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Nima- and Aurora-related kinases of malaria parasites.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Biochimica et Biophysica Acta, Vol. 1834, No. 7. (2013), pp. 1336-1345, doi:10.1016/j.bbapap.2013.02.022

Completion of the life cycle of malaria parasite requires a succession of developmental stages which vary greatly with respect to proliferation status, implying a tightly regulated control of the parasite's cell cycle, which remains to be understood at the molecular level. Progression of the eukaryotic cell cycle is controlled by members of mitotic kinase of the families CDK (cyclin-dependent kinases), Aurora, Polo and NIMA. Plasmodium parasites possess cyclin-dependent protein kinases and cyclins, which strongly suggests that some of the principles underlying cell cycle control in higher eukaryotes also operate in this organism. However, atypical features of Plasmodium cell cycle organization and important divergences in the composition of the cell cycle machinery suggest the existence of regulatory mechanisms that are at variance with those of higher eukaryotes. This review focuses on several recently described Plasmodium protein kinases related to the NIMA and Aurora kinase families and discusses their functional involvement in parasite's biology. Given their demonstrated essential roles in the erythrocytic asexual cycle and/or sexual stages, these enzymes represent novel potential drug targets for antimalarial intervention aiming at inhibiting parasite replication and/or blocking transmission of the disease. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
Teresa Carvalho, Christian Doerig, Luc Reininger
Categories: malaria news feeds

A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Cell Host Microbe, Vol. 17, No. 3. (2015), pp. 404-413, doi:10.1016/j.chom.2015.01.014

The genome-wide identification of gene functions in malaria parasites is hampered by a lack of reverse genetic screening methods. We present a large-scale resource of barcoded vectors with long homology arms for effective modification of the Plasmodium berghei genome. Cotransfecting dozens of vectors into the haploid blood stages creates complex pools of barcoded mutants, whose competitive fitness can be measured during infection of a single mouse using barcode sequencing (barseq). To validate the utility of this resource, we rescreen the P. berghei kinome, using published kinome screens for comparison. We find that several protein kinases function redundantly in asexual blood stages and confirm the targetability of kinases cdpk1, gsk3, tkl3, and PBANKA_082960 by genotyping cloned mutants. Thus, parallel phenotyping of barcoded mutants unlocks the power of reverse genetic screening for a malaria parasite and will enable the systematic identification of genes essential for in vivo parasite growth and transmission.
Ana Gomes, Ellen Bushell, Frank Schwach, Gareth Girling, Burcu Anar, Michael Quail, Colin Herd, Claudia Pfander, Katarzyna Modrzynska, Julian Rayner, Oliver Billker
Categories: malaria news feeds

Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Nat. Chem. Biol., Vol. 4, No. 6. (2008), pp. 347-356, doi:10.1038/nchembio.87

Calcium-dependent protein kinases play a crucial role in intracellular calcium signaling in plants, some algae and protozoa. In Plasmodium falciparum, calcium-dependent protein kinase 1 (PfCDPK1) is expressed during schizogony in the erythrocytic stage as well as in the sporozoite stage. It is coexpressed with genes that encode the parasite motor complex, a cellular component required for parasite invasion of host cells, parasite motility and potentially cytokinesis. A targeted gene-disruption approach demonstrated that pfcdpk1 seems to be essential for parasite viability. An in vitro biochemical screen using recombinant PfCDPK1 against a library of 20,000 compounds resulted in the identification of a series of structurally related 2,6,9-trisubstituted purines. Compound treatment caused sudden developmental arrest at the late schizont stage in P. falciparum and a large reduction in intracellular parasites in Toxoplasma gondii, which suggests a possible role for PfCDPK1 in regulation of parasite motility during egress and invasion.
Nobutaka Kato, Tomoyo Sakata, Ghislain Breton, Karine Roch, Advait Nagle, Carsten Andersen, Badry Bursulaya, Kerstin Henson, Jeffrey Johnson, Kota Kumar, Felix Marr, Daniel Mason, Case McNamara, David Plouffe, Vandana Ramachandran, Muriel Spooner, Tove Tuntland, Yingyao Zhou, Eric Peters, Arnab Chatterjee, Peter Schultz, Gary Ward, Nathanael Gray, Jeffrey Harper, Elizabeth Winzeler
Categories: malaria news feeds

