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Journal article
Plasmodium Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis
eLife, v 8
19 Mar 2019
PMID: 30888318
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Niemann-Pick Type C1-Related protein, NCR1). We isolated parasites with resistance-conferring mutations in
NCR1 (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.
This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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Details
- Title
- Plasmodium Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis
- Creators
- Eva S Istvan - Washington University in St. LouisSudipta Das - Drexel UniversitySuyash Bhatnagar - Drexel UniversityJosh R Beck - Washington University in St. LouisEdward Owen - Pennsylvania State UniversityManuel Llinas - Pennsylvania State UniversitySuresh M Ganesan - Massachusetts Institute of TechnologyJacquin C Niles - Massachusetts Institute of TechnologyElizabeth Winzeler - University of California, San DiegoAkhil B Vaidya - Drexel UniversityDaniel E Goldberg - Washington University in St. Louis
- Publication Details
- eLife, v 8
- Publisher
- eLife
- Grant note
- R01AI132508 / National Institute of Allergy and Infectious Diseases 1DP2OD007124 / NIH HHS OPP 1054480 / Bill and Melinda Gates Foundation OPP1132313 / Bill and Melinda Gates Foundation K99/R00 HL133453 / NHLBI NIH HHS K99 HL133453 / NHLBI NIH HHS R00 HL133453 / NHLBI NIH HHS R01AI098413 / National Institute of Allergy and Infectious Diseases R01 AI103058 / NIAID NIH HHS R01 AI132508 / NIAID NIH HHS R01 AI098413 / NIAID NIH HHS DP2 OD007124 / NIH HHS R01 AI028398 / NIAID NIH HHS R01 AI090141 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000461751100001
- Scopus ID
- 2-s2.0-85063291544
- Other Identifier
- 991019167564104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biology