16 results on '"Silvia Haase"'
Search Results
2. Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets
- Author
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Dihia Moussaoui, James P Robblee, Daniel Auguin, Elena B Krementsova, Silvia Haase, Thomas CA Blake, Jake Baum, Julien Robert-Paganin, Kathleen M Trybus, and Anne Houdusse
- Subjects
malaria ,mliding motility ,erythrocytes invasion ,myosin A ,PfELC ,antimalarial drugs ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Parasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity, and ultimately pathogenesis of Plasmodium falciparum rely on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria. Here, we present the full-length structure of PfMyoA in two states of its motor cycle. We report novel interactions that are essential for motor priming and the mode of recognition of its two light chains (PfELC and MTIP) by two degenerate IQ motifs. Kinetic and motility assays using PfMyoA variants, along with molecular dynamics, demonstrate how specific priming and atypical sequence adaptations tune the motor’s mechano-chemical properties. Supported by evidence for an essential role of the PfELC in malaria pathogenesis, these structures provide a blueprint for the design of future anti-malarials targeting both the glideosome motor and its regulatory elements.
- Published
- 2020
- Full Text
- View/download PDF
3. The exported protein PbCP1 localises to cleft-like structures in the rodent malaria parasite Plasmodium berghei.
- Author
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Silvia Haase, Eric Hanssen, Kathryn Matthews, Ming Kalanon, and Tania F de Koning-Ward
- Subjects
Medicine ,Science - Abstract
Protein export into the host red blood cell is one of the key processes in the pathobiology of the malaria parasite Plasmodiumtrl falciparum, which extensively remodels the red blood cell to ensure its virulence and survival. In this study, we aimed to shed further light on the protein export mechanisms in the rodent malaria parasite P. berghei and provide further proof of the conserved nature of host cell remodeling in Plasmodium spp. Based on the presence of an export motif (R/KxLxE/Q/D) termed PEXEL (Plasmodium export element), we have generated transgenic P. berghei parasite lines expressing GFP chimera of putatively exported proteins and analysed one of the newly identified exported proteins in detail. This essential protein, termed PbCP1 (P. berghei Cleft-like Protein 1), harbours an atypical PEXEL motif (RxLxY) and is further characterised by two predicted transmembrane domains (2TMD) in the C-terminal end of the protein. We have functionally validated the unusual PEXEL motif in PbCP1 and analysed the role of the 2TMD region, which is required to recruit PbCP1 to discrete membranous structures in the red blood cell cytosol that have a convoluted, vesico-tubular morphology by electron microscopy. Importantly, this study reveals that rodent malaria species also induce modifications to their host red blood cell.
- Published
- 2013
- Full Text
- View/download PDF
4. Plasmodium falciparumprotein Pfs16 is a target for transmission-blocking antimalarial drug development
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Matthew J. Fuchter, Sarah Jordan, Gema Vizcay-Barrena, Sabrina Yahiya, Silvia Haase, Ainoa Rueda-Zubiaurre, Ursula Straschil, Oliver J. Fischer, Jake Baum, Michael J. Delves, Anna Barnard, Charlie N Saunders, Edward W. Tate, and Saqib Hassan
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Thermal shift assay ,biology ,Chemistry ,Phenotypic screening ,Cell ,Plasmodium falciparum ,biology.organism_classification ,Cell morphology ,Cell biology ,medicine.anatomical_structure ,Membrane protein ,medicine ,Gametocyte ,Gene - Abstract
Phenotypic cell-based screens are critical to the discovery of new antimalarial lead compounds. However, identification and validation of cellular targets of lead compounds is required following discovery in a phenotypic screen. We recently discovered aPlasmodiumtransmission-blocking N-((4-hydroxychroman-4-yl)methyl)-sulfonamide (N-4HCS) compound,DDD01035881, in a phenotypic screen.DDD01035881and its potent derivatives have been shown to blockPlasmodiummale gamete formation (microgametogenesis) with nanomolar activity. Here, we synthesised a photoactivatable N-4HCS derivative, probe2, to identify the N-4HCS cellular target. Using probe2in photo-affinity labelling coupled with mass spectrometry, we identified the 16 kDaPlasmodium falciparumparasitophorous vacuole membrane protein Pfs16 as the likely cellular target of the N-4HCS series. Further validating Pfs16 as the cellular target of the N-4HCS series, the Cellular Thermal Shift Assay (CETSA) confirmed DDD01035881 stabilised Pfs16 in lysate from activated mature gametocytes. Additionally, photo-affinity labelling combined with in-gel fluorescence and immunoblot analysis confirmed the N-4HCS series interacted with Pfs16. High-resolution, widefield fluorescence and electron microscopy of N-4HCS-inhibited parasites was found to result in a cell morphology entirely consistent with targeted gene disruption ofPfs16. Taken together, these data strongly implicate Pfs16 as the target ofDDD01035881and establish the N-4HCS scaffold family as a powerful starting point from which future transmission-blocking antimalarials can be developed.
