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Plasmodium falciparum is the most virulent causative agent of malaria in man accounting for 80% of all malarial infections and 90% of the one million annual deaths attributed to malaria. P. falciparum is a unicellular, Apicomplexan parasite, that spends part of its lifecycle in the mosquito and part in man and it has evolved a special form of motility that enables it to burrow into animal cells, a process termed "host cell invasion". The acute, life threatening, phase of malarial infection arises when the merozoite form of the parasite undergoes multiple cycles of red blood cell invasion and rapid proliferation. Here, we discuss the molecular machinery that enables malarial parasites to invade red blood cells and we focus particularly on the ATP-driven acto-myosin motor that powers invasion.

We have determined the kinetic and motile properties of a myosin 5a HMM construct in which four calmodulin-binding IQ motifs are replaced by the putative single alpha helical domain (SAH) of similar length from Dictyostelium myosin, MyoM. Electron microscopy of this chimera showed that the SAH domain was straight and 17 nm long as predicted, restoring the truncated lever to the length of wild type (Myo5-6IQ). The powerstroke (21.5 nm) measured in the optical trap was slightly less than that for Myo5-6IQ (25 nm) but much greater than for Myo5-2IQ (10 nm). Myo5-2IQ-SAH moves processively along actin at physiological ATP concentrations with similar stride length to Myo5-6IQ in TIRF microscopy assays, and the average run length was also similar. Stopped-flow fluorescence experiments indicated that unlike WT Myo5-6IQ the rear head did not mechanically gate the rate of ADP release from the lead head of the chimera and the rate of ADP dissociation was the same from both heads. These data show that the SAH domain can form part of a functional lever in myosins although its bending stiffness might be lower. We conclude that SAH domains can act as mechanically-competent structural extensions in physiological conditions and that gated dissociation of ADP from the lead head of myosin 5 is not required for processive movement.Funded by BBSRC BB/