun. doi:10.1128/IAI.05861-11.
- Orito Y, Ishino T, Iwanaga S, Kaneko I, Kato T, Menard R, Chinzei Y, Yuda M (2012) Liver-specific protein 2: a Plasmodium protein exported to the hepatocyte cytoplasm and required for merozoite formation. Mol Microbiol doi: 10.1111/mmi.12083
- Ploemen IH, Croes HJ, van Gemert GJ, Wijers-Rouw M, Hermsen CC, Sauerwein RW (2012) Plasmodium berghei Δp52&p36 Parasites develop independent of a parasitophorous vacuole membrane in Huh-7 liver cells. PLoS One 7(12):e50772. doi: 10.1371/journal.pone.0050772
- Ord RL, Rodriguez M, Yamasaki T, Takeo S, Tsuboi T, Lobo CA (2012). "Targeting Sialic Acid Dependent and Independent Pathways of Invasion in Plasmodium falciparum". PLoS ONE 7 (1): e30251. doi:10.1371/journal.pone.0030251. PMC 3257272. PMID 22253925. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3257272/.
- Taylor HM, Triglia T, Thompson J, Sajid M, Fowler R et al. (2001). "Plasmodium falciparum homologue of the genes for Plasmodium vivax and Plasmodium yoelii adhesive proteins, which is transcribed but not translated". Infect Immun 69 (6): 3635–3645. doi:10.1128/IAI.69.6.3635-3645.2001. PMC 98354. PMID 11349024. //www.ncbi.nlm.nih.gov/pmc/articles/PMC98354/.
- Baum J, Chen L, Healer J, et al. (February 2009). "Reticulocyte-binding protein homologue 5 - an essential adhesin involved in invasion of human erythrocytes by Plasmodium falciparum". Int. J. Parasitol. 39 (3): 371–80. doi:10.1016/j.ijpara.2008.10.006. PMID 19000690.
- Gunalan K, Gao X, Liew KJ, Preiser PR (2011). "Differences in erythrocyte receptor specificity of different parts of the Plasmodium falciparum reticulocyte binding protein homologue 2a.". Infect Immun. doi:10.1128/IAI.00201-11.
- Triglia T, Chen L, Lopaticki S, Dekiwadia C, Riglar DT, Hodder AN, Ralph SA, Baum J et al. (2011). "Plasmodium falciparum merozoite invasion is inhibited by antibodies that target the PfRh2a and b binding domains". PLoS Pathog 7 (6): e1002075.
- Chen L, Lopaticki S, Riglar DT, Dekiwadia C, Uboldi AD, Tham WH, O'Neill MT, Richard D et al. (2011). "An EGF-like protein forms a complex with PfRh5 and is required for invasion of human erythrocytes by Plasmodium falciparum". PLoS Pathog 7 (9): e1002199. doi:10.1371/journal.ppat.1002199. PMC 3164636. PMID 21909261. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3164636/.
- Crosnier C, Bustamante LY, Bartholdson SJ, et al. (December 2011). "Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum". Nature 480 (7378): 534–7. doi:10.1038/nature10606. PMC 3245779. PMID 22080952. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3245779/.
- Singh S, Alam MM, Pal-Bhowmick I, Brzostowski JA, Chitnis CE (2010). "Distinct external signals trigger sequential release of apical organelles during erythrocyte invasion by malaria parasites". PLoS Pathog 6: e1000746. doi:10.1371/journal.ppat.1000746.
- Rydzak J, Kryńska K, Suchanowska A, Kaczmarek R, Lukasiewicz J, Czerwiński M, Jaśkiewicz E (2012) Bacterially expressed truncated F2 domain of Plasmodium falciparum EBA-140 antigen can bind to human erythrocytes. Acta Biochim Pol
- Martinez C, Marzec T, Smith CD, Tell LA, Sehgal RN (2012) Identification and expression of maebl, an erythrocyte-binding gene, in Plasmodium gallinaceum. Parasitol Res
- Lin DH, Malpede BM, Batchelor JD, Tolia NH (2012) Crystal and solution structures of Plasmodium falciparum erythrocyte binding antigen 140 reveal determinants of receptor specificity during erythrocyte invasion. J Biol Chem
- Li X, Marinkovic M, Russo C, McKnight CJ, Coetzer TL, Chishti AH (2012). "Identification of a specific region of Plasmodium falciparum EBL-1 that binds to host receptor glycophorin B and inhibits merozoite invasion in human red blood cells.". Mol Biochem Parasitol 183 (1): 23–31. doi:10.1016/j.molbiopara.2012.01.002. PMID 22273481.
- Lopaticki S, Maier AG, Thompson J, Wilson DW, Tham WH et al. (2011). "Reticulocyte and erythrocyte binding-like proteins function cooperatively in invasion of human erythrocytes by malaria parasites". Infect Immun 79 (3): 1107–1117. doi:10.1128/IAI.01021-10. PMC 3067488. PMID 21149582. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3067488/.
- Bartholdson SJ, Bustamante LY, Crosnier C, Johnson S, Lea S, Rayner JC, Wright GJ (2012) Semaphorin-7A is an erythrocyte receptor for P. falciparum merozoite-specific TRAP homolog, MTRAP. PLoS Pathog 8(11):e1003031. doi: 10.1371/journal.ppat.1003031
- Pelleau S, Diop S, Badiane MD, Vitte J, Beguin P, Nato F, Diop BM, Bongrand P, Parzy D, Jambou R (2012) Enhanced basophil reactivities during severe malaria and their relationship with the plasmodial histamine releasing factor PfTCTP. Infect Immun
- Arumugam TU, Takeo S, Yamasaki T, Thonkukiatkul A, Miura K, Otsuki H, Zhou H, Long CA, Sattabongkot J, Thompson J, Wilson DW, Beeson JG, Healer J, Crabb BS, Cowman AF, Torii M, Tsuboi T (2011). "Discovery of GAMA, a Plasmodium falciparum merozoite micronemal protein, as a novel blood-stage vaccine candidate antigen.". Infect Immun 79 (11): 4523–32. doi:10.1128/IAI.05412-11. PMC 3257921. PMID 21896773. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3257921/.
- Andreína Pacheco M, Elango AP, Rahman AA, Fisher D, Collins WE, Barnwell JW, Escalante AA (2012) Evidence of purifying selection on merozoite surface protein 8 (MSP8) and 10 (MSP10) in Plasmodium spp. Infect Genet Evol
- Dreyer AM, Matile H, Papastogiannidis P, Kamber J, Favuzza P, Voss TS, Wittlin S, Pluschke G (2012) Passive immunoprotection of Plasmodium falciparum-infected mice designates the CyRPA as candidate malaria vaccine antigen. J Immunol
- Chatterjee S, Singh S, Sohoni R, Kattige V, Deshpande C, Chiplunkar S, Kumar N, Sharma S (2000) Characterization of domains of the phosphoriboprotein P0 of Plasmodium falciparum. Mol Biochem Parasitol 107(2):143-154
- Farrell A, Thirugnanam S, Lorestani A, Dvorin JD, Eidell KP, Ferguson DJ, Anderson-White BR, Duraisingh MT, Marth GT et al. (2012). "A DOC2 protein identified by mutational profiling is essential for apicomplexan parasite exocytosis". Science 335 (6065): 218–221.
- Duncan RR, Shipston MJ, Chow RH (2000). "Double C2 protein. A review". Biochimie 82 (5): 421–426. doi:10.1016/S0300-9084(00)00214-5. PMID 10865129.
- Tyagi RK, Sharma YD (2012) Erythrocyte binding activity displayed by a selective group of Plasmodium vivax tryptophan rich antigens is inhibited by patients' antibodies. PLoS One 7(12):e50754. doi: 10.1371/journal.pone.0050754
- Levano-Garcia J, Dluzewski AR, Markus RP, Garcia CR (2010). "Purinergic signalling is involved in the malaria parasite Plasmodium falciparum invasion to red blood cells". Purinergic Signal 6 (4): 365–372. doi:10.1007/s11302-010-9202-y. PMC 3033500. PMID 21437007. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3033500/.
- Pal-Bhowmick I, Andersen J, Srinivasan P, Narum DL, Bosch J, Miller LH (2012) Binding of aldolase and glyceraldehyde-3-phosphate dehydrogenase to the cytoplasmic tails of Plasmodium falciparum merozoite Duffy binding-like and reticulocyte homology ligands. MBio. 2012 Sep 18;3(5). pii: e00292-12. doi: 10.1128/mBio.00292-12
- Ridzuan, MA; Moon, RW; Knuepfer, E; Black, S; Holder, AA; Green, JL (2012). "Subcellular location, phosphorylation and assembly into the motor complex of GAP45 during Plasmodium falciparum schizont development". PLoS ONE 7 (3): e33845.
- Thomas, DC; Ahmed, A; Gilberger, TW; Sharma, P (2012). "Regulation of Plasmodium falciparum Glideosome Associated Protein 45 (PfGAP45) Phosphorylation". PLoS ONE 7 (4): e35855.
- Lamarque M, Besteiro S, Papoin J, Roques M, Vulliez-Le Normand B, Morlon-Guyot J, Dubremetz JF, Fauquenoy S et al. (2011). "The RON2-AMA1 interaction is a critical step in moving junction-dependent invasion by apicomplexan parasites". PLoS Pathog 7 (2): e1001276.
- Bansal A, Singh S, More KR, Hans D, Nangalia K, Yogavel M, Sharma A, Chitnis CE (2012) Characterization of Plasmodium falciparum calcium dependent protein kinase 1 (PfCDPK1) and its role in microneme secretion during erythrocyte invasion. J Biol Chem
- Zuccala ES, Gout AM, Dekiwadia C, Marapana DS, Angrisano F, Turnbull L, Riglar DT, Rogers KL, Whitchurch CB, Ralph SA, Speed TP, Baum J (2012) Subcompartmentalisation of proteins in the rhoptries correlates with ordered events of erythrocyte invasion by the blood stage malaria parasite. PLoS One 7(9):e46160
- Kemp LE, Yamamoto M, Soldati-Favre D (2012) Subversion of host cellular functions by the apicomplexan parasites. FEMS Microbiol Rev doi: 10.1111/1574-6976.12013
- Straub KW, Peng ED, Hajagos BE, Tyler JS, Bradley PJ (2011). "The moving junction protein RON8 facilitates firm attachment and host cell invasion in Toxoplasma gondii". PLoS Pathog 7 (3): e1002007.