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- 2021
- Full Text
- View/download PDF
5. Structure of Full Length Plasmodium Myosin A and its light chain PfELC, dual targets against malaria parasite pathogenesis
- Author
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Jake Baum, Julien Robert-Paganin, James P. Robblee, Silvia Haase, Anne Houdusse, Thomas Blake, Dihia Moussaoui, Kathleen M. Trybus, Daniel Auguin, Elena B. Krementsova, Biologie Cellulaire et Cancer, and Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Infectivity ,0303 health sciences ,biology ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,030306 microbiology ,Priming (immunology) ,Computational biology ,Immunoglobulin light chain ,biology.organism_classification ,medicine.disease ,Plasmodium ,3. Good health ,Pathogenesis ,03 medical and health sciences ,Myosin ,medicine ,Parasite hosting ,Malaria ,030304 developmental biology - Abstract
Parasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity and ultimately pathogenesis of this parasite relies on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria. Here we present the full-length structure of PfMyoA in two states of its motor cycle. We report novel interactions that are essential for motor priming and the mode of recognition of its two light chains (PfELC and MTIP) by two degenerate IQ motifs. Kinetic and motility assays using PfMyoA variants, along with molecular dynamics, demonstrate how specific priming and atypical sequence adaptations tune the motor’s mechano-chemical properties. Supported by evidence for an essential role of the PfELC in malaria pathogenesis, these structures provide a blueprint for the design of future antimalarials targeting both the glideosome motor and its regulatory elements.HighlightsThe first structures of the full length PfMyoA motor in two states of its motor cycle.A unique priming of the PfMyoA lever arm results from specific lever arm/motor domain interactions, which allows for a larger powerstroke to enhance speed.Sequence adaptations within the motor domain and degenerate IQ motifs in the lever arm dictate PfMyoA motor properties.PfELC is essential for blood cell invasion and is a weak link in the assembly of a fully functional motor, providing a second novel target for antimalarial drug design.
- Published
- 2020
6. Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets
- Author
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Julien Robert-Paganin, Kathleen M. Trybus, Silvia Haase, Thomas Blake, Daniel Auguin, Elena B. Krementsova, Jake Baum, James P. Robblee, Dihia Moussaoui, Anne Houdusse, Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Laboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC), Université d'Orléans (UO)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Life Sciences, and Imperial College London
- Subjects
0301 basic medicine ,Anti malarial ,QH301-705.5 ,[SDV]Life Sciences [q-bio] ,Science ,030106 microbiology ,Drug target ,malaria ,antimalarial drugs ,Computational biology ,Biology ,Immunoglobulin light chain ,myosin A ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Myosin ,parasitic diseases ,medicine ,erythrocytes invasion ,Biology (General) ,ComputingMilieux_MISCELLANEOUS ,mliding motility ,General Immunology and Microbiology ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,General Neuroscience ,Molecular biophysics ,Plasmodium falciparum ,General Medicine ,biology.organism_classification ,medicine.disease ,3. Good health ,030104 developmental biology ,Structural biology ,Medicine ,PfELC ,Malaria - Abstract
Parasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity, and ultimately pathogenesis ofPlasmodium falciparumrely on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria. Here, we present the full-length structure of PfMyoA in two states of its motor cycle. We report novel interactions that are essential for motor priming and the mode of recognition of its two light chains (PfELC and MTIP) by two degenerate IQ motifs. Kinetic and motility assays using PfMyoA variants, along with molecular dynamics, demonstrate how specific priming and atypical sequence adaptations tune the motor’s mechano-chemical properties. Supported by evidence for an essential role of the PfELC in malaria pathogenesis, these structures provide a blueprint for the design of future anti-malarials targeting both the glideosome motor and its regulatory elements.