Role of Plasmodium berghei cGMP-dependent protein kinase in late liver stage development.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Journal of Biological Chemistry, Vol. 285, No. 5. (2010), pp. 3282-3288, doi:10.1074/jbc.M109.070367

The liver is the first organ infected by Plasmodium sporozoites during malaria infection. In the infected hepatocytes, sporozoites undergo a complex developmental program to eventually generate hepatic merozoites that are released into the bloodstream in membrane-bound vesicles termed merosomes. Parasites blocked at an early developmental stage inside hepatocytes elicit a protective host immune response, making them attractive targets in the effort to develop a pre-erythrocytic stage vaccine. Here, we generated parasites blocked at a late developmental stage inside hepatocytes by conditionally disrupting the Plasmodium berghei cGMP-dependent protein kinase in sporozoites. Mutant sporozoites are able to invade hepatocytes and undergo intracellular development. However, they remain blocked as late liver stages that do not release merosomes into the medium. These late arrested liver stages induce protection in immunized animals. This suggests that, similar to the well studied early liver stages, late stage liver stages too can confer protection from sporozoite challenge.
Adebola Falae, Audrey Combe, Anburaj Amaladoss, Teresa Carvalho, Robert Menard, Purnima Bhanot
Categories: malaria news feeds

The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Eukaryotic Cell, Vol. 9, No. 1. (2010), pp. 37-45, doi:10.1128/EC.00186-09

A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for > or =6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria.
Helen Taylor, Louisa McRobert, Munira Grainger, Audrey Sicard, Anton Dluzewski, Christine Hopp, Anthony Holder, David Baker
Categories: malaria news feeds

The coming-out of malaria gametocytes.

CiteULike malaria tags - 16 February 2017 - 2:22pm
J. Biomed. Biotechnol., Vol. 2010 (2010), doi:10.1155/2010/976827

The tropical disease malaria, which results in more than one million deaths annually, is caused by protozoan parasites of the genus Plasmodium and transmitted by blood-feeding Anopheline mosquitoes. Parasite transition from the human host to the mosquito vector is mediated by gametocytes, sexual stages that are formed in human erythrocytes, which therefore play a crucial part in the spread of the tropical disease. The uptake by the blood-feeding mosquito triggers important molecular and cellular changes in the gametocytes, thus mediating the rapid adjustment of the parasite from the warm-blooded host to the insect host and subsequently initiating reproduction. The contact with midgut factors triggers gametocyte activation and results in their egress from the enveloping erythrocyte, which then leads to gamete formation and fertilization. This review summarizes recent findings on the role of gametocytes during transmission to the mosquito and particularly focuses on the molecular mechanisms underlying gametocyte activation and emergence from the host erythrocyte during gametogenesis.
A Kuehn, G Pradel
Categories: malaria news feeds

Changes in the transcriptome of the malaria parasite Plasmodium falciparum during the initial phase of transmission from the human to the mosquito.

CiteULike malaria tags - 16 February 2017 - 2:22pm
BMC Genomics, Vol. 14 (2013), doi:10.1186/1471-2164-14-256

The obtained transcriptome data demonstrate the regulations of gene expression immediately following malaria parasite transmission to the mosquito. Our findings support the identification of proteins important for sexual reproduction and further development of the mosquito midgut stages and provide insights into the genetic basis of the rapid adaption of Plasmodium to the insect vector.
CJ Ngwa, M Scheuermayer, GR Mair, S Kern, T Brügl, CC Wirth, MN Aminake, J Wiesner, R Fischer, A Vilcinskas, G Pradel
Categories: malaria news feeds

Co-expression network with protein-protein interaction and transcription regulation in malaria parasite Plasmodium falciparum.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Gene, Vol. 518, No. 1. (2013), pp. 7-16, doi:10.1016/j.gene.2012.11.092

This study based on gene co-expression network could shed new insights on the mechanisms of pathogenesis, even virulence and P. falciparum development.
FD Yu, SY Yang, YY Li, W Hu
Categories: malaria news feeds

Quantitative time-course profiling of parasite and host cell proteins in the human malaria parasite Plasmodium falciparum.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Mol. Cell Proteomics, Vol. 10, No. 8. (2011), pp. M110-006411, doi:10.1074/mcp.M110.006411

