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Plasmodium falciparum Niemann-Pick Type C1-Related Protein is a Druggable Target Required for Parasite Membrane Homeostasis

Eva S. Istvan, Sudipta Das, Suyash Bhatnagar, Josh R. Beck, Edward Owen, Manuel Llinás, Suresh M. Ganesan, Jacquin C. Niles, Elizabeth A. Winzeler, Akhil B. Vaidya, Daniel E. Goldberg
doi: https://doi.org/10.1101/371484
Eva S. Istvan
1Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
2Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
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Sudipta Das
3Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
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Suyash Bhatnagar
3Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
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Josh R. Beck
1Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
2Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
4Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011
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Edward Owen
5Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, and Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
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Manuel Llinás
5Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, and Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
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Suresh M. Ganesan
6Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Jacquin C. Niles
6Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Elizabeth A. Winzeler
7Department of Pediatrics, School of Medicine, University of California San Diego School of Medicine, La Jolla, California 92093, USA
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Akhil B. Vaidya
3Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
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Daniel E. Goldberg
1Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
2Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
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Abstract

Plasmodium parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Plasmodium falciparum Niemann-Pick Type C1-Related protein, PfNCR1). We isolated parasites with resistance-conferring mutations in PfNCR1 during selections with three diverse small-molecule antimalarial compounds and show that the mutations are causative for compound resistance. PfNCR1 protein knockdown results in severely attenuated growth and confers hypersensitivity to the compounds. Compound treatment or protein knockdown leads to increased sensitivity of the parasite plasma membrane (PPM) to the amphipathic glycoside saponin and engenders digestive vacuoles (DVs) that are small and malformed. Immuno-electron microscopy and split-GFP experiments localize PfNCR1 to the PPM. Our experiments show that PfNCR1 activity is critically important for the composition of the PPM and is required for DV biogenesis, suggesting PfNCR1 as a novel antimalarial drug target.

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Posted July 18, 2018.
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Plasmodium falciparum Niemann-Pick Type C1-Related Protein is a Druggable Target Required for Parasite Membrane Homeostasis
Eva S. Istvan, Sudipta Das, Suyash Bhatnagar, Josh R. Beck, Edward Owen, Manuel Llinás, Suresh M. Ganesan, Jacquin C. Niles, Elizabeth A. Winzeler, Akhil B. Vaidya, Daniel E. Goldberg
bioRxiv 371484; doi: https://doi.org/10.1101/371484
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Plasmodium falciparum Niemann-Pick Type C1-Related Protein is a Druggable Target Required for Parasite Membrane Homeostasis
Eva S. Istvan, Sudipta Das, Suyash Bhatnagar, Josh R. Beck, Edward Owen, Manuel Llinás, Suresh M. Ganesan, Jacquin C. Niles, Elizabeth A. Winzeler, Akhil B. Vaidya, Daniel E. Goldberg
bioRxiv 371484; doi: https://doi.org/10.1101/371484

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