- Published
- 2020
- Full Text
- View/download PDF
7. Actomyosin forces and the energetics of red blood cell invasion by the malaria parasite Plasmodium falciparum
- Author
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Thomas Blake, Jake Baum, Silvia Haase, Wellcome Trust, and Human Frontier Science Program
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Plasmodium ,Life Cycles ,Erythrocytes ,Protozoan Proteins ,Video microscopy ,Biochemistry ,0302 clinical medicine ,Contractile Proteins ,1108 Medical Microbiology ,Myosin ,Parasite hosting ,Malaria, Falciparum ,Biology (General) ,Protozoans ,0303 health sciences ,Microscopy ,biology ,Physics ,Nonmuscle Myosin Type IIA ,Malarial Parasites ,Classical Mechanics ,Eukaryota ,Light Microscopy ,Actomyosin ,Deformation ,3. Good health ,Cell biology ,Actin Cytoskeleton ,1107 Immunology ,Physical Sciences ,0605 Microbiology ,Research Article ,QH301-705.5 ,Video Microscopy ,Parasitic Life Cycles ,Immunology ,Motor Proteins ,Plasmodium falciparum ,Actin Motors ,Myosins ,Research and Analysis Methods ,Microbiology ,Parasite Replication ,03 medical and health sciences ,Molecular Motors ,Virology ,Parasite Groups ,Genetics ,medicine ,Animals ,Humans ,Parasites ,Molecular Biology ,Actin ,030304 developmental biology ,Parasitic life cycles ,Damage Mechanics ,Merozoites ,Organisms ,Biology and Life Sciences ,Proteins ,Cell Biology ,RC581-607 ,biology.organism_classification ,medicine.disease ,Parasitic Protozoans ,Malaria ,Cytoskeletal Proteins ,Parasitology ,Immunologic diseases. Allergy ,Apicomplexa ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
All symptoms of malaria disease are associated with the asexual blood stages of development, involving cycles of red blood cell (RBC) invasion and egress by the Plasmodium spp. merozoite. Merozoite invasion is rapid and is actively powered by a parasite actomyosin motor. The current accepted model for actomyosin force generation envisages arrays of parasite myosins, pushing against short actin filaments connected to the external milieu that drive the merozoite forwards into the RBC. In Plasmodium falciparum, the most virulent human malaria species, Myosin A (PfMyoA) is critical for parasite replication. However, the precise function of PfMyoA in invasion, its regulation, the role of other myosins and overall energetics of invasion remain unclear. Here, we developed a conditional mutagenesis strategy combined with live video microscopy to probe PfMyoA function and that of the auxiliary motor PfMyoB in invasion. By imaging conditional mutants with increasing defects in force production, based on disruption to a key PfMyoA phospho-regulation site, the absence of the PfMyoA essential light chain, or complete motor absence, we define three distinct stages of incomplete RBC invasion. These three defects reveal three energetic barriers to successful entry: RBC deformation (pre-entry), mid-invasion initiation, and completion of internalisation, each requiring an active parasite motor. In defining distinct energetic barriers to invasion, these data illuminate the mechanical challenges faced in this remarkable process of protozoan parasitism, highlighting distinct myosin functions and identifying potential targets for preventing malaria pathogenesis., Author summary Malaria is a widespread infectious disease carried by mosquitoes, caused by several species of single-celled parasites of which the deadliest is Plasmodium falciparum. After a bite from an infected mosquito and a silent symptomatic liver stage, symptomatic disease ensues, caused by cyclical invasion of red blood cells and replication over a 48-hour cycle. The force required for invasion is thought to depend on a parasite molecular motor known as myosin A (PfMyoA), but it is unclear which steps of invasion need force from this motor and what roles are played by PfMyoA and related motor proteins. Here, we generated a series of modified parasites with mutated motor proteins, resulting in a range of invasion defects from mild to completely blocked. We analysed these parasites during invasion by video microscopy, identifying mutants that stalled at different stages or took longer to invade. Together, our analysis reveals three distinct energetic steps during invasion when PfMyoA is required and sheds light on the contribution of other motor proteins. Since parasite myosins are only distantly related to those of humans, understanding their roles during invasion could unearth effective and specific targets for future drug development.