Studies of the Plasmodium falciparum transcriptome have shown that the tightly controlled progression of the parasite through the intra-erythrocytic developmental cycle (IDC) is accompanied by a continuous gene expression cascade in which most expressed genes exhibit a single transcriptional peak. Because the biochemical and cellular functions of most genes are mediated by the encoded proteins, understanding the relationship between mRNA and protein levels is crucial for inferring biological activity from transcriptional gene expression data. Although studies on other organisms show that <50% of protein abundance variation may be attributable to corresponding mRNA levels, the situation in Plasmodium is further complicated by the dynamic nature of the cyclic gene expression cascade. In this study, we simultaneously determined mRNA and protein abundance profiles for P. falciparum parasites during the IDC at 2-hour resolution based on oligonucleotide microarrays and two-dimensional differential gel electrophoresis protein gels. We find that most proteins are represented by more than one isoform, presumably because of post-translational modifications. Like transcripts, most proteins exhibit cyclic abundance profiles with one peak during the IDC, whereas the presence of functionally related proteins is highly correlated. In contrast, the abundance of most parasite proteins peaks significantly later (median 11 h) than the corresponding transcripts and often decreases slowly in the second half of the IDC. Computational modeling indicates that the considerable and varied incongruence between transcript and protein abundance may largely be caused by the dynamics of translation and protein degradation. Furthermore, we present cyclic abundance profiles also for parasite-associated human proteins and confirm the presence of five human proteins with a potential role in antioxidant defense within the parasites. Together, our data provide fundamental insights into transcript-protein relationships in P. falciparum that are important for the correct interpretation of transcriptional data and that may facilitate the improvement and development of malaria diagnostics and drug therapy.
BJ Foth, N Zhang, BK Chaal, SK Sze, PR Preiser, Z Bozdech
Categories: malaria news feeds

A draft of protein interactions in the malaria parasite P. Falciparum.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Journal of Proteome Research, Vol. 6, No. 4. (2007), pp. 1461-1470, doi:10.1021/pr0605769

Recent advances have provided a working interactome map for the human malaria parasite Plasmodium falciparum. The aforementioned map, generated from genome-scale analyses, has provided a basis for proteomic studies of the parasite; however, such large-scale approaches commonly suffer from undersampling and lack of coverage. The current map bears no exception, containing only one-quarter of the organism's proteins. Inspired by the needs of the current map and the wealth of bioinformatics data, we assembled a map of 19 979 interactions among 2321 proteins in P. falciparum. The resultant map was generated by computationally inferring protein-protein interactions from evolutionarily conserved protein interactions, underlying domain interactions, and experimental observations. To compile this information into a repository of meaningful data, we assessed interaction quality by applying a logistic regression method, which correlated the presence of an interaction with relevant cellular parameters. Interestingly, it was found that sub-networks from different sources are quite dissimilar in their topologies and overlap to a very small extent. Applying Markov clustering, we observe a typical cluster composition, featuring common cellular functions that were previously reported absent, making this map a valuable resource for understanding the biology of this organism.
S Wuchty, JJ Ipsaro
Categories: malaria news feeds

Rich-club phenomenon in the interactome of P. Falciparum膒artifact or signature of a parasitic life style?

CiteULike malaria tags - 16 February 2017 - 2:22pm
PLoS ONE, Vol. 2, No. 3. (2007), doi:10.1371/journal.pone.0000335

Recent advances have provided a first experimental protein interaction map of the human malaria parasite P. falciparum, which appears to be remotely related to interactomes of other eukaryotes. Here, we present a comparative topological analysis of this experimentally determined web with a network of conserved interactions between proteins in S. cerevisiae, C. elegans and D. melanogaster that have an ortholog in Plasmodium. Focusing on experimental interactions, we find a significant presence of a "rich-club," a topological characteristic that features an "oligarchy" of highly connected proteins being intertwined with one another. In complete contrast, the network of interologs and particularly the web of evolutionary-conserved interactions in P. falciparum lack this feature. This observation prompts the question of whether this result points to a topological signature of the parasite's biology, since experimentally obtained interactions widely cover parasite-specific functions. Significantly, hub proteins that appear in such an oligarchy revolve around invasion functions, shaping an island of parasite-specific activities in a sea of evolutionary inherited interactions. This presence of a biologically unprecedented network feature in the human malaria parasite might be an artifact of the quality and the methods to obtain interaction data in this organism. Yet, the observation that rich-club proteins have distinctive and statistically significant functions that revolve around parasite-specific activities point to a topological signature of a parasitic life style.
S Wuchty
Categories: malaria news feeds

