Structure of Full Length Plasmodium Myosin A and its light chain PfELC, dual targets against malaria parasite pathogenesis

Moussaoui, D.; Robblee, J. P.; Auguin, D.; Krementsova, E. B.; Haase, S.; Blake, T. C. A.; Baum, J.; Robert-Paganin, J.; Trybus, K. M.; Houdusse, A.

doi:10.1101/2020.06.30.179788

bioRxiv · 10.1101/2020.06.30.179788

Structure of Full Length Plasmodium Myosin A and its light chain PfELC, dual targets against malaria parasite pathogenesis

Moussaoui, D.·Robblee, J. P.·Auguin, D.·Krementsova, E. B.·Haase, S.·Blake, T. C. A.·Baum, J.·Robert-Paganin, J.·Trybus, K. M.·Houdusse, A.

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Abstract

Parasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity and ultimately pathogenesis of this parasite relies on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria. Here we present the full-length structure of PfMyoA in two states of its motor cycle. We report novel interactions that are essential for motor priming and the mode of recognition of its two light chains (PfELC and MTIP) by two degenerate IQ motifs. Kinetic and motility assays using PfMyoA variants, along with molecular dynamics, demonstrate how specific priming and atypical sequence adaptations tune the motor’s mechano-chemical properties. Supported by evidence for an essential role of the PfELC in malaria pathogenesis, these structures provide a blueprint for the design of future antimalarials targeting both the glideosome motor and its regulatory elements.HighlightsThe first structures of the full length PfMyoA motor in two states of its motor cycle.A unique priming of the PfMyoA lever arm results from specific lever arm/motor domain interactions, which allows for a larger powerstroke to enhance speed.Sequence adaptations within the motor domain and degenerate IQ motifs in the lever arm dictate PfMyoA motor properties.PfELC is essential for blood cell invasion and is a weak link in the assembly of a fully functional motor, providing a second novel target for antimalarial drug design.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Moussaoui, D., Robblee, J. P., Auguin, D., Krementsova, E. B., Haase, S., Blake, T. C. A., Baum, J., Robert-Paganin, J., Trybus, K. M., Houdusse, A.. 2020-07-01. Structure of Full Length Plasmodium Myosin A and its light chain PfELC, dual targets against malaria parasite pathogenesis. https://doi.org/10.1101/2020.06.30.179788

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