- Published
- 2020
8. Actomyosin forces and the energetics of red blood cell invasion by the malaria parasitePlasmodium falciparum
- Author
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Silvia Haase, Thomas Blake, and Jake Baum
- Subjects
biology ,Plasmodium falciparum ,medicine.disease ,biology.organism_classification ,Plasmodium ,Cell biology ,Red blood cell ,medicine.anatomical_structure ,Myosin ,medicine ,Parasite hosting ,Malaria ,Actin ,Function (biology) - Abstract
SummaryAll symptoms of malaria disease are associated with the asexual blood stages of development, involving cycles of red blood cell (RBC) invasion and egress by thePlasmodiumspp. merozoite. Merozoite invasion is rapid and is actively powered by a parasite actomyosin motor. The current accepted model for actomyosin force generation envisages arrays of parasite myosins, pushing against short actin filaments connected to the external milieu that drive the merozoite forwards into the RBC. InPlasmodium falciparum, the most virulent human malaria species, Myosin A (PfMyoA) is critical for parasite replication. However, the precise function of PfMyoA in invasion, its regulation, the role of other myosins and overall energetics of invasion remain unclear. Here, we developed a conditional mutagenesis strategy combined with live video microscopy to probe PfMyoA function and that of the auxiliary motor PfMyoB in invasion. By imaging conditional mutants with increasing defects in force production, based on disruption to a key PfMyoA phospho-regulation site, the absence of the PfMyoA essential light chain, or complete motor absence, we define three distinct stages of incomplete RBC invasion. These three defects reveal three energetic barriers to successful entry: RBC deformation (pre-entry), mid-invasion initiation, and completion of internalisation, each requiring an active parasite motor. In defining distinct energetic barriers to invasion, these data illuminate the mechanical challenges faced in this remarkable process of protozoan parasitism, highlighting distinct myosin functions and identifying potential targets for preventing malaria pathogenesis.
- Published
- 2020
- Full Text
- View/download PDF
9. Identification and characterisation of a phospholipid scramblase in the malaria parasite Plasmodium falciparum
- Author
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Dounia Cherkaoui, Melanie Condron, Sarah Jordan, Jake Baum, Jacqueline M. Gulbis, Silvia Haase, and David M. Miller
- Subjects
Phospholipid scramblase ,biology ,Plasmodium falciparum ,biology.organism_classification ,medicine.disease ,Plasmodium ,Cell biology ,law.invention ,law ,biology.protein ,medicine ,Recombinant DNA ,Translocase ,Parasite hosting ,Malaria ,Gene knockout - Abstract
Recent studies highlight the emerging role of lipids as important messengers in malaria parasite biology. In an attempt to identify interacting proteins and regulators of these dynamic and versatile molecules, we hypothesised the involvement of phospholipid translocases and their substrates in the infection of the host erythrocyte by the malaria parasite Plasmodium spp. Here, using a data base mining approach, we have identified a putative phospholipid (PL) scramblase in P. falciparum (PfPLSCR) that is conserved across the genus and in closely related unicellular algae. By reconstituting recombinant PfPLSCR into liposomes, we demonstrate metal ion dependent PL translocase activity and substrate preference, confirming PfPLSCR as a bona fide scramblase. We confirm that PfPLSCR is expressed during asexual and sexual parasite development, localising to different membranous compartments of the parasite throughout the intra-erythrocytic life cycle. Two different gene knockout approaches, however, suggest that PfPLSCR is not essential for erythrocyte invasion and asexual parasite development, pointing towards a possible role in other stages of the parasite life cycle.