Interactome mapping in malaria parasites: Challenges and opportunities.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Methods Mol. Biol., Vol. 812 (2012), pp. 121-145, doi:10.1007/978-1-61779-455-1_7

Nearly two-thirds of the proteins encoded by Plasmodium falciparum, the parasite that causes the most deadly form of malaria, are annotated as "hypothetical." The yeast two-hybrid assay, which requires no prior knowledge about the target protein, has great potential to provide functional information about these uncharacterized proteins. However, P. falciparum yeast two-hybrid screens are hampered by the poor expression of P. falciparum genes in yeast. AU-rich sequences in nascent P. falciparum transcripts resemble the 3' end processing sites in yeast mRNAs, and are prematurely cleaved and polyadenylated. In most cases, these aberrant messages are degraded and yield no protein. To overcome this limitation, we have developed methods to extensively fragment P. falciparum genes. Novel yeast two-hybrid vectors, in which auxotrophic markers are fused to the 3' ends of the cloned inserts, are employed to identify those gene fragments that are expressed in yeast. In this chapter, we provide detailed protocols for fragmenting P. falciparum genes, creating P. falciparum activation domain libraries, and performing P. falciparum yeast two-hybrid screens. Though focused on P. falciparum, the approaches described here are applicable to other organisms and are likely to be especially useful for those with AT-rich genomes, which are also likely to be poorly expressed in yeast.
DJ LaCount
Categories: malaria news feeds

A comprehensive Plasmodium falciparum protein interaction map reveals a distinct architecture of a core interactome.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Proteomics, Vol. 9, No. 7. (2009), pp. 1841-1849, doi:10.1002/pmic.200800383

We derive a map of protein interactions in the parasite Plasmodium falciparum from conserved interactions in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and Escherichia coli and pool them with experimental interaction data. The application of a clique-percolation algorithm allows us to find overlapping clusters, strongly correlated with yeast specific conserved protein complexes. Such clusters contain core activities that govern gene expression, largely dominated by components of protein production and degradation processes as well as RNA metabolism. A critical role of protein hubs in the interactome of P. falciparum is supported by their appearance in multiple clusters and the tendencies of their interactions to reach into many distinct protein clusters. Parasite proteins with a human ortholog tend to appear in single complexes. Annotating each protein with the stage where it is maximally expressed we observe a high level of cluster integrity in the ring stage. While we find no signal in the trophozoite phase, expression patterns are reversed in the schizont phase, implying a preponderance of parasite specific functions in this late, invasive schizont stage. As such, the inference of potential protein interactions and their analysis contributes to our understanding of the parasite, indicating basic pathways and processes as unique targets for therapeutic intervention.
S Wuchty, JH Adams, MT Ferdig
Categories: malaria news feeds

Proteomic and genetic analyses demonstrate that Plasmodium berghei blood stages export a large and diverse repertoire of proteins.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Mol. Cell Proteomics, Vol. 12, No. 2. (2013), pp. 426-448, doi:10.1074/mcp.M112.021238

Malaria parasites actively remodel the infected red blood cell (irbc) by exporting proteins into the host cell cytoplasm. The human parasite Plasmodium falciparum exports particularly large numbers of proteins, including proteins that establish a vesicular network allowing the trafficking of proteins onto the surface of irbcs that are responsible for tissue sequestration. Like P. falciparum, the rodent parasite P. berghei ANKA sequesters via irbc interactions with the host receptor CD36. We have applied proteomic, genomic, and reverse-genetic approaches to identify P. berghei proteins potentially involved in the transport of proteins to the irbc surface. A comparative proteomics analysis of P. berghei non-sequestering and sequestering parasites was used to determine changes in the irbc membrane associated with sequestration. Subsequent tagging experiments identified 13 proteins (Plasmodium export element (PEXEL)-positive as well as PEXEL-negative) that are exported into the irbc cytoplasm and have distinct localization patterns: a dispersed and/or patchy distribution, a punctate vesicle-like pattern in the cytoplasm, or a distinct location at the irbc membrane. Members of the PEXEL-negative BIR and PEXEL-positive Pb-fam-3 show a dispersed localization in the irbc cytoplasm, but not at the irbc surface. Two of the identified exported proteins are transported to the irbc membrane and were named erythrocyte membrane associated proteins. EMAP1 is a member of the PEXEL-negative Pb-fam-1 family, and EMAP2 is a PEXEL-positive protein encoded by a single copy gene; neither protein plays a direct role in sequestration. Our observations clearly indicate that P. berghei traffics a diverse range of proteins to different cellular locations via mechanisms that are analogous to those employed by P. falciparum. This information can be exploited to generate transgenic humanized rodent P. berghei parasites expressing chimeric P. berghei/P. falciparum proteins on the surface of rodent irbc, thereby opening new avenues for in vivo screening adjunct therapies that block sequestration.
EM Pasini, JA Braks, J Fonager, O Klop, E Aime, R Spaccapelo, TD Otto, M Berriman, JA Hiss, AW Thomas, M Mann, CJ Janse, CHM Kocken, B Franke-Fayard
Categories: malaria news feeds