- Wang B, Lu F, Cheng Y, Li J, Ito D, Sattabongkot J, Tsuboi T, Han ET (2012) Identification and characterization of the Plasmodium falciparum RhopH2 ortholog in Plasmodium vivax. Parasitol Res
- Olivieri A, Collins CR, Hackett F, Withers-Martinez C, Marshall J, Flynn HR, Skehel JM, Blackman MJ (2011). "Juxtamembrane shedding of Plasmodium falciparum AMA1 Is sequence independent and essential, and helps evade invasion-inhibitory antibodies". PLoS Pathog 7 (12): e1002448.
- Srinivasan P, Beatty WL, Diouf A, Herrera R, Ambroggio X, Moch JK, Tyler JS, Narum DL, Pierce SK, Boothroyd JC, Haynes JD, Miller LH (2011). "Binding of Plasmodium merozoite proteins RON2 and AMA1 triggers commitment to invasion.". Proc Natl Acad Sci U S A. doi:10.1073/pnas.1110303108.
- Tang J, Dai Y, Zhang H, Culleton RL, Liu Y, Zhao S, Wang X, Guan X, Kaneko O, Zhu Y (2012) Positive diversifying selection on Plasmodium vivax RON2 protein. Parasitology
- Vulliez-Le Normand, B; Tonkin, ML; Lamarque, MH; Langer, S; Hoos, S; Roques, M; Saul, FA; Faber, BW et al. (Jun 2012). "Structural and functional insights into the malaria parasite moving junction complex". PLoS Pathog 8 (6): e1002755.
- Moreno-Perez DA, Montenegro M, Patarroyo ME, Patarroyo MA (2011). "Identification, characterization and antigenicity of the Plasmodium vivax rhoptry neck protein 1 (PvRON1)". Malar. J. 10: 314. doi:10.1186/1475-2875-10-314. PMC 3215230. PMID 22024312. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3215230/.
- Hegge S, Münter S, Steinbüchel M, Heiss K, Engel U, Matuschewski K, Frischknecht F (2010). "Multistep adhesion of Plasmodium sporozoites.". FASEB J..
- Boyle MJ, Richards JS, Gilson PR, Chai W, Beeson JG (2010). "Interactions with heparin-like molecules during erythrocyte invasion by P. falciparum merozoites.". Blood 115 (22): 4559–68. doi:10.1182/blood-2009-09-243725. PMID 20220119.
- Wickert H, Göttler W, Krohne G, Lanzer M (2004) Maurer's cleft organization in the cytoplasm of Plasmodium falciparum-infected erythrocytes: new insights from three-dimensional reconstruction of serial ultrathin sections. Eur J Cell Biol 83(10):567-582
- Tsarukyanova I, Drazba JA, Fujioka H, Yadav SP, Sam-Yellowe TY (2009). "Proteins of the Plasmodium falciparum two transmembrane Maurer's cleft protein family, PfMC-2TM, and the 130 kDa Maurer's cleft protein define different domains of the infected erythrocyte intramembranous network". Parasitol Res 104 (4): 875–891. doi:10.1007/s00436-008-1270-3. PMID 19130087.
- Spycher C, Rug M, Klonis N, Ferguson DJ, Cowman AF, Beck HP, Tilley L (2006). "Genesis of and Trafficking to the Maurer's Clefts of Plasmodium falciparum-Infected Erythrocytes". Mol Cell Biol 26 (11): 4074–4085. doi:10.1128/MCB.00095-06. PMC 1489082. PMID 16705161. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1489082/.
- Cooke BM, Buckingham DW, Glenister FK, Fernandez KM, Bannister LH, Marti M, Mohandas N, Coppel RL (2006). "A Maurer's cleft–associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells". J Cell Biol 172 (6): 899–908. doi:10.1083/jcb.200509122. PMC 2063733. PMID 16520384. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2063733/.
- Spycher C, Klonis N, Spielmann T, Kump E, Steiger S, et al (2003) MAHRP-1, a novel Plasmodium falciparum histidine-rich protein, binds ferriprotoporphyrin IX and localizes to the Maurer's clefts. J Biol Chem 278: 35373–35383
- Hawthorne PL, Trenholme KR, Skinner-Adams TS, Spielmann T, Fischer K, et al A novel Plasmodium falciparum ring stage protein, REX, is located in Maurer's clefts. Mol Biochem Parasitol 136: 181–189
- Dixon MW, Kenny S, McMillan PJ, Hanssen E, Trenholme KR, Gardiner DL, Tilley L (2011) Genetic ablation of a Maurer's cleft protein prevents assembly of the Plasmodium falciparum virulence complex. Mol Microbiol doi:10.1111/j.1365-2958.2011.07740.x
- Atkinson CT, Aikawa M, Perry G, Fujino T, Bennett V, Davidson EA, Howard RJ (1988) Ultrastructural localization of erythrocyte cytoskeletal and integral membrane proteins in Plasmodium falciparum-infected erythrocytes. Eur J Cell Biol 45(2):192-199
- Cyrklaff M, Sanchez CP, Kilian N, Bisseye C, Simpore J, Frischknecht F, Lanzer M (2012) Hemoglobins S and C interfere with actin remodeling in Plasmodium falciparum-infected erythrocytes. Science 334(6060):1283-1286
- Kulangara C, Luedin S, Dietz O, Rusch S, Frank G, Mueller D, Moser M, Kajava AV, Corradin G, Beck HP, Felger I (2012) Cell biological characterization of the malaria vaccine candidate trophozoite exported protein 1. PLoS One 7(10):e46112. doi: 10.1371/journal.pone.0046112
- Hanssen E, Hawthorne P, Dixon MW, Trenholme KR, McMillan PJ et al (2008) Targeted mutagenesis of the ring-exported protein-1 of Plasmodium falciparum disrupts the architecture of Maurer's cleft organelles. Mol Microbiol 69: 938–953
- Glenister FK, Fernandez KM, Kats LM, Hanssen E, Mohandas N et al (2009) Functional alteration of red blood cells by a megadalton protein of Plasmodium falciparum. Blood 113: 919–928
- Mattei D, Scherf A (1992) The Pf332 gene codes for a megadalton protein of Plasmodium falciparum asexual blood stages. Mem Inst Oswaldo Cruz 87: 163–168
- Moll K, Chene A, Ribacke U, Kaneko O, Nilsson S et al (2007) A novel DBL-domain of the P. falciparum 332 molecule possibly involved in erythrocyte adhesion. PLoS ONE 2: e477
- Hinterberg K, Scherf A, Gysin J, Toyoshima T, Aikawa M et al (1994) Plasmodium falciparum: the Pf332 antigen is secreted from the parasite by a brefeldin A dependent pathway and is translocated to the erythrocyte membrane via the Maurer's clefts. Exp Parasitol 79: 279–291
- Pavithra SR, Kumar R, Tatu U (2007) Systems analysis of chaperone networks in the malarial parasite Plasmodium falciparum. PLoS Comput Biol 3: 1701–1715
- Nilsson S, Angeletti D, Wahlgren M, Chen Q, Moll K (2012) Plasmodium falciparum antigen 332 is a resident peripheral membrane protein of Maurer's clefts. PLoS One 7(11):e46980. doi: 10.1371/journal.pone.0046980
- Hinterberg K, Scherf A, Gysin J, Toyoshima T, Aikawa M et al (1994) Plasmodium falciparum: the Pf332 antigen is secreted from the parasite by a brefeldin A dependent pathway and is translocated to the erythrocyte membrane via the Maurer's clefts. Exp Parasitol 79: 279–291
- Hodder AN, Maier AG, Rug M, Brown M, Hommel M et al (2009) Analysis of structure and function of the giant protein Pf332 in Plasmodium falciparum. Mol Microbiol 71: 48–65
- Waller KL, Stubberfield LM, Dubljevic V, Buckingham DW, Mohandas N et al (2010) Interaction of the exported malaria protein Pf332 with the red blood cell membrane skeleton. Biochim Biophys Acta 1798: 861–871 doi: 10.1016/j.bbamem.2010.01.018
- Gardner, Malcom; Hall, N; Fung, E; White, O; Berriman, M; Hyman, RW; Carlton, JM; Pain, A et al. (3 October 2002). "Genome sequence of the human malaria parasite Plasmodium falciparum". Nature 419 (6906): 498–511. doi:10.1038/nature01097. PMID 12368864. http://www.nature.com/nature/journal/v419/n6906/full/nature01097.html.
- Abu Bakar N, Klonis N, Hanssen E, Chan C, Tilley L (2010). "Digestive-vacuole genesis and endocytic processes in the early intraerythrocytic stages of Plasmodium falciparum.". J Cell Sci..
- Vaid A, Ranjan R, Smythe WA, Hoppe HC, Sharma P (2010). "PfPI3K, a Phosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin trafficking.". Blood.
- Eksi S, Williamson KC (2011). "Protein targeting to the parasitophorous vacuole membrane of Plasmodium falciparum.". Eukaryot Cell..
- Vera IM, Beatty WL, Sinnis P, Kim K (2011). "Plasmodium protease ROM1 is important for proper formation of the parasitophorous vacuole". PLoS Pathog 7 (9): e1002197.
- Arisue N, Hashimoto T, Mitsui H, Palacpac NM, Kaneko A, Kawai S, Hasegawa M, Tanabe K, Horii T (2012) The Plasmodium apicoplast genome: conserved structure and close relationship of P. ovale to rodent malaria parasites. Mol Biol Evol
- Kumar A, Tanveer A, Biswas S, Ram ER, Gupta A, Kumar B, Habib S (2010). "Nuclear-encoded DnaJ homolog of Plasmodium falciparum interacts with replication ori of the apicoplast genome.". Mol. Microbiol..
- Kennedy SR, Chen CY, Schmitt MW, Bower CN, Loeb LA (2011). "The biochemistry and fidelity of synthesis by the apicoplast genome replication DNA polymerase Pfprex from the malaria parasite Plasmodium falciparum.". J Mol Biol.
- Gallagher JR, Matthews KA, Prigge ST (2011) P. falciparum apicoplast transit peptides are unstructured in vitro and during apicoplast import. Traffic doi:10.1111/j.1600-0854.2011.01232.x
- Tonkin CJ, Roos DS, McFadden GI (2006) N-terminal positively charged amino acids, but not their exact position, are important for apicoplast transit peptide fidelity in Toxoplasma gondii. Mol Biochem Parasitol 150(2):192-200
- Tawk L, Dubremetz JF, Montcourrier P, Chicanne G, Merezegue F, Richard V, Payrastre B, Meissner M, Vial HJ, Roy C, Wengelnik K, Lebrun M (2011) Phosphatidylinositol 3-monophosphate is involved in toxoplasma apicoplast biogenesis. PloS Pathog. 7(2):e1001286
- Biot C, Botté CY, Dubar F, Maréchal E (2012) Targeting malaria parasite at the level of apicoplast: an update. Med Sci (Paris) 28(2):163-171
- Deschermeier C, Hecht LS, Bach F, Rützel K, Stanway RR, Nagel A, Seeber F, Heussler VT (2011) Mitochondrial lipoic acid scavenging is essential for Plasmodium berghei liver stage development. Cell Microbiol doi:10.1111/j.1462-5822.2011.01729.x
- Yeh E, Derisi JL (2011). "Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum". PLoS Biol 9 (8): e1001138.
- Kumar B, Chaubey S, Shah P, Tanveer A, Charan M, Siddiqi MI, Habib S (2011). "Interaction between sulphur mobilisation proteins SufB and SufC: Evidence for an iron-sulphur cluster biogenesis pathway in the apicoplast of Plasmodium falciparum.". Int J Parasitol.
- Seeber F, Soldati-Favre D (2010) Metabolic pathways in the apicoplast of apicomplexa. Int Rev Cell Mol Biol 281: 161–228
- Haussig JM, Matuschewski K, Kooij TW (2011) Inactivation of a Plasmodium apicoplast protein attenuates formation of liver merozoites. Mol Microbiol doi:10.1111/j.1365-2958.2011.07787.x
- Ponpuak M, Klemba M, Park M, Gluzman IY, Lamppa GK, Goldberg DE (2006). "A role for falcilysin in transit peptide degradation in the Plasmodium falciparum apicoplast". Mol Microbiol 63 (2): 314–334.
- Chaudhari R, Narayan A, Patankar S (2012) A novel trafficking pathway in Plasmodium falciparum for the organellar localization of glutathione peroxidase-like thioredoxin peroxidase. FEBS J doi: 10.1111/j.1742-4658.2012.08746.x.
- Kitamura K, Kishi-Itakura C, Tsuboi T, Sato S, Kita K, Ohta N, Mizushima N (2012) Autophagy-related Atg8 localizes to the apicoplast of the human malaria parasite Plasmodium falciparum. PLoS One 7(8):e42977.
- Banerjee T, Jaijyan DK, Surolia N, Singh AP, Surolia A (2012) Apicoplast triose phosphate transporter (TPT) gene knockout is lethal for Plasmodium. Mol Biochem Parasitol pii: S0166-6851(12)00241-1. doi: 10.1016/j.molbiopara.2012.09.008
- El Bakkouri M, Rathore S, Calmettes C, Wernimont AK, Liu K, Sinha D, Asad M, Jung P, Hui R, Mohmmed A, Houry WA (2012) Structural insights into the inactive subunit of the apicoplast-localized caseinolytic protease complex of Plasmodium falciparum. J Biol Chem
- McMillan PJ, Stimmler LM, Foth BJ, McFadden GI, Müller S (January 2005). "The human malaria parasite Plasmodium falciparum possesses two distinct dihydrolipoamide dehydrogenases". Molecular Microbiology 55 (1): 27–38. doi:10.1111/j.1365-2958.2004.04398.x. PMID 15612914. http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0950-382X&date=2005&volume=55&issue=1&spage=27.
- Foth BJ, Stimmler LM, Handman E, Crabb BS, Hodder AN, McFadden GI (January 2005). "The malaria parasite Plasmodium falciparum has only one pyruvate dehydrogenase complex, which is located in the apicoplast". Molecular Microbiology 55 (1): 39–53. doi:10.1111/j.1365-2958.2004.04407.x. PMID 15612915. http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0950-382X&date=2005&volume=55&issue=1&spage=39.
- Balabaskaran Nina P, Morrisey JM, Ganesan SM, Ke H, Pershing AM, Mather MW, Vaidya AB (2011). "ATP synthase complex of Plasmodium falciparum: dimeric assembly in mitochondrial membranes and resistance to genetic disruption.". J Biol Chem.
- Eckers E, Petrungaro C, Gross D, Riemer J, Hell K, Deponte M (2012) Divergent molecular evolution of the mitochondrial sulfhydryl:cytochrome c oxidoreductase Erv in opisthokonts and parasitic protists. J Biol Chem
- Hino A, Hirai M, Tanaka TQ, Watanabe YI, Matsuoka H, Kita K (2012) Critical roles of the mitochondrial complex II in oocyst formation of rodent malaria parasite Plasmodium berghei. J Biochem
- Tanaka TQ, Hirai M, Watanabe YI, Kita K (2012) Towards understanding the role of mitochondrial complex II in the intraerythrocytic stages of Plasmodium falciparum: Gene targeting of the Fp subunit. Parasitol Int
- Nozawa A, Fujimoto R, Matsuoka H, Tsuboi T, Tozawa Y (2011) Biochem Biophys Res Commun
- Rathore S, Jain S, Sinha D, Gupta M, Asad M, Srivastava A, Narayanan MS, Ramasamy G, Chauhan VS et al. (2011). "Disruption of a mitochondrial protease machinery in Plasmodium falciparum is an intrinsic signal for parasite cell death". Cell Death Dis 2 (11): e231. doi:10.1038/cddis.2011.118.
- Fisher N, Abd Majid R, Antoine T, Al-Helal M, Warman AJ, Johnson DJ, Lawrenson AS, Ranson H, O'Neill PM, Ward SA, Biagini GA (2012). "Cytochrome b mutation Y268S conferring the atovaquone resistance phenotype in the malaria parasite results in reduced parasite bc1 catalytic turnover and protein expression.". J Biol Chem.
- Ke H, Morrisey J, Ganesan SM, Mather MW, Vaidya AB (2012) Mitochondrial RNA polymerase is an essential enzyme in erythrocytic stages of Plasmodium falciparum. Mol Biochem Parasitol
- Feagin JE, Harrell MI, Lee JC, Coe KJ, Sands BH, Cannone JJ, Tami G, Schnare MN, Gutell RR (2012) The fragmented mitochondrial ribosomal RNAs of Plasmodium falciparum. PLoS One 7(6):e38320.
- Masuda-Suganuma H, Usui M, Fukumoto S, Inoue N, Kawazu SI (2012) Mitochondrial peroxidase TPx-2 is not essential in the blood and insect stages of Plasmodium berghei. Parasit Vectors 5(1):252
- Wunderlich J, Rohrbach P, Dalton JP (2012) The malaria digestive vacuole. Front Biosci (Schol Ed) 4:1424-1448
- Ch'ng JH, Liew K, Goh AS, Sidhartha E, Tan KS (2011). "Drug-induced permeabilization of parasite's digestive vacuole is a key trigger of programmed cell death in Plasmodium falciparum". Cell Death Dis 2 (10): e216. doi:10.1038/cddis.2011.97.
- Bohórquez EB, Chua M, Meshnick SR (2012) Quinine localizes to a non-acidic compartment within the food vacuole of the malaria parasite Plasmodium falciparum. Malar J
- Dasari P, Heber SD, Beisele M, Torzewski M, Reifenberg K, Orning C, Fries A, Zapf AL, Baumeister S, Lingelbach K, Udomsangpetch R, Bhakdi SC, Reiss K, Bhakdi S (2012) Digestive vacuole of Plasmodium falciparum released during erythrocyte rupture dually activates complement and coagulation. Blood
- Ehlgen, F; Pham, JS; de Koning-Ward, T; Cowman, AF; Ralph, SA (2012). "Investigation of the Plasmodium falciparum food vacuole through inducible expression of the chloroquine resistance transporter (PfCRT)". PLoS ONE 7 (6): e38781.
- Griffin CE, Hoke JM, Samarakoon U, Duan J, Mu J, Ferdig MT, Warhurst DC, Cooper RA (2012) Mutation in the Plasmodium falciparum CRT protein determines the stereospecific activity of the antimalarial Cinchona alkaloids. Antimicrob Agents Chemother
- Kapishnikov S, Weiner A, Shimoni E, Guttmann P, Schneider G, Dahan-Pasternak N, Dzikowski R, Leiserowitz L, Elbaum M (2012) Oriented nucleation of hemozoin at the digestive vacuole membrane in Plasmodium falciparum. Proc Natl Acad Sci USA
- Orjih AU, Mathew TC, Cherian PT (2012) Erythrocyte membranes convert monomeric ferriprotoporphyrin IX to β-hematin in acidic environment at malarial fever temperature. Exp Biol Med (Maywood)
- Figueiredo LM, Rocha EP, Mancio-Silva L, Prevost C, Hernandez-Verdun D, Scherf A (2005). "The unusually large Plasmodium telomerase reverse-transcriptase localizes in a discrete compartment associated with the nucleolus". Nucleic Acids Res 33 (3): 1111–1122. doi:10.1093/nar/gki260. PMC 549419. PMID 15722485. //www.ncbi.nlm.nih.gov/pmc/articles/PMC549419/.
- Chung DW, Ponts N, Prudhomme J, Rodrigues EM, Le Roch KG (2012) Characterization of the ubiquitylating components of the human malaria parasite's protein degradation pathway. PLoS One 7(8):e43477
- Nishimoto Y, Arisue N, Kawai S, Escalante AA, Horii T, Tanabe K, Hashimoto T. (2008). "Evolution and phylogeny of the heterogeneous cytosolic SSU rRNA genes in the genus Plasmodium". Mol Phylogenet Evol. 47 (1): 45–53. doi:10.1016/j.ympev.2008.01.031. PMID 18334303.
- Das S, Basu H, Korde R, Tewari R, Sharma S (2012) Arrest of nuclear division in Plasmodium through blockage of erythrocyte surface exposed ribosomal protein P2. PLoS Pathog 8(8):e1002858
- Miao J, Li J, Fan Q, Li X, Li X, Cui L (2010). "The Puf-family RNA-binding protein PfPuf2 regulates sexual development and sex differentiation in the malaria parasite Plasmodium falciparum.". J. Cell Sci..
- Laurentino EC, Taylor S, Mair GR, Lasonder E, Bartfai R, Stunnenberg HG, Kroeze H, Ramesar J, Franke-Fayard B, Khan SM, Janse CJ, Waters AP (2011) Experimentally controlled down regulation of the histone chaperone FACT in Plasmodium berghei reveals that it is critical to male gamete fertility. Cell Microbiol doi:10.1111/j.1462-5822.2011.01683.x
- Guttery DS, Ferguson DJ, Poulin B, Xu Z, Straschil U, Klop O, Solyakov L, Sandrini SM, Brady D et al. (2012). "A Putative Homologue of CDC20/CDH1 in the malaria parasite is essential for male gamete development". PLoS Pathog 8 (2): e1002554.
- Eksi S, Morahan BJ, Haile Y, Furuya T, Jiang H, Ali O, Xu H, Kiattibutr K, Suri A, Czesny B, Adeyemo A, Myers TG, Sattabongkot J, Su XZ, Williamson KC (2012) Plasmodium falciparum Gametocyte development 1 (Pfgdv1) and gametocytogenesis early gene identification and commitment to sexual development. PLoS Pathog 8(10):e1002964. doi: 10.1371/journal.ppat.1002964
- Dvorin, JD; Martyn, DC; Patel, SD; Grimley, JS; Collins, CR; Hopp, CS; Bright, AT; Westenberger, S et al. (2010). "A Plant-Like Kinase in Plasmodium falciparum Regulates Parasite Egress From Erythrocytes". Science 328 (5980): 910–912. doi:10.1126/science.1188191. PMC 3109083. PMID 20466936. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3109083/.
- Millholland MG, Chandramohanadas R, Pizarro A, Wehr A, Shi H, Darling C, Lim CT, Greenbaum DC (2011). "The malaria parasite progressively dismantles the host erythrocyte cytoskeleton for efficient egress.". Mol Cell Proteomics.
- Dasari P, Reiss K, Lingelbach K, Baumeister S, Lucius R, Udomsangpetch R, Bhakdi SC, Bhakdi S (2011). "Digestive vacuoles of Plasmodium falciparum are selectively phagocytosed by and impair killing function of polymorphonuclear leukocytes.". Blood.
- Arisue, N; Kawai, S; Hirai, M; Palacpac, NM; Jia, M; Kaneko, A; Tanabe, K; Horii, T (2011). "Clues to evolution of the SERA multigene family in 18 Plasmodium species". PLoS ONE 6 (3): e17775.
- Ruecker A, Shea M, Hackett F, Suarez C, Hirst EM, Milutinovic K, Withers-Martinez C, Blackman MJ (2012) Proteolytic activation of the essential parasitophorous vacuole cysteine protease SERA6 accompanies malaria parasite egress from its host erythrocyte. J Biol Chem
- Agarwal S, Singh MK, Garg S, Chitnis CE, Singh S (2012) Ca(2+) Mediated exocytosis of subtilisin-like protease 1: A key step in egress of P. falciparum merozoites. Cell Microbiol doi: 10.1111/cmi.12086
- Talman AM, Lacroix C, Marques SR, Blagborough AM, Carzaniga R, Ménard R, Sinden RE (2011) PbGEST mediates malaria transmission to both mosquito and vertebrate host. Mol Microbiol doi:10.1111/j.1365-2958.2011.07823.x
- Talevich E, Tobin AB, Kannan N, Doerig C (2012) An evolutionary perspective on the kinome of malaria parasites. Philos Trans R Soc Lond B Biol Sci 367(1602):2607-2618
- Agarwal S, Kern S, Halbert J, Przyborski JM, Baumeister S, Dandekar T, Doerig C, Pradel G.(2011) Two nucleus-localized CDK-like kinases with crucial roles for malaria parasite erythrocytic replication are involved in phosphorylation of splicing factor. J. Cell. Biochem. doi:10.1002/jcb.23034
- Dorin-Semblat D, Schmitt S, Semblat JP, Sicard A, Reininger L, Goldring D, Patterson S, Quashie N et al. (2011). "Plasmodium falciparum NIMA-related kinase Pfnek-1: sex specificity and assessment of essentiality for the erythrocytic asexual cycle". Microbiology 157 (10): 2785–2794. doi:10.1099/mic.0.049023-0.
- Reininger L, Tewari R, Fennell C, Holland Z, Goldring D, Ranford-Cartwright L, Billker O, Doerig C (2009) An essential role for the Plasmodium Nek-2 Nima-related protein kinase in the sexual development of malaria parasites. J Biol Chem 284(31):20858-20568
- Low H, Chua CS, Sim TS (2011). "Plasmodium falciparum possesses a unique dual-specificity serine/threonine and tyrosine kinase, Pfnek3.". Cell Mol Life Sci.
- Reininger L, Garcia M, Tomlins A, Müller S, Doerig C (2012) The Plasmodium falciparum, Nima-related kinase Pfnek-4: a marker for asexual parasites committed to sexual differentiation. Malar J. 11(1):250.
- Lin DT, Goldman ND, Syin C (1996) Stage-specific expression of a Plasmodium falciparum protein related to the eukaryotic mitogen-activated protein kinases. Mol Biochem Parasitol 78(1-2):67-77
- Talevich E, Mirza A, Kannan N (2011). "Structural and evolutionary divergence of eukaryotic protein kinases in Apicomplexa". BMC Evol Biol 11 (1): 321.
- Trivedi V, Nag S (2012) In silico characterization of atypical kinase, PFD0975w from Plasmodium kinome: A suitable target for drug discovery. Chem Biol Drug Des doi:10.1111/j.1747-0285.2012.01321.x.
- Chouhan DK, Sharon A, Bal C (2012) Molecular and structural insight into plasmodium falciparum RIO2 kinase. J Mol Model
- Nag S, Prasad KM, Bhowmick A, Deshmukh R, Trivedi V (2012) PfRIO-2 kinase is a potential therapeutic target of antimalarial protein kinase inhibitors. Curr Drug Discov Technol
- Dastidar EG, Dayer G, Holland ZM, Dorin-Semblat D, Claes A, Chene A, Sharma A, Hamelin R, Moniatte M, Lopez-Rubio JJ, Scherf A, Doerig C (2012) Involvement of Plasmodium falciparum protein kinase CK2 in the chromatin assembly pathway. BMC Biol 10(1):5
- Ma J, Rahlfs S, Jortzik E, Heiner Schirmer R, Przyborski J, Becker K (2012) Subcellular localization of adenylate kinases in Plasmodium falciparum. FEBS Lett
- Dvorin JD, Martyn DC, Patel SD, Grimley JS, Collins CR, (2010) A plant-like kinase in Plasmodium falciparum regulates parasite egress from erythrocytes. Science 328: 910–912
- Ishino T, Orito Y, Chinzei Y, Yuda M (2006) A calcium-dependent protein kinase regulates Plasmodium ookinete access to the midgut epithelial cell. Mol Microbiol 59: 1175–1184
- Billker O, Dechamps S, Tewari R, Wenig G, Franke-Fayard B, et al. (2004) Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite. Cell 117: 503–514
- McCoy JM, Whitehead L, van Dooren GG, Tonkin CJ (2012) TgCDPK3 regulates calcium-dependent egress of Toxoplasma gondii from host cells. PLoS Pathog 8(12):e1003066. doi: 10.1371/journal.ppat.1003066
- Kato N, Sakata T, Breton G, Le Roch KG, Nagle A, et al (2008) Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility. Nat Chem Biol 4: 347–356
- Green JL, Rees-Channer RR, Howell SA, Martin SR, Knuepfer E, et al (2008) The motor complex of Plasmodium falciparum: phosphorylation by a calcium-dependent protein kinase. J Biol Chem 283: 30980–30989.
- Sebastian S, Brochet M, Collins MO, Schwach F, Jones ML, Goulding D, Rayner JC, Choudhary JS, Billker O (2012) A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs. Cell Host Microbe 12(1):9-19
- Hopp CS, Flueck C, Solyakov L, Tobin A, Baker DA (2012) Spatiotemporal and functional characterisation of the Plasmodium falciparum cGMP-dependent protein kinase. PLoS One 7(11):e48206. doi: 10.1371/journal.pone.0048206
- Wilkes JM, Doerig C (2008) The protein-phosphatome of the human malaria parasite Plasmodium falciparum. BMC Genomics 9: 412
- Rosenthal PJ (2011). "Falcipains and other cysteine proteases of malaria parasites". Adv Exp Med Biol. Advances in Experimental Medicine and Biology 712: 30–48. doi:10.1007/978-1-4419-8414-2_3. ISBN 978-1-4419-8413-5. PMID 21660657.
- Ragheb D, Dalal S, Bompiani KM, Ray WK, Klemba M (2011). "Distribution and biochemical properties of an M1-family aminopeptidase in Plasmodium falciparum indicate a role in vacuolar hemoglobin catabolism.". J Biol Chem.
- Harbut MB, Velmourougane G, Dalal S, Reiss G, Whisstock JC, Onder O, Brisson D, McGowan S, Klemba M, Greenbaum DC (2011). "Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases.". Proc Natl Acad Sci USA.
- Sivaraman KK, Oellig CA, Huynh K, Atkinson SC, Poreba M, Perugini MA, Trenholme KR, Gardiner DL, Salvesen G, Drag M, Dalton JP, Whisstock JC, McGowan S (2012) X-ray crystal structure and specificity of the Plasmodium falciparum malaria aminopeptidase PfM18AAP. J Mol Biol
- Gupta D, Yedidi RS, Varghese S, Kovari LC, Woster PM (2010). "Mechanism-based inhibitors of the aspartyl protease plasmepsin II as potential antimalarial agents.". J. Med. Chem..
