Abstract
Plasmodium falciparum, the causative agent of malaria, moves by an atypical process called gliding motility. Actomyosin interactions are central to gliding motility. However, the details of these interactions remained elusive until now. Here, we report an atomic structure of the divergent Plasmodium falciparum actomyosin system determined by electron cryomicroscopy at the end of the powerstroke (Rigor state). The structure provides insights into the detailed interactions that are required for the parasite to produce the force and motion required for infectivity. Remarkably, the footprint of the myosin motor on filamentous actin is conserved with respect to higher eukaryotes, despite important variability in the Plasmodium falciparum myosin and actin elements that make up the interface. Comparison with other actomyosin complexes reveals a conserved core interface common to all actomyosin complexes, with an ancillary interface involved in defining the spatial positioning of the motor on actin filaments.
Highlights
Plasmodium falciparum, the causative agent of malaria, moves by an atypical process called gliding motility
Only sparse and non-cooperative binding to both rabbit skeletal and JASstabilized PfAct[1] filaments was observed for all pairs. This lack of cooperativity contrasts with the highly cooperative nature of essentially all other previously reported myosin motors binding to actin filaments, which appear either fully decorated or as bare filament stretches in the same field of view in cryo-EM preparations, significantly assisting in particle selection and image processing
Actin-activated ATPase assays showed that the phosphomimetic mutation T417D located in the hypertrophic cardiomyopathy (HCM) loop of the PfMyoA heavy chain[23] resulted in a ~3-fold enhancement in actin binding affinity while Vmax is unchanged[24]
Summary
Plasmodium falciparum, the causative agent of malaria, moves by an atypical process called gliding motility. Phosphorylation tunes the properties of PfMyoA, which can work in two regimes: phosphorylated PfMyoA moves actin at high speed but has low ensemble force; unphosphorylated PfMyoA produces more force but at the expense of speed[6,8] These results led us to consider PfMyoA as a tunable molecular engine that could function optimally either at high speed in highly mobile stages such as sporozoites that need to move at more than 2 μm s−1, or with high force in invasive stages such as merozoites that produce forces of ~40 pN to invade the host cell[8]. The contact sites important for filament formation contain notable sequence deviations, within the DNase-1–binding loop (Dloop) which is essential for polymerization[10] These sequence differences result in a critical concentration for assembly (in the absence of JAS) that is an order of magnitude higher than for skeletal muscle actin filaments or JAS-stabilized PfAct[113]. PfAct[1] filaments are highly unstable once ATP has been hydrolyzed and readily depolymerize[13], likely explaining why these filaments have been difficult to visualize in vivo
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