Cell biology and immunology of malaria.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Immunol. Rev., Vol. 240, No. 1. (2011), pp. 297-316, doi:10.1111/j.1600-065X.2010.00988.x

Malaria is a vector-borne infectious disease caused by unicellular parasites of the genus Plasmodium. These obligate intracellular parasites have the unique capacity to infect and replicate within erythrocytes, which are terminally differentiated host cells that lack antigen presentation pathways. Prior to the cyclic erythrocytic infections that cause the characteristic clinical symptoms of malaria, the parasite undergoes an essential and clinically silent expansion phase in the liver. By infecting privileged host cells, employing programs of complex life stage conversions and expressing varying immunodominant antigens, Plasmodium parasites have evolved mechanisms to downmodulate protective immune responses against ongoing and even future infections. Consequently, anti-malaria immunity develops only gradually over many years of repeated and multiple infections in endemic areas. The identification of immune correlates of protection among the abundant non-protective host responses remains a research priority. Understanding the molecular and immunological mechanisms of the crosstalk between the parasite and the host is a prerequisite for the rational discovery and development of a safe, affordable, and protective anti-malaria vaccine.
JC Hafalla, O Silvie, K Matuschewski
Categories: malaria news feeds

Phylogenomic analyses of malaria parasites and evolution of their exported proteins.

CiteULike malaria tags - 16 February 2017 - 2:22pm
BMC Evol. Biol., Vol. 11 (2011), doi:10.1186/1471-2148-11-167

Our phylogenomic analyses strongly support the hypotheses that the Laverania have been founded by a single Plasmodium species switching from birds to African great apes or vice versa. The deviations from the canonical PEXEL motif in orthologs may explain the comparably low number of exported proteins that have been predicted in non-Laverania.
C Pick, I Ebersberger, T Spielmann, I Bruchhaus, T Burmester
Categories: malaria news feeds

Uncovering common principles in protein export of malaria parasites.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Cell Host Microbe, Vol. 12, No. 5. (2012), pp. 717-729, doi:10.1016/j.chom.2012.09.010

For proliferation, the malaria parasite Plasmodium falciparum needs to modify the infected host cell extensively. To achieve this, the parasite exports proteins containing a Plasmodium export element (PEXEL) into the host cell. Phosphatidylinositol-3-phosphate binding and cleavage of the PEXEL are thought to mediate protein export. We show that these requirements can be bypassed, exposing a second level of export control in the N terminus generated after PEXEL cleavage that is sufficient to distinguish exported from nonexported proteins. Furthermore, this region also corresponds to the export domain of a second group of exported proteins lacking PEXELs (PNEPs), indicating shared export properties among different exported parasite proteins. Concordantly, export of both PNEPs and PEXEL proteins depends on unfolding, revealing translocation as a common step in export. However, translocation of transmembrane proteins occurs at the parasite plasma membrane, one step before translocation of soluble proteins, indicating unexpectedly complex translocation events at the parasite periphery.
C Grüring, A Heiber, F Kruse, S Flemming, G Franci, SF Colombo, E Fasana, H Schoeler, N Borgese, HG Stunnenberg, JM Przyborski, TW Gilberger, T Spielmann
Categories: malaria news feeds

Thioredoxin and glutathione systems in Plasmodium falciparum.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Int. J. Med. Microbiol., Vol. 302, No. 4膒5. (2012), pp. 187-194, doi:10.1016/j.ijmm.2012.07.007

