Structural and functional studies of heme binding proteins toward the understanding of malaria
Author(s)Goren, Allena Mistral.
Massachusetts Institute of Technology. Department of Chemistry.
Catherine L. Drennan.
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Malaria, a potentially lethal parasitic infection, causes approximately half a million deaths each year. Currently, nearly half of the world's population is at risk of being infected with Plasmodium, the parasite causing malaria. In this thesis, we use biochemical and biophysical techniques to describe the iron binding properties of two proteins relevant to the biological study of Plasmodium falciparum. The first is a previously uncharacterized protein, which we have named MFP, or malarial ferrous protein, that is found in the parasitophorous vacuole of Plasmodium. The second is mRuby2, a fluorescent probe often utilized in biological work to track the localization of proteins. Herein, we report on the novel heme-binding properties of both proteins. We have identified a novel function of mRuby2, a commonly used fluorescent probe. Upon incubation with heme, the fluorescence of mRuby2 decreases, providing a potential use for the protein as a heme probe as well as a limitation of its utility for in vivo localization studies. MFP is a putative lipocalin-like protein that we have identified as binding both an [Fe-S] cluster and a heme moiety. We show that the [4Fe-4S] cluster of MFP inhibits heme binding to the protein and have proposed a potential structural model to explain this finding. Taken together, our data show a complicated metal-binding protein with a yet unknown in vivo function. The identification and initial characterization of MFP, a conserved protein essential for Plasmodium viability during the blood stage of infection, has provided a new potential therapeutic target for the treatment of malaria.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2019Cataloged from PDF version of thesis.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology