The malaria parasite exports hundreds of proteins to the red blood cell in order to commandeer the host cell for its own nefarious purposes. This proposal aims to study a protease called plasmepsin V. It has recently been discovered that plasmepsin V recognizes and cleaves a sequence on the proteins that the parasite has designated for export. This is crucial for proteins to get out into the host cell. The proposal addresses the questions: What is special about plasmepsin V compared with mammalian counterparts? What is the specificity of this enzyme for its substrate? How does plasmepsin V interact with other cellular components to ensure that proteins to be exported get to their destination? The proposed experiments will involve enzymology, site-directed mutagenesis and protein-protein interaction studies. The goal is to understand plasmepsin V function to inform antimalarial drug development efforts.

Public Health Relevance

Malaria afflicts hundreds of millions of people worldwide and over a thousand a year in this country, mostly those that have recently been abroad. Because of drug resistance there is a desperate need for new antimalarial treatments. The proposed research will study an important new target for drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047798-14
Application #
8582054
Study Section
Special Emphasis Panel (ZRG1-PTHE-N (09))
Program Officer
Mcgugan, Glen C
Project Start
2000-07-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
14
Fiscal Year
2014
Total Cost
$141,750
Indirect Cost
$29,250
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Beck, Josh R; Muralidharan, Vasant; Oksman, Anna et al. (2014) PTEX component HSP101 mediates export of diverse malaria effectors into host erythrocytes. Nature 511:592-5
Russo, Ilaria; Babbitt, Shalon; Muralidharan, Vasant et al. (2010) Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte. Nature 463:632-6
Goldberg, Daniel E; Cowman, Alan F (2010) Moving in and renovating: exporting proteins from Plasmodium into host erythrocytes. Nat Rev Microbiol 8:617-21
Russo, Ilaria; Oksman, Anna; Goldberg, Daniel E (2009) Fatty acid acylation regulates trafficking of the unusual Plasmodium falciparum calpain to the nucleolus. Mol Microbiol 72:229-45
Russo, Ilaria; Oksman, Anna; Vaupel, Barbara et al. (2009) A calpain unique to alveolates is essential in Plasmodium falciparum and its knockdown reveals an involvement in pre-S-phase development. Proc Natl Acad Sci U S A 106:1554-9
Drew, Mark E; Banerjee, Ritu; Uffman, Eric W et al. (2008) Plasmodium food vacuole plasmepsins are activated by falcipains. J Biol Chem 283:12870-6
Lisk, Godfrey; Pain, Margaret; Gluzman, Ilya Y et al. (2008) Changes in the plasmodial surface anion channel reduce leupeptin uptake and can confer drug resistance in Plasmodium falciparum-infected erythrocytes. Antimicrob Agents Chemother 52:2346-54
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Klonis, Nectarios; Tan, Olivia; Jackson, Katherine et al. (2007) Evaluation of pH during cytostomal endocytosis and vacuolar catabolism of haemoglobin in Plasmodium falciparum. Biochem J 407:343-54
Liu, Jun; Istvan, Eva S; Goldberg, Daniel E (2006) Hemoglobin-degrading plasmepsin II is active as a monomer. J Biol Chem 281:38682-8

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