Despite a 50% decrease in malaria infections between 2000 and 2010, malaria is still one of the three leading infectious diseases with an estimated 216 million cases worldwide in 2010. More than 90% of all malaria infections were caused by Plasmodium falciparum, a unicellular eukaryotic parasite that faces oxidative stress challenges while developing in Anopheles mosquitoes and humans. Reactive oxygen and nitrogen species threatening the parasite are either endogenously produced by heme derived from hemoglobin degradation or they are from exogenous sources such as the host immune defense. In order to maintain the intracellular redox balance, P. falciparum employs a complex thioredoxin and glutathione system based on the thioredoxin reductase/thioredoxin and glutathione reductase/glutathione couples. P. falciparum thioredoxin reductase reduces thioredoxin and a range of low molecular weight compounds, while glutathione reductase is highly specific for its substrate glutathione disulfide. Since Plasmodium spp. lack catalase and a classical glutathione peroxidase, their redox balance depends on a complex set of five peroxiredoxins differentially located in the cytosol, apicoplast, mitochondria, and nucleus with partially overlapping substrate preferences. Moreover, P. falciparum employs a set of members belonging to the thioredoxin superfamily such as three thioredoxins, two thioredoxin-like proteins, a dithiol and three monocysteine glutaredoxins, and a redox-active plasmoredoxin with largely redundant functions. This review aims at summarizing our current knowledge on the functional redox networks of the malaria parasite P. falciparum.
E Jortzik, K Becker
Categories: malaria news feeds

Wherever I may roam: Protein and membrane trafficking in P. Falciparum-infected red blood cells.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Mol. Biochem. Parasitol., Vol. 186, No. 2. (2012), pp. 95-116, doi:10.1016/j.molbiopara.2012.09.007

Quite aside from its immense importance as a human pathogen, studies in recent years have brought to light the fact that the malaria parasite Plasmodium falciparum is an interesting eukaryotic model system to study protein trafficking. Studying parasite cell biology often reveals an overrepresentation of atypical cell biological features, possibly driven by the parasites' need to survive in an unusual biological niche. Malaria parasites possess uncommon cellular compartments to which protein traffic must be directed, including secretory organelles such as rhoptries and micronemes, a lysosome-like compartment referred to as the digestive vacuole and a complex (four membrane-bound) plastid, the apicoplast. In addition, the parasite must provide proteins to extracellular compartments and structures including the parasitophorous vacuole, the parasitophorous vacuolar membrane, the Maurer's clefts and both cytosol and plasma membrane of the host cell, the mature human red blood cell. Although some of these unusual destinations are possessed by other cell types, only Plasmodium parasites contain them all within one cell. Here we review what is known about protein and membrane transport in the P. falciparum-infected cell, highlighting novel features of these processes. A growing body of evidence suggests that this parasite is a real "box of tricks" with regards to protein traffic. Possibly, these tricks may be turned against the parasite by exploiting them as novel therapeutic targets.
M Deponte, HC Hoppe, MCS Lee, AG Maier, D Richard, M Rug, T Spielmann, JM Przyborski
Categories: malaria news feeds

A protein interaction network of the malaria parasite Plasmodium falciparum.

CiteULike malaria tags - 16 February 2017 - 2:22pm
Nature, Vol. 438, No. 7064. (2005), pp. 103-107, doi:10.1038/nature04104

Plasmodium falciparum causes the most severe form of malaria and kills up to 2.7 million people annually. Despite the global importance of P. falciparum, the vast majority of its proteins have not been characterized experimentally. Here we identify P. falciparum protein-protein interactions using a high-throughput version of the yeast two-hybrid assay that circumvents the difficulties in expressing P. falciparum proteins in Saccharomyces cerevisiae. From more than 32,000 yeast two-hybrid screens with P. falciparum protein fragments, we identified 2,846 unique interactions, most of which include at least one previously uncharacterized protein. Informatic analyses of network connectivity, coexpression of the genes encoding interacting fragments, and enrichment of specific protein domains or Gene Ontology annotations were used to identify groups of interacting proteins, including one implicated in chromatin modification, transcription, messenger RNA stability and ubiquitination, and another implicated in the invasion of host cells. These data constitute the first extensive description of the protein interaction network for this important human pathogen.
DJ LaCount, M Vignali, R Chettier, A Phansalkar, R Bell, JR Hesselberth, LW Schoenfeld, I Ota, S Sahasrabudhe, C Kurschner, S Fields, RE Hughes
Categories: malaria news feeds

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