Abstract
Plasmodium parasites are obligate intracellular protozoa and causative agents of malaria, responsible for half a million deaths each year. The lifecycle progression of the parasite is reliant on cell motility, a process driven by myosin A, an unconventional single-headed class XIV molecular motor. Here we demonstrate that myosin A from Plasmodium falciparum (PfMyoA) is critical for red blood cell invasion. Further, using a combination of X-ray crystallography, kinetics, and in vitro motility assays, we elucidate the non-canonical interactions that drive this motor’s function. We show that PfMyoA motor properties are tuned by heavy chain phosphorylation (Ser19), with unphosphorylated PfMyoA exhibiting enhanced ensemble force generation at the expense of speed. Regulated phosphorylation may therefore optimize PfMyoA for enhanced force generation during parasite invasion or for fast motility during dissemination. The three PfMyoA crystallographic structures presented here provide a blueprint for discovery of specific inhibitors designed to prevent parasite infection.
Highlights
Plasmodium parasites are obligate intracellular protozoa and causative agents of malaria, responsible for half a million deaths each year
Despite global efforts to control the disease, malaria is still responsible for half a million deaths each year, with the vast majority of mortality caused by P. falciparum[1]
Host cell membrane wrapping forces likely play a role in merozoite invasion of red blood cells[11], their role has not been tested in the absence of a parasite motor
Summary
Plasmodium parasites are obligate intracellular protozoa and causative agents of malaria, responsible for half a million deaths each year. Merozoites, in contrast to sporozoites, are relatively non-motile stages that target erythrocytes, where they develop and lead to all symptoms associated with malaria disease Beyond this asexual replicative stage of development, some parasites switch commitment to develop into sexual forms (following an as yet unknown signal) producing male and female gametocytes that re-establish mosquito infection on the bite[2] (Supplementary Fig. 1a). The connectors (Switch-2, the Relay helix, and the SH1-helix) are structural elements that coordinate rearrangements of the four motor subdomains, whose motions are amplified into a larger swing of the distal light chain binding lever arm (Supplementary Fig. 2) Mutations of this SH2-SH1Gly greatly impede motor activity in class 2 myosins (Myo2) by reducing the flexibility of the fulcrum[16,17,18]. These insights provide a complete foundation from which to understand the noncanonical mechanism of force production in these globally significant parasites
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