Malaria parasite invasion of red blood cells is powered by Myosin A (MyoA), the actomyosin motor which is a core component of the glideosome. Our previous phosphoproteomic study identified a cyclic GMP-dependent phosphorylation site on MyoA at Ser19, suggesting that cyclic nucleotide signalling may directly regulate motor activity during invasion. However, the functional significance of this phosphorylation site remains unclear. Here, we show that Plasmodium falciparum MyoA phosphorylation at Ser19 is dynamically regulated during the intraerythrocytic cycle, peaking in extracellular merozoites and rapidly declining following invasion. Using conditional depletion of MyoA, we show that MyoA is essential for red blood cell invasion but dispensable for gametocyte development. Conditional complementation with mutant versions of MyoA that either mimic (S19D) or ablate phosphorylation (S19A) reveal markedly impaired asexual parasite proliferation, highlighting the importance of precise regulation of MyoA phosphorylation at Ser19. In vitro motility assays using parasite-derived MyoA showed that ablating phosphorylation either pharmacologically or by introducing an S19A mutation, reduces motor speed. Conversely, introducing a phosphomimetic S19D mutation restores motility levels comparable to phosphorylated wild type MyoA. Collectively, these results establish MyoA Ser19 phosphorylation as a regulatory switch for actomyosin motor activity.
Nofal, S. D., Koussis, K., Vahokoski, J., Kursula, I., Molloy, J. E., Blackman, M. J., Flueck, C., Baker, D. A.
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