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Plasmodium myosin A drives parasite invasion by an atypical force generating mechanism

Author

Listed:
  • Julien Robert-Paganin

    (Structural Motility, UMR 144 CNRS/Curie Institute, 26 rue d’ulm)

  • James P. Robblee

    (University of Vermont)

  • Daniel Auguin

    (Université d’Orléans, INRA, USC1328)

  • Thomas C. A. Blake

    (Imperial College London)

  • Carol S. Bookwalter

    (University of Vermont)

  • Elena B. Krementsova

    (University of Vermont)

  • Dihia Moussaoui

    (Structural Motility, UMR 144 CNRS/Curie Institute, 26 rue d’ulm)

  • Michael J. Previs

    (University of Vermont)

  • Guillaume Jousset

    (Structural Motility, UMR 144 CNRS/Curie Institute, 26 rue d’ulm)

  • Jake Baum

    (Imperial College London)

  • Kathleen M. Trybus

    (University of Vermont)

  • Anne Houdusse

    (Structural Motility, UMR 144 CNRS/Curie Institute, 26 rue d’ulm)

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.

Suggested Citation

  • Julien Robert-Paganin & James P. Robblee & Daniel Auguin & Thomas C. A. Blake & Carol S. Bookwalter & Elena B. Krementsova & Dihia Moussaoui & Michael J. Previs & Guillaume Jousset & Jake Baum & Kathl, 2019. "Plasmodium myosin A drives parasite invasion by an atypical force generating mechanism," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11120-0
    DOI: 10.1038/s41467-019-11120-0
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    Cited by:

    1. Daniel Auguin & Julien Robert-Paganin & Stéphane Réty & Carlos Kikuti & Amandine David & Gabriele Theumer & Arndt W. Schmidt & Hans-Joachim Knölker & Anne Houdusse, 2024. "Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Janeska J. Jonge & Andreas Graw & Vasileios Kargas & Christopher Batters & Antonino F. Montanarella & Tom O’Loughlin & Chloe Johnson & Susan D. Arden & Alan J. Warren & Michael A. Geeves & John Kendri, 2024. "Motor domain phosphorylation increases nucleotide exchange and turns MYO6 into a faster and stronger motor," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Dihia Moussaoui & James P. Robblee & Julien Robert-Paganin & Daniel Auguin & Fabio Fisher & Patricia M. Fagnant & Jill E. Macfarlane & Julia Schaletzky & Eddie Wehri & Christoph Mueller-Dieckmann & Ja, 2023. "Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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