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- 2020
- Full Text
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10. Transcriptional profiling of growth perturbations of the human malaria parasite Plasmodium falciparum
- Author
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Ana Cabrera, Sachel Mok, Guangan Hu, Maya Kono, Silvia Haase, Sabna Cheemadan, Peter R. Preiser, Tobias Spielmann, Tim-W. Gilberger, Zbynek Bozdech, Klemens Engelberg, and Balbir Kaur Chaal
- Subjects
Transcription, Genetic ,Plasmodium falciparum ,Protozoan Proteins ,Biomedical Engineering ,Bioengineering ,Biology ,Applied Microbiology and Biotechnology ,Antimalarials ,Interaction network ,Transcription (biology) ,parasitic diseases ,Gene expression ,medicine ,Animals ,Humans ,Parasite hosting ,Gene Regulatory Networks ,Malaria, Falciparum ,Gene ,Genetics ,Merozoites ,Gene Expression Profiling ,medicine.disease ,biology.organism_classification ,Virology ,Markov Chains ,Yeast ,Gene Expression Regulation ,Molecular Medicine ,Algorithms ,Malaria ,Biotechnology - Abstract
Functions have yet to be defined for the majority of genes of Plasmodium falciparum, the agent responsible for the most serious form of human malaria. Here we report changes in P. falciparum gene expression induced by 20 compounds that inhibit growth of the schizont stage of the intraerythrocytic development cycle. In contrast with previous studies, which reported only minimal changes in response to chemically induced perturbations of P. falciparum growth, we find that approximately 59% of its coding genes display over three-fold changes in expression in response to at least one of the chemicals we tested. We use this compendium for guilt-by-association prediction of protein function using an interaction network constructed from gene co-expression, sequence homology, domain-domain and yeast two-hybrid data. The subcellular localizations of 31 of 42 proteins linked with merozoite invasion is consistent with their role in this process, a key target for malaria control. Our network may facilitate identification of novel antimalarial drugs and vaccines.
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- 2010
- Full Text
- View/download PDF
11. Plasmodium falciparumpossesses two GRASP proteins that are differentially targeted to the Golgi complex via a higher- and lower-eukaryote-like mechanism
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Alan F. Cowman, Susann Herrmann, Ana Cabrera, Silvia Haase, Moritz Treeck, Bernardo J. Foth, Klemens Engelberg, Christine Langer, Matthias Marti, Andreas Krueger, Nicole S. Struck, Tobias Spielmann, and Tim W. Gilberger
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Molecular Sequence Data ,Plasmodium falciparum ,Protozoan Proteins ,Golgi Apparatus ,medicine.disease_cause ,Evolution, Molecular ,symbols.namesake ,Protein targeting ,medicine ,Animals ,Amino Acid Sequence ,Myristoylation ,biology ,Golgi Matrix Proteins ,Membrane Proteins ,Golgi Targeting ,Cell Biology ,Golgi apparatus ,biology.organism_classification ,Cell biology ,Transport protein ,Protein Transport ,Eukaryotic Cells ,Membrane protein ,symbols ,Eukaryote ,Organelle biogenesis - Abstract
Plasmodium falciparum, the causative agent of malaria, relies on a complex protein-secretion system for protein targeting into numerous subcellular destinations. Recently, a homologue of the Golgi re-assembly stacking protein (GRASP) was identified and used to characterise the Golgi organisation in this parasite. Here, we report on the presence of a splice variant that leads to the expression of a GRASP isoform. Although the first GRASP protein (GRASP1) relies on a well-conserved myristoylation motif, the variant (GRASP2) displays a different N-terminus, similar to GRASPs found in fungi. Phylogenetic analyses between GRASP proteins of numerous taxa point to an independent evolution of the unusual N-terminus that could reflect unique requirements for Golgi-dependent protein sorting and organelle biogenesis in P. falciparum. Golgi association of GRASP2 depends on the hydrophobic N-terminus that resembles a signal anchor, leading to a unique mode of Golgi targeting and membrane attachment.