- Bhaumik P, Xiao H, Hidaka K, Gustchina A, Kiso Y, Yada RY, Wlodawer A (2011) Structural insights into activation and inhibition of histo-aspartic protease (HAP) from Plasmodium falciparum. Biochemistry
- Francis SE, Banerjee R, Goldberg DE (1997) Biosynthesis and maturation of the malaria aspartic hemoglobinases plasmepsins I and II. J Biol Chem 272(23):14961-1498
- Bhaumik P, Gustchina A, Wlodawer A (2012) Structural studies of vacuolar plasmepsins. Biochim Biophys Acta 1824(1):207-23. doi: 10.1016/j.bbapap.2011.04.008
- Moura PA, Dame JB, Fidock DA (2009) Role of Plasmodium falciparum digestive vacuole plasmepsins in the specificity and antimalarial mode of action of cysteine and aspartic protease inhibitors. Antimicrob Agents Chemother 53(12):4968-4978
- Banerjee R, Francis SE, Goldberg DE (2003) Food vacuole plasmepsins are processed at a conserved site by an acidic convertase activity in Plasmodium falciparum. Mol Biochem Parasitol 129(2):157-165
- Kim YM, Lee MH, Piao TG, Lee JW, Kim JH, Lee S, Choi KM, Jiang JH, Kim TU, Park H (2006) Prodomain processing of recombinant plasmepsin II and IV, the aspartic proteases of Plasmodium falciparum, is auto- and trans-catalytic. J Biochem 139(2):189-195
- Klemba M, Goldberg DE (2005) Characterization of plasmepsin V, a membrane-bound aspartic protease homolog in the endoplasmic reticulum of Plasmodium falciparum. Mol Biochem Parasitol 143(2):183-191
- Marapana DS, Wilson DW, Zuccala ES, Dekiwadia CD, Beeson JG, Ralph SA, Baum J (2012) Malaria parasite signal peptide peptidase is an ER-resident protease required for growth but not invasion. Traffic doi: 10.1111/j.1600-0854.2012.01402.x.
- Ejigiri I, Ragheb DR, Pino P, Coppi A, Bennett BL, Soldati-Favre D, Sinnis P (2012) Shedding of TRAP by a rhomboid protease from the malaria sporozoite surface is essential for gliding motility and sporozoite infectivity. PLoS Pathog 8(7):e1002725
- Ponder EL, Albrow VE, Leader BA, Békés M, Mikolajczyk J, Fonović UP, Shen A, Drag M et al. (2011). "Functional characterization of a SUMO deconjugating protease of Plasmodium falciparum using newly identified small molecule inhibitors". Chem Biol. 18 (6): 711–721. doi:10.1016/j.chembiol.2011.04.010. PMC 3131532. PMID 21700207. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3131532/.
- Alam A, Bhatnagar RK, Chauhan VS (2012) Expression and characterization of catalytic domain of Plasmodium falciparum subtilisin-like protease 3. Mol Biochem Parasitol
- Harris PK, Yeoh S, Dluzewski AR, O'Donnell RA, Withers-Martinez C, Hackett F, Bannister LH, Mitchell GH, Blackman MJ (2005) Molecular identification of a malaria merozoite surface sheddase. PLoS Pathog 1(3):241-251
- Lalle M, Curra C, Ciccarone F, Pace T, Cecchetti S, Fantozzi L, Ay B, Braun Breton C, Ponzi M. (2010). "Dematin, a component of the erythrocyte membrane-skeleton, is internalized by the malaria parasite and associates with Plasmodium 14-3-3.". J. Biol. Chem..
- Sicard A, Semblat JP, Doerig C, Hamelin R, Moniatte M, Dorin-Semblat D, Spicer JA, Srivastava A, Retzlaff S, Heussler V, Waters AP, Doerig C (2011). "Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes.". Cell Microbiol..
- Bagnaresi P, de Barros NM, Assis DM, Melo PM, Fonseca RG, Juliano MA, Pesquero JB, Juliano L, Rosenthal PJ, Carmona AK, Gazarini ML (2012) Intracellular proteolysis of kininogen by malaria parasites promotes release of active kinins. Malar J 11(1):156
- Henry RI, Cobbold SA, Allen RJ, Khan A, Hayward R, Lehane AM, Bray PG, Howitt SM, Biagini GA, Saliba KJ, Kirk K (2010). "An acid-loading chloride transport pathway in the intraerythrocytic malaria parasite, Plasmodium falciparum.". J. Biol. Chem..
- Müller IB, Knöckel J, Eschbach ML, Bergmann B, Walter RD, Wrenger C (2010) Secretion of an acid phosphatase provides a possible mechanism to acquire) host nutrients by Plasmodium falciparum. Cell Microbiol.
- Cobbold SA, Martin RE, Kirk K (2010). "Methionine transport in the malaria parasite Plasmodium falciparum.". Parasitol..
- Sinou V, Quang LH, Pelleau S, Huong VN, Huong NT, Tai LM, Bertaux L, Desbordes M, Latour C, Long LQ, Thanh NX, Parzy D (2011) Polymorphism of Plasmodium falciparum Na+/H+ exchanger is indicative of a low in vitro quinine susceptibility in isolates from Viet Nam. Malar J. 2011 Jun 14;10(1):164
- Kone A, Mu J, Maiga H, Beavogui AA, Yattara O, Sagara I, Tekete MM, Traore OB, Dara A, Dama S, Diallo N, Kodio A, Traoré A, Björkman A, Gil JP, Doumbo OK, Wellems TE, Djimde AA (2012) Quinine treatment selects Pfnhe1 ms47601 polymorphism in Malian patients with falciparum malaria. J Infect Dis
- Salcedo-Sora JE, Ochong E, Beveridge S, Johnson D, Nzila A, Biagini GA, Stocks PA, O'Neill PM, Krishna S, Bray PG, Ward SA (2011). "The molecular basis of folate salvage in Plasmodium falciparum: Characterization of two folate transporters.". J Biol Chem.
- Downie MJ, El Bissati K, Bobenchik AM, Nic Lochlainn L, Amerik A, Zufferey R, Kirk K, Ben Mamoun C (2010). "PfNT2: a permease of the equilibrative nucleoside transporter family in the endoplasmic reticulum of Plasmodium falciparum.". J Biol Chem..
- Rached FB, Ndjembo-Ezougou C, Chandran S, Talabani H, Yera H, Dandavate V, Bourdoncle P, Meissner M, Tatu U, Langsley G (2011) Construction of a Plasmodium falciparum Rab-interactome identifies CK1 and PKA as Rab-effector kinases in malaria parasites. Biol Cell doi:10.1111/boc.201100081
- Bhattacharjee S, Stahelin RV, Speicher KD, Speicher DW, Haldar K (2012). "Endoplasmic reticulum PI(3)P lipid binding targets malaria proteins to the Host Cell". Cell 148 (1-2): 201–212.
- Sharma A, Sharma A, Dixit S, Sharma A (2011) Structural insights into thioredoxin-2: a component of malaria parasite protein secretion machinery. Sci Rep 1:179
- Cabrera A, Herrmann S, Warszta D, Santos JM, John Peter AT, Kono M, Debrouver S, Jacobs T, Spielmann T, Ungermann C, Soldati-Favre D, Gilberger TW (2012) Dissection of minimal sequence requirements for rhoptry membrane targeting in the malaria parasite. Traffic 9999(999A). doi: 10.1111/j.1600-0854.2012.01394.x.
- Riegelhaupt PM, Frame IJ, Akabas MH (2010) Transmembrane segment 11 appears to line the purine permeation pathway of the Plasmodium falciparum equilibrative nucleoside transporter 1 (PfENT1). J Biol Chem.
- Frame IJ, Merino EF, Schramm VL, Cassera MB, Akabas MH (2012) Malaria parasite type 4 equilibrative nucleoside transporters (ENT4) are purine transporters with distinct substrate specificity. Biochem J
- Quashie NB, Ranford-Cartwright LC, De Koning HP (2010) Uptake of purines in Plasmodium falciparum-infected human erythrocytes is mostly mediated by the human equilibrative nucleoside transporter and the human Facilitative Nucleobase Transporter. Malar. J. Jan 29;9(1):36
- Niemand J, Louw AI, Birkholtz L, Kirk K (2012) Polyamine uptake by the intraerythrocytic malaria parasite, Plasmodium falciparum. Int J Parasitol
- Nguitragool W, Bokhari AA, Pillai AD, Rayavara K, Sharma P, Turpin B, Aravind L, Desai S (2011). "Malaria parasite clag genes determine nutrient uptake channel activity on infected red blood cells". Cell 145 (5): 665–677. doi:10.1016/j.cell.2011.05.002. PMC 3105333. PMID 21620134. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3105333/.
- Alkhalil A, Hong L, Nguitragool W, Desai SA (2011). "Voltage-dependent inactivation of the plasmodial surface anion channel via a cleavable cytoplasmic component.". Biochim Biophys Acta.
- Pillai AD, Nguitragool W, Lyko B, Dolinta K, Butler MM, Nguyen ST, Peet NP, Bowlin TL, Desai SA (2012) Solute restriction reveals an essential role for clag3-associated channels in malaria parasite nutrient acquisition. Mol Pharmacol
- Chen LY (2012) Glycerol inhibits water permeation through Plasmodium falciparum aquaglyceroporin. J Struct Biol pii: S1047-8477(12)00289-4. doi: 10.1016/j.jsb.2012.10.007
- Eastman RT, Pattaradilokrat S, Raj DK, Dixit S, Deng B, Miura K, Yuan J, Tanaka TQ, Johnson RL, Jiang H, Huang R, Williamson K, Lambert LE, Long C, Austin CP, Wu Y, Su XZ (2012) A class of tricyclic compounds blocking malaria oocyst development and transmission. Antimicrob Agents Chemother
- Choveaux DL, Przyborski JM, Goldring JD (2012) A Plasmodium falciparum copper-binding membrane protein with copper transport motifs. Malar J 11(1):397
- Bullen HE, Charnaud SC, Kalanon M, Riglar DT, Dekiwadia C, Kangwanrangsan N, Torii M, Tsuboi T, Baum J, Ralph SA, Cowman AF, de Koning-Ward TF, Crabb BS, Gilson PR (2012). "Biosynthesis, localisation and macromolecular arrangement of the Plasmodium falciparum translocon of exported proteins; PTEX.". J Biol Chem.
- Bhattacharjee S, Stahelin RV, Speicher KD, Speicher DW, Haldar K (2012) Endoplasmic reticulum PI(3)P lipid binding targets malaria proteins to the host cell. Cell 148(1-2):201-212
- Boddey JA, Hodder AN, Günther S, Gilson PR, Patsiouras H, Kapp EA, Pearce JA, de Koning-Ward TF, Simpson RJ, Crabb BS, Cowman AF (2010) An aspartyl protease directs malaria effector proteins to the host cell. Nature 463(7281):627-631
- Bhattacharjee S, Hiller NL, Liolios K, Win J, Kanneganti TD, Young C, Kamoun S, Haldar K (2006) The malarial host-targeting signal is conserved in the Irish potato famine pathogen. PLoS Pathog 2(5):e50.
