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Functional dissection of myosin motors from the malaria parasite Plasmodium falciparum

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Title: Functional dissection of myosin motors from the malaria parasite Plasmodium falciparum
Authors: Blake, Thomas
Item Type: Thesis or dissertation
Abstract: The symptoms of malaria arise from cycles of red blood cell (RBC) invasion by Plasmodium spp. merozoites. This process has been studied by video microscopy for 50 years and the ordered stages of invasion have been well established for much longer. Merozoite entry is rapid and actively powered by a parasite acto-myosin motor. The canonical model for force production depends on arrays of a myosin motor (MyoA) working against short actin filaments connected to the external substrate. However, the molecular processes that underlie these well-described events, and the energetic barriers that the merozoite must overcome, remain unclear. Though MyoA has been shown to be critical for invasion of other parasite stages and species, the importance of MyoA has not been shown for Plasmodium falciparum merozoites. Work on other parasites has uncovered retrograde flow of plasma membrane and host cell activity as other sources of force production, casting doubt on the mechanical role of MyoA. Answering these questions has been hampered by limited structural understanding of the acto-myosin system in merozoites. In this study, conditional genetic modification of P. falciparum MyoA (PfMyoA) showed it is critical for invasion. The transgenic platform was then adapted for other motor proteins, showing that PfMyoA light chain PfELC is also critical but auxiliary motor PfMyoB is not. The range of defects in these mutants uncovered three distinct energetic barriers during merozoite invasion. Finally, probing the arrangement of the motor by electron microscopy revealed a multi-member complex of PfMyoA. Together, this study re-affirms the importance of PfMyoA for merozoite invasion and illuminates the energetic barriers that the motor is required to overcome.
Content Version: Open Access
Issue Date: Jun-2020
Date Awarded: Oct-2020
URI: http://hdl.handle.net/10044/1/89132
DOI: https://doi.org/10.25560/89132
Copyright Statement: Creative Commons Attribution NonCommercial ShareAlike Licence
Supervisor: Baum, Jacob
Sponsor/Funder: Wellcome Trust (London, England)
Funder's Grant Number: 109007/Z/15/A
Department: Life Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Life Sciences PhD theses



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