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- 2008
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12. A Conserved Region in the EBL Proteins Is Implicated in Microneme Targeting of the Malaria ParasitePlasmodium falciparum
- Author
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Julie Healer, Alan F. Cowman, Moritz Treeck, Silvia Haase, Tim W. Gilberger, Nicole S. Struck, Christine Langer, and Susann Herrmann
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Cytoplasm ,Plasmodium falciparum ,Protozoan Proteins ,Golgi Apparatus ,Antigens, Protozoan ,Biology ,Transfection ,medicine.disease_cause ,Biochemistry ,Conserved sequence ,Microneme ,parasitic diseases ,Protein targeting ,medicine ,Animals ,Humans ,Apical membrane antigen 1 ,Molecular Biology ,Conserved Sequence ,Rhoptry ,Membrane Proteins ,Biological Transport ,Cell Biology ,biology.organism_classification ,Protein Structure, Tertiary ,Cell biology ,Microscopy, Fluorescence ,Membrane protein ,Ectodomain ,Carrier Proteins - Abstract
The proliferation of the malaria parasite Plasmodium falciparum within the human host is dependent upon invasion of erythrocytes. This process is accomplished by the merozoite, a highly specialized form of the parasite. Secretory organelles including micronemes and rhoptries play a pivotal role in the invasion process by storing and releasing parasite proteins. The mechanism of protein sorting to these compartments is unclear. Using a transgenic approach we show that trafficking of the most abundant micronemal proteins (members of the EBL-family: EBA-175, EBA-140/BAEBL, and EBA-181/JSEBL) is independent of their cytoplasmic and transmembrane domains, respectively. To identify the minimal sequence requirements for microneme trafficking, we generated parasites expressing EBA-GFP chimeric proteins and analyzed their distribution within the infected erythrocyte. This revealed that: (i) a conserved cysteine-rich region in the ectodomain is necessary for protein trafficking to the micronemes and (ii) correct sorting is dependent on accurate timing of expression.
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- 2006
- Full Text
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13. The Exported Protein PbCP1 Localises to Cleft-Like Structures in the Rodent Malaria Parasite Plasmodium berghei
- Author
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Eric Hanssen, Kathryn Matthews, Tania F. de Koning-Ward, Ming Kalanon, and Silvia Haase
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Erythrocytes ,Plasmodium berghei ,Protozoan Proteins ,lcsh:Medicine ,Gene Expression ,Biochemistry ,Green fluorescent protein ,Mice ,Protein structure ,Cytosol ,Molecular Cell Biology ,lcsh:Science ,Peptide sequence ,0303 health sciences ,Mice, Inbred BALB C ,Multidisciplinary ,3. Good health ,Transport protein ,Cell biology ,Transmembrane domain ,Protein Transport ,medicine.anatomical_structure ,Infectious Diseases ,Medicine ,Research Article ,Recombinant Fusion Proteins ,Green Fluorescent Proteins ,Molecular Sequence Data ,Biology ,Microbiology ,03 medical and health sciences ,parasitic diseases ,medicine ,Parasitic Diseases ,Animals ,Amino Acid Sequence ,030304 developmental biology ,Life Cycle Stages ,030306 microbiology ,lcsh:R ,Proteins ,biology.organism_classification ,Malaria ,Protein Structure, Tertiary ,Red blood cell ,Luminescent Proteins ,Organismal Proteins ,Membrane protein ,Immunology ,lcsh:Q ,Parasitology - Abstract
Protein export into the host red blood cell is one of the key processes in the pathobiology of the malaria parasite Plasmodiumtrl falciparum, which extensively remodels the red blood cell to ensure its virulence and survival. In this study, we aimed to shed further light on the protein export mechanisms in the rodent malaria parasite P. berghei and provide further proof of the conserved nature of host cell remodeling in Plasmodium spp. Based on the presence of an export motif (R/KxLxE/Q/D) termed PEXEL (Plasmodium export element), we have generated transgenic P. berghei parasite lines expressing GFP chimera of putatively exported proteins and analysed one of the newly identified exported proteins in detail. This essential protein, termed PbCP1 (P. berghei Cleft-like Protein 1), harbours an atypical PEXEL motif (RxLxY) and is further characterised by two predicted transmembrane domains (2TMD) in the C-terminal end of the protein. We have functionally validated the unusual PEXEL motif in PbCP1 and analysed the role of the 2TMD region, which is required to recruit PbCP1 to discrete membranous structures in the red blood cell cytosol that have a convoluted, vesico-tubular morphology by electron microscopy. Importantly, this study reveals that rodent malaria species also induce modifications to their host red blood cell.