- Grüring C, Heiber A, Kruse F, Flemming S, Franci G, Colombo SF, Fasana E, Schoeler H, Borgese N, Stunnenberg HG, Przyborski JM, Gilberger TW, Spielmann T (2012) Uncovering common principles in protein export of malaria parasites. Cell Host Microbe 12(5):717-29. doi: 10.1016/j.chom.2012.09.010
- Deligianni E, Morgan RN, Bertuccini L, Kooij TW, Laforge A, Nahar C, Poulakakis N, Schüler H, Louis C, Matuschewski K, Siden-Kiamos I (2011) Critical role for a stage-specific actin in male exflagellation of the malaria parasite. Cell Microbiol doi:10.1111/j.1462-5822.2011.01652.x
- Wong W, Skau CT, Marapana DS, Hanssen E, Taylor NL, Riglar DT, Zuccala ES, Angrisano F, Lewis H, Catimel B, Clarke OB, Kershaw NJ, Perugini MA, Kovar DR, Gulbis JM, Baum J (2011). "Minimal requirements for actin filament disassembly revealed by structural analysis of malaria parasite actin-depolymerizing factor 1.". Proc Natl Acad Sci USA.
- Singh BK, Sattler JM, Chatterjee M, Huttu J, Schüler H, Kursula I (2011). "Crystal structures explain functional differences in the two actin depolymerization factors of the malaria parasite". J Biol Chem 286 (32): 28256–28264. doi:10.1074/jbc.M111.211730. PMC 3151070. PMID 21832095. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3151070/.
- Skillman KM, Diraviyam K, Khan A, Tang K, Sept D, Sibley LD (2011). "Evolutionarily divergent, unstable filamentous actin is essential for gliding motility in apicomplexan parasites". PLoS Pathog 7 (10): e1002280.
- Zhang Q, Huang Y, Zhang Y, Fang X, Claes A, Duchateau M, Namane A, Lopez-Rubio JJ, Pan W, Scherf A (2011) A critical role of perinuclear filamentous actin in spatial repositioning and mutually exclusive expression of virulence genes in malaria parasites. Cell Host Microbe 10(5):451-463
- Angrisano F, Delves MJ, Sturm A, Mollard V, McFadden GI, Sinden RE, Baum J (2011). "A GFP-actin reporter line to explore microfilament dynamics across the malaria parasite lifecycle.". Mol Biochem Parasitol.
- Ignatev, A; Bhargav, SP; Vahokoski, J; Kursula, P; Kursula, I (2012). "The lasso segment is required for functional dimerization of the Plasmodium formin 1 FH2 domain". PLoS ONE 7 (3): e33586.
- Uchime O, Herrera R, Reiter K, Kotova S, Shimp RL Jr, Miura K, Jones D, Lebowitz J, Ambroggio X, Hurt DE, Jin AJ, Long C, Miller LH, Narum DL (2012) Analysis of the conformation and function of the Plasmodium falciparum merozoite proteins MTRAP and PTRAMP. Eukaryot Cell
- Makkonen M, Bertling E, Chebotareva N, Baum J, Lappalainen P (2012) Mammalian and malaria parasite cyclase-associated proteins catalyze nucleotide exchange on G-actin Through a conserved mechanism. J Biol Chem
- Hellmann JK, Münter S, Kudryashev M, Schulz S, Heiss K, Müller AK, Matuschewski K, Spatz JP et al. (2011). "Environmental constraints guide migration of malaria parasites during transmission". PLoS Pathog 7 (6): e1002080.
- Song G, Koksal AC, Lu C, Springer TA (2012) Shape change in the receptor for gliding motility in Plasmodium sporozoites. Proc Natl Acad Sci USA
- Ejigiri I, Ragheb DR, Pino P, Coppi A, Bennett BL, Soldati-Favre D, Sinnis P (2012) Shedding of TRAP by a rhomboid protease from the malaria sporozoite surface is essential for gliding motility and sporozoite infectivity. PLoS Pathog 8(7):e1002725
- Ramakrishnan C, Dessens JT, Armson R, Pinto SB, Talman AM, Blagborough AM, Sinden RE (2011). "Vital functions of the malarial ookinete protein, CTRP, reside in the A domains.". Int J Parasitol.
- Bergmann-Leitner ES, Legler PM, Savranskaya T, Ockenhouse CF, Angov E (2011). "Cellular and humoral immune effector mechanisms required for sterile protection against sporozoite challenge induced with the novel malaria vaccine candidate CelTOS.". Vaccine.
- Douse CH, Green JL, Salgado PS, Simpson PJ, Thomas JC, Langsley G, Holder AA, Tate EW, Cota E (2012) Regulation of the Plasmodium motor complex: phosphorylation of Myosin A Tail Interacting Protein (MTIP) loosens its grip on MyoA. J Biol Chem
- Qureshi BM, Hofmann NE, Arroyo-Olarte RD, Nickl B, Hoehne W, Jungblut PR, Lucius R, Scheerer P, Gupta N (2012) Dynein light chain 8a of Toxoplasma gondii, a unique conoid-localized β-strand-swapped homodimer, is required for an efficient parasite growth. FASEB J
- Ghosh AK, Jacobs-Lorena M (2011) Surface-expressed enolases of Plasmodium and other pathogens. Mem Inst Oswaldo Cruz 106 Suppl 1:85-90
- Currà C, Pace T, Franke-Fayard BM, Picci L, Bertuccini L, Ponzi M (2011) Erythrocyte remodeling in Plasmodium berghei infection: the contribution of SEP family members. Traffic doi:10.1111/j.1600-0854.2011.01313.x
- Mackellar DC, O'Neill MT, Aly AS, Sacci JB Jr, Cowman AF, Kappe SH (2010) Plasmodium falciparum PF10_0164 (ETRAMP10.3) is an essential parasitophorous vacuole and exported protein of blood stages. Eukaryot. Cell
- Mackellar DC, Vaughan AM, Aly AS, Deleon S, Kappe SH (2011) A systematic analysis of the early transcribed membrane protein family throughout the life cycle of Plasmodium yoelii. Cell Microbiol. doi:10.1111/j.1462-5822.2011.01656.x
- Tham, WH; Wilson, DW; Lopaticki, S; Schmidt, CQ; Tetteh-Quarcoo, PB; Barlow, PN; Richard, D; Corbin, JE et al. (2010). "Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand". Proc Natl Acad Sci U S A 107 (40): 17327–17332. doi:10.1073/pnas.1008151107. PMC 2951459. PMID 20855594. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2951459/.
- Gómez, ND; Safeukui, I; Adelani, AA; Tewari, R; Reddy, JK; Rao, S; Holder, A; Buffet, P et al. (2011). "Deletion of a malaria invasion gene reduces death and anemia, in model hosts". PLoS ONE 6 (9): e25477.
- Kilili GK, Lacount DJ (2011). "An erythrocyte cytoskeleton-binding motif in exported Plasmodium falciparum proteins.". Eukaryot Cell.
- Gilson PR, Nebl T, Vukcevic D, Moritz RL, Sargeant T, Speed TP, Schofield L, Crabb BS (2006) Identification and stoichiometry of glycosylphosphatidylinositolanchored membrane proteins of the human malaria parasite Plasmodium falciparum. Mol Cell Proteomics 5:1286-1299
- Alexandre JS, Kaewthamasorn M, Yahata K, Nakazawa S, Kaneko O (2011) Positive selection on the Plasmodium falciparum clag2 gene encoding a component of the erythrocyte-binding rhoptry protein complex. Trop Med Health 39(3):77-82
- Sakamoto H, Takeo S, Maier AG, Sattabongkot J, Cowman AF, Tsuboi T (2012). "Antibodies against a Plasmodium falciparum antigen PfMSPDBL1 inhibit merozoite invasion into human erythrocytes.". Vaccine.
- da Cruz LN, Juliano MA, Budu A, Juliano L, Holder AA, Blackman MJ, Garcia CR (2012) Extracellular ATP triggers proteolysis and cytosolic Ca2+ rise in Plasmodium berghei and Plasmodium yoelii malaria parasites. Malar J 11(1):69.
- Waisberg M, Cerqueira GC, Yager SB, Francischetti IM, Lu J, Gera N, Srinivasan P, Miura K, Rada B, Lukszo J, Barbian KD, Leto TL, Porcella SF, Narum DL, El-Sayed N, Miller LH, Pierce SK (2012) Plasmodium falciparum merozoite surface protein 1 blocks the proinflammatory protein S100P. Proc Natl Acad Sci USA
- Schlarman, MS; Roberts, RN; Kariuki, MM; Lacrue, AN; Ou, R; Beerntsen, BT (2012). "PFE0565w, a Plasmodium falciparum protein Expressed in salivary gland sporozoites". Am J Trop Med Hyg 86 (6): 943–954.
- Ding Y, Huang X, Liu T, Fu Y, Tan Z, Zheng H, Zhou T, Dai J, Xu W (2012) The Plasmodium circumsporozoite protein, a novel NF-κB inhibitor, suppresses the growth of SW480. Pathol Oncol Res
- Taechalertpaisarn T, Crosnier C, Bartholdson SJ, Hodder AN, Thompson J, Bustamante LY, Wilson DW, Sanders PR, Wright GJ, Rayner JC, Cowman AF, Gilson PR, Crabb BS (2012) Biochemical and functional analysis of two Plasmodium falciparum blood-stage 6-cys proteins: P12 and P41. PLoS One 7(7):e41937.
- Elliott JF, Albrecht GR, Gilladoga A, Handunnetti SM, Neequaye J, Lallinger G, Minjas JN, Howard RJ (1990) Genes for Plasmodium falciparum surface antigens cloned by expression in COS cells. Proc Natl Acad Sci USA 87(16):6363-6367
- Saeed S, Tremp AZ, Dessens JT (2012) Conformational co-dependence between Plasmodium berghei LCCL proteins promotes complex formation and stability. Mol Biochem Parasitol
- Diez-Silva M, Park Y, Huang S, Bow H, Mercereau-Puijalon O, Deplaine G, Lavazec C, Perrot S, Bonnefoy S, Feld MS, Han J, Dao M, Suresh S (2012) Pf155/RESA protein influences the dynamic microcirculatory behavior of ring-stage Plasmodium falciparum infected red blood cells. Sci Rep 2:614
- Huang YT, Lu XM, Jin XB, Zhu JY (2012) Research advances on circumsporzoite protein of Plasmodium. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 30(3):238-242
- Ponts N, Saraf A, Chung DW, Harris A, Prudhomme J, Washburn MP, Florens L, Le Roch KG (2011). "Unraveling the human malaria parasite's ubiquitome.". J Biol Chem.
- Hain AU, Weltzer RR, Hammond H, Jayabalasingham B, Dinglasan RR, Graham DR, Colquhoun DR, Coppens I, Bosch J (2012) Structural characterization and inhibition of the Plasmodium Atg8-Atg3 interaction. J Struct Biol pii: S1047-8477(12)00243-2. doi: 10.1016/j.jsb.2012.09.001.
- Balu B, Maher SP, Pance A, Chauhan C, Naumov AV, Andrews RM, Ellis PD, Khan SM, Lin JW, Janse CJ, Rayner JC, Adams JH (2011). "CCR4-associated factor-1 coordinates expression of Plasmodium falciparum egress and invasion proteins.". Eukaryot Cell.
- Mehta J, Tuteja R (2011) Inhibition of unwinding and ATPase activities of Plasmodium falciparum Dbp5/DDX19 homolog. Commun Integr Biol 4(3):299-303
- Aly AS, Lindner SE, Mackellar DC, Peng X, Kappe SH (2011). "SAP1 is a critical post-transcriptional regulator of infectivity in malaria parasite sporozoite stages". Mol Microbiol 79 (4): 929–939. doi:10.1111/j.1365-2958.2010.07497.x. PMID 21299648.
- Gissot M, Briquet S, Refour P, Boschet C, Vaquero C (2005). "PfMyb1, a Plasmodium falciparum transcription factor, is required for intra-erythrocytic growth and controls key genes for cell cycle regulation". J Mol Biol 346 (1): 29–42. doi:10.1016/j.jmb.2004.11.045. PMID 15663925.
- Sierra-Miranda M, Delgadillo DM, Mancio-Silva L, Vargas M, Villegas-Sepulveda N, Martínez-Calvillo S, Scherf A, Hernández-Rivas R (2012) Two long non-coding RNAs generated from subtelomeric regions accumulate in a novel perinuclear compartment in Plasmodium falciparum. Mol Biochem Parasitol
- Botha M, Chiang AN, Needham PG, Stephens LL, Hoppe HC, Külzer S, Przyborski JM, Lingelbach K, Wipf P, Brodsky JL, Shonhai A, Blatch GL (2010). "Plasmodium falciparum encodes a single cytosolic type I Hsp40 that functionally interacts with Hsp70 and is upregulated by heat shock.". Cell Stress Chaperones.
- Morahan BJ, Strobel C, Hasan U, Czesny B, Mantel PY, Marti M, Eksi S, Williamson KC (2011). "Functional analysis of the exported type IV HSP40 protein PfGECO in P. falciparum gametocytes.". Eukaryot Cell.
- Gitau GW, Mandal P, Blatch GL, Przyborski J, Shonhai A (2011) Characterisation of the Plasmodium falciparum Hsp70-Hsp90 organising protein (PfHop). Cell Stress Chaperones
- Chua CS, Low H, Lehming N, Sim TS (2011). "Molecular analysis of Plasmodium falciparum co-chaperone Aha1 supports its interaction with and regulation of Hsp90 in the malaria parasite.". Int J Biochem Cell Biol.
- Montagna GN, Buscaglia CA, Munter S, Goosmann C, Frischknecht F, Brinkmann V, Matuschewski K (2011) Critical role for heat shock protein 20 (HSP20) in migration of malarial sporozoites. J Biol Chem
- Acharya P, Chaubey S, Grover M, Tatu U (2012) An exported heat shock protein 40 associates with pathogenesis-related knobs in Plasmodium falciparum infected erythrocytes. PLoS One 7(9):e44605
- Johnson RA, McFadden GI, Goodman CD (2011). Langsley, Gordon. ed. "Characterization of two malaria parasite organelle translation elongation factor g proteins: the likely targets of the anti-malarial fusidic acid". PLoS ONE 6 (6): e20633. doi:10.1371/journal.pone.0020633. PMC 3112199. PMID 21695207. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3112199/.
- Siribal S, Weinfeld M, Karimi-Busheri F, Mark Glover JN, Bernstein NK, Aceytuno D, Chavalitshewinkoon-Petmitr P (2011). "Molecular characterization of Plasmodium falciparum putative polynucleotide kinase/phosphatase.". Mol Biochem Parasitol.
- Zhu AY, Zhou Y, Khan S, Deitsch K, Hao Q, Lin H (2011). "Plasmodium falciparum Sir2A preferentially hydrolyzes medium and long chain fatty acyl lysine.". ACS Chem Biol.
- Joshi MB, Lin DT, Chiang PH, Goldman ND, Fujioka H, Aikawa M, Syin C (1999) Molecular cloning and nuclear localization of a histone deacetylase homologue in Plasmodium falciparum. Mol Biochem Parasitol 99(1):11-19
- Chêne A, Vembar SS, Rivière L, Lopez-Rubio JJ, Claes A, Siegel TN, Sakamoto H, Scheidig-Benatar C, Hernandez-Rivas R, Scherf A (2011). "PfAlbas constitute a new eukaryotic DNA/RNA-binding protein family in malaria parasites.". Nucleic Acids Res.
- Harris EY, Ponts N, Le Roch KG, Lonardi S (2011). "Chromatin-driven de novo discovery of DNA binding motifs in the human malaria parasite". BMC Genomics 12 (1): 601.
- Jackson KE, Pham JS, Kwek M, De Silva NS, Allen SM, Goodman CD, McFadden GI, de Pouplana LR, Ralph SA (2011). "Dual targeting of aminoacyl-tRNA synthetases to the apicoplast and cytosol in Plasmodium falciparum.". Int J Parasitol.
- Bhatt TK, Khan S, Dwivedi VP, Banday MM, Sharma A, Chandele A, Camacho N, de Pouplana LR, Wu Y, Craig AG, Mikkonen AT, Maier AG, Yogavel M, Sharma A (2011) Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses. Nat Commun 2:530. doi:10.1038/ncomms1522
- Zhang M, Mishra S, Sakthivel R, Rojas M, Ranjan R, Sullivan WJ Jr, Fontoura BM, Ménard R, Dever TE, Nussenzweig V (2012) PK4, a eukaryotic initiation factor 2α(eIF2α) kinase, is essential for the development of the erythrocytic cycle of Plasmodium. Proc Natl Acad Sci USA
- Hoeijmakers WA, Flueck C, Françoijs KJ, Smits AH, Wetzel J, Volz JC, Cowman AF, Voss T, Stunnenberg HG, Bártfai R (2012) Plasmodium falciparum centromeres display a unique epigenetic makeup and cluster prior to and during schizogony. Cell Microbiol doi:10.1111/j.1462-5822.2012.01803.x.
- Antony E, Weiland EA, Korolev S, Lohman TM (2012) Plasmodium falciparum SSB tetramer wraps single stranded DNA with similar topology but opposite polarity to E. coli SSB. J Mol Biol
- Antony E, Kozlov AG, Nguyen B, Lohman TM (2012) Plasmodium falciparum SSB tetramer binds single stranded DNA only in a fully wrapped mode. J Mol Biol
- Ahmad M, Singh S, Afrin F, Tuteja R (2012) Novel RuvB nuclear ATPase is specific to intraerythrocytic mitosis during schizogony of Plasmodium falciparum. Mol Biochem Parasitol
- Pradhan A, Tuteja R (2007) Bipolar, Dual Plasmodium falciparum helicase 45 expressed in the intraerythrocytic developmental cycle is required for parasite growth. J Mol Biol 373(2):268-281
- Lima WR, Moraes M, Alves E, Azevedo MF, Passos DO, Garcia CR (2012) The PfNF-YB transcription factor is a downstream target of melatonin and cAMP signalling in the human malaria parasite Plasmodium falciparum. J Pineal Res doi: 10.1111/j.1600-079X.2012.01021.x.
- Pace T, Olivieri A, Sanchez M, Albanesi V, Picci L, Siden Kiamos I, Janse CJ, Waters AP, Pizzi E, Ponzi M (2006) Set regulation in asexual and sexual Plasmodium parasites reveals a novel mechanism of stage-specific expression. Mol Microbiol 60(4):870-882
- Eshar S, Allemand E, Sebag A, Glaser F, Muchardt C, Mandel-Gutfreund Y, Karni R, Dzikowski R (2012) A novel Plasmodium falciparum SR protein is an alternative splicing factor required for the parasites' proliferation in human erythrocytes. Nucleic Acids Res
- Singh PK, Kanodia S, Dandin CJ, Vijayraghavan U, Malhotra P (2012) Plasmodium falciparum Prp16 homologue and its role in splicing. Biochim Biophys Acta. 2012 Sep 7. pii: S1874-9399(12)00157-5. doi: 10.1016/j.bbagrm.2012.08.014
- Ghorbal M, Scheidig-Benatar C, Bouizem S, Thomas C, Paisley G, Faltermeier C, Liu M, Scherf A, Lopez-Rubio JJ, Gopaul DN (2012) Initial characterization of the Pf-int recombinase from the malaria parasite Plasmodium falciparum. PLoS One 7(10):e46507. doi: 10.1371/journal.pone.0046507
- Painter HJ, Campbell TL, Llinas M (2011) The Apicomplexan AP2 family: integral factors regulating Plasmodium development. Mol Biochem Parasitol 176: 1–7
- Iwanaga S, Kaneko I, Kato T, Yuda M (2012) Identification of an AP2-family protein that is critical for malaria liver stage development. PLoS One 7(11):e47557. doi: 10.1371/journal.pone.0047557
- Tarique M, Satsangi AT, Ahmad M, Singh S, Tuteja R (2011). "Plasmodium falciparum MLH is schizont stage specific endonuclease.". Mol Biochem Parasitol.