- Published
- 2013
14. New insights into protein export in malaria parasites
- Author
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Tania F. de Koning-Ward and Silvia Haase
- Subjects
Signal peptide ,Plasmodium ,Erythrocytes ,Endoplasmic reticulum ,Immunology ,Protozoan Proteins ,Virulence ,Vacuole ,Biology ,Protein Sorting Signals ,medicine.disease ,Translocon ,Microbiology ,Cell biology ,Red blood cell ,Protein Transport ,medicine.anatomical_structure ,Biochemistry ,Virology ,parasitic diseases ,medicine ,Parasite hosting ,Aspartic Acid Endopeptidases ,Humans ,Malaria - Abstract
In order to survive and promote its virulence the malaria parasite must export hundreds of its proteins beyond an encasing vacuole and membrane into the host red blood cell. In the last few years, several major advances have been made that have significantly contributed to our understanding of this export process. These include: (i) the identification of sequences that direct protein export (a signal sequence and a motif termed PEXEL), which have allowed predictions of the exportomes of Plasmodium species that are the cause of malaria, (ii) the recognition that the fate of proteins destined for export is already decided within the parasite's endoplasmic reticulum and involves the PEXEL motif being recognized and cleaved by the aspartic protease plasmepsin V and (iii) the discovery of the Plasmodium translocon of exported proteins (PTEX) that is responsible for the passage of proteins across the vacuolar membrane. We review protein export in Plasmodium and these latest developments in the field that have now provided a new platform from which trafficking of malaria proteins can be dissected.
- Published
- 2010
15. Finding help: Turkish-speaking refugees and migrants with a history of psychosis
- Author
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Taner Güvenir, Gerard Leavey, Simon Dein, and Silvia Haase-Casanovas
- Subjects
Adult ,Male ,medicine.medical_specialty ,Health (social science) ,Turkey ,Refugee ,03 medical and health sciences ,0302 clinical medicine ,Intervention (counseling) ,medicine ,Humans ,030212 general & internal medicine ,Psychiatry ,Language ,Refugees ,Poverty ,Patient Acceptance of Health Care ,Mental health ,Help-seeking ,United Kingdom ,030227 psychiatry ,Psychiatry and Mental health ,Psychotic Disorders ,Domestic violence ,Private healthcare ,Female ,Cross-cultural psychiatry ,Psychology ,Attitude to Health - Abstract
There is a large population of Turkish-speaking migrants living in London, many of whom are refugees (Enneli, Modood, & Bradley, 2005). Primary care and secondary mental health services have consistently reported poor continuity of care among patients from this community. The aim of this study was to explore the possible interconnection of causal attributions and pathways into care among Turkish-speaking, mainly Kurdish, patients with a past history of psychosis. Narratives of illness were elicited from informants. Physical symptomatology was a prominent feature of presentation in this group. These patients did not discuss their health problems conceptualized as uniform ‘models' of illness, but rather in an attributional style that emphasized the experience of traumatic life events, often related to the overarching problem of exile and settlement. Childhood and family issues of poverty and domestic violence were often raised by patients, but tended to be backgrounded as having little contributory significance. These patients sought intervention, serially or in combination, from a diverse range of practitioners, including private healthcare and traditional healers or hocas. Their explanatory models of illness were complex and fragmentary and the relationship between explanations and help seeking is seldom linear. The implications of these findings for health services are discussed. © 2007, Sage Publications. All rights reserved.
- Published
- 2007
16. A common protein export pathway in malaria parasites
- Author
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Paul R. Gilson, Justin A Boddey, Sarah C. Charnaud, Hayley E Bullen, Tania F. de Koning-Ward, Brendan S. Crabb, Alan F. Cowman, and Silvia Haase
- Subjects
Invited Speaker Presentation ,Virulence ,Protein Export Pathway ,Biology ,Translocon ,medicine.disease ,Bioinformatics ,Cell biology ,Cytosol ,Infectious Diseases ,Parasitology ,medicine ,Extracellular ,Parasite hosting ,Malaria - Abstract
Protozoan parasites that cause malaria export hundreds of proteins into their host red blood cell cytosol, and some even beyond that to the extracellular environment. These proteins have a wide range of functions that are crucial to parasite virulence and/or parasite survival in the human host. It has been thought for some time that a common link to all these proteins is the mechanism by which they are exported. Recently, we have revealed much of how this export occurs, including the discovery of a novel translocon through which exported proteins must pass. As a common portal for many essential proteins this translocon becomes a strongly validated drug target.
- Published
- 2010
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