- Patzewitz EM, Wong EH, Müller S (2011) Dissecting the role of glutathione biosynthesis in Plasmodium falciparum. Mol Microbiol doi:10.1111/j.1365-2958.2011.07933.x
- Jortzik E, Becker K (2012) Thioredoxin and glutathione systems in Plasmodium falciparum. Int J Med Microbiol
- Atamna H, Ginsburg H (1997) The malaria parasite supplies glutathione to its host cell - investigation of glutathione transport and metabolism in human erythrocytes infected with Plasmodium falciparum. Eur J Biochem 250(3):670-679
- Barrand MA, Winterberg M, Ng F, Nguyen M, Kirk K, Hladky SB (2012) Glutathione export from human erythrocytes and Plasmodium falciparum malaria parasites. Biochem J
- Ginsburg H, Golenser J (2003) Glutathione is involved in the antimalarial action of chloroquine and its modulation affects drug sensitivity of human and murine species of Plasmodium. Redox Rep 8(5):276-279
- Putonti C, Quach B, Kooistra RA, Kanzok SM (2012) The evolution and putative function of phosducin-like proteins in the malaria parasite Plasmodium. Infect Genet Evol pii: S1567-1348(12)00294-8. doi: 10.1016/j.meegid.2012.08.023
- Hakimi H, Asada M, Angeles JM, Kawai S, Inoue N, Kawazu SI (2012) Plasmodium vivax and P. knowlesi: cloning, expression and functional analysis of 1-Cys peroxiredoxin. Exp Parasitol pii: S0014-4894(12)00329-3. doi: 10.1016/j.exppara.2012.10.018
- Kimura R, Komaki-Yasuda K, Kawazu SI, Kano S (2012) 2-Cys peroxiredoxin of Plasmodium falciparum is involved in resistance to heat stress of the parasite. Parasitol Int pii: S1383-5769(12)00157-2. doi: 10.1016/j.parint.2012.11.005
- Usui M, Masuda-Suganuma H, Fukumoto S, Angeles JM, Inoue N, Kawazu SI (2012) Expression profiles of peroxiredoxins in liver stage of the rodent malaria parasite Plasmodium berghei. Parasitol Int pii: S1383-5769(12)00159-6. doi: 10.1016/j.parint.2012.11.007
- Williams M, Sprenger J, Human E, Al-Karadaghi S, Persson L, Louw AI, Birkholtz LM (2011). "Biochemical characterisation and novel classification of monofunctional S-adenosylmethionine decarboxylase of Plasmodium falciparum.". Mol Biochem Parasitol.
- Spalding MD, Allary M, Gallagher JR, Prigge ST (2010). "Validation of a modified method for Bxb1 mycobacteriophage integrase-mediated recombination in Plasmodium falciparum by localization of the H-protein of the glycine cleavage complex to the mitochondrion. Mol. Biochem.". Parasitol..
- Pornthanakasem W, Kongkasuriyachai D, Uthaipibull C, Yuthavong Y, Leartsakulpanich U (2012) Plasmodium serine hydroxymethyltransferase: indispensability and display of distinct localization. Malar J 11(1):387
- Jortzik E, Mailu BM, Preuss J, Fischer M, Bode L, Rahlfs S, Becker K (2011). "Glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase: a unique bifunctional enzyme from Plasmodium falciparum.". Biochem J..
- Stover, NA; Dixon, TA; Cavalcanti, AR (2011). "Multiple independent fusions of glucose-6-phosphate dehydrogenase with enzymes in the pentose phosphate pathway". PLoS ONE 6 (8): e22269.
- Raabe A, Berry L, Sollelis L, Cerdan R, Tawk L, Vial HJ, Billker O, Wengelnik K (2011) Genetic and transcriptional analysis of phosphoinositide-specific phospholipase C in Plasmodium Exp Parasitol
- Samanta M, Murthy MR, Balaram H, Balaram P (2011) Revisiting the mechanism of the triose-phosphate isomerase reaction: The role of the fully conserved glutamic acid 97 Residue. Chembiochem doi:10.1002/cbic.201100116
- Boysen KE, Matuschewski K (2011). "Arrested oocyst maturation in Plasmodium parasites lacking type II NADH:ubiquinone dehydrogenase.". J Biol Chem.
- Tapas S, Kumar A, Dhindwal S, Preeti, Kumar P (2011). "Structural analysis of chorismate synthase from Plasmodium falciparum: A novel target for antimalaria drug discovery.". Int J Biol Macromol.
- Choi JY, Augagneur Y, Ben Mamoun C, Voelker DR (2011). "Identification of a gene encoding Plasmodium knowlesi phosphatidylserine decarboxylase by genetic complementation in yeast, and characterization of in vitro maturation of the encoded enzyme.". J Biol Chem.
- Sussmann RA, Angeli CB, Peres VJ, Kimura EA, Katzin AM (2011). "Intraerythrocytic stages of Plasmodium falciparum biosynthesize vitamin E.". FEBS Lett.
- Lee SG, Kim Y, Alpert TD, Nagata A, Jez JM (2011). "Structure and reaction mechanism of phosphoethanolamine methyltransferase from the malaria parasite Plasmodium falciparum: An anti-parasitic drug target.". J Biol Chem.
- Freville A, Landrieu I, Garcia-Gimeno MA, Vicogne J, Montbarbon M, Bertin B, Verger A, Kalamou H, Sanz P, Werkmeister E, Pierrot C, Khalife J (2011). "Plasmodium falciparum inhibitor 3 homolog increases protein phosphatase type 1 activity and is essential for parasitic survival.". J Biol Chem.
- Guédez G, Hipp K, Windeisen V, Derrer B, Gengenbacher M, Böttcher B, Sinning I, Kappes B, Tews I et al. (2012). "Assembly of the eukaryotic PLP-synthase complex from Plasmodium and activation of the Pdx1 enzyme". Structure 20 (1): 172–184.
- Knöckel J, Müller IB, Butzloff S, Bergmann B, Walter RD, Wrenger C (2012). "The antioxidative effect of de novo generated vitamin B6 in Plasmodium falciparum validated by protein interference.". Biochem J.
- Takashima Y, Mizohata E, Tokuoka K, Krungkrai SR, Kusakari Y, Konishi S, Satoh A, Matsumura H, Krungkrai J, Horii T, Inoue T (2012) Crystallization and preliminary X-ray diffraction analysis of orotate phosphoribosyltransferase from the human malaria parasite Plasmodium falciparum. Acta Crystallogr Sect F Struct Biol Cryst Commun 68(2):244-246
- Umeda T, Tanaka N, Kusakabe Y, Nakanishi M, Kitade Y, Nakamura KT (2011) Molecular basis of fosmidomycin's action on the human malaria parasite Plasmodium falciparum. Sci Rep ;1:9.
- Zocher K, Fritz-Wolf K, Kehr S, Fischer M, Rahlfs S, Becker K (2012) Biochemical and structural characterization of Plasmodium falciparum glutamate dehydrogenase 2. Mol Biochem Parasitol
- Liu YL, Guerra F, Wang K, Wang W, Li J, Huang C, Zhu W, Houlihan K, Li Z, Zhang Y, Nair SK, Oldfield E (2012) Structure, function and inhibition of the two- and three-domain 4Fe-4S IspG proteins. Proc Natl Acad Sci USA
- Law AW, Lescar J, Hao Q, Kotaka M (2012) Expression, purification, crystallization and preliminary X-ray analysis of Plasmodium falciparum GTP:AMP phosphotransferase. Acta Crystallogr Sect F Struct Biol Cryst Commun 68(6):671-674
- Schwentke A, Krepstakies M, Müller AK, Hammerschmidt C, Motaal B, Bernhard T, Hauber J, Kaiser A (2012) In vitro and in vivo silencing of plasmodial dhs and eIF-5A genes in a putative, non-canonical RNAi-related pathway. BMC Microbiol 12(1):107
- Salazar E, Bank EM, Ramsey N, Hess KC, Deitsch KW, Levin LR, Buck J (2012) Characterization of Plasmodium falciparum adenylyl cyclase-β and its role in erythrocytic stage parasites. PLoS One 7(6):e39769.
- Osman W, Endo S, Oh-Hashi K, Kitamura Y, Kitade Y (2012) Molecular characterization and mutational analysis of recombinant diadenosine 5',5″-P1,P4-tetraphosphate hydrolase from Plasmodium falciparum. Biol Pharm Bull 35(7):1191-1196
- Jones ML, Collins MO, Goulding D, Choudhary JS, Rayner JC (2012) Analysis of protein palmitoylation reveals a pervasive role in Plasmodium development and pathogenesis. Cell Host Microbe 12(2):246-258
- Denloye T, Dalal S, Klemba M (2012) Characterization of a glycerophosphodiesterase with an unusual tripartite distribution and an important role in the asexual blood stages of Plasmodium falciparum. Mol Biochem Parasitol pii: S0166-6851(12)00222-8. doi: 10.1016/j.molbiopara.2012.09.004
- Eichhorn T, Winter D, Büchele B, Dirdjaja N, Frank M, Lehmann WD, Mertens R, Krauth-Siegel RL, Simmet T, Granzin J, Efferth T (2012) Molecular interaction of artemisinin with translationally controlled tumor protein (TCTP) of Plasmodium falciparum. Biochem Pharmacol pii: S0006-2952(12)00678-8. doi: 10.1016/j.bcp.2012.10.006
- Rackham MD, Brannigan JA, Moss DK, Yu Z, Wilkinson AJ, Holder AA, Tate EW, Leatherbarrow RJ (2012) Discovery of novel and ligand-efficient inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferase. J Med Chem
- Wasserman M, Vernot JP, Mendoza PM (1990) Role of calcium and erythrocyte cytoskeleton phosphorylation in the invasion of Plasmodium falciparum. Parasitol Res 76(8):681-688
- Tanabe K (1990) Ion metabolism in malaria-infected erythrocytes. Blood Cells 16(2-3):437-449
- Enomoto M, Kawazu S, Kawai S, Furuyama W, Ikegami T, Watanabe J, Mikoshiba K (2012) Blockage of spontaneous Ca(2+) oscillation causes cell death in intraerythrocitic Plasmodium falciparum. PLoS One 7(7):e39499.
- Stritzke C, Nalaskowski MM, Fanick W, Lin H, Mayr GW (2012) A Plasmodium multi-domain protein possesses multiple inositol phosphate kinase activities. Mol Biochem Parasitol pii: S0166-6851(12)00249-6. doi: 10.1016/j.molbiopara.2012.10.005
No one has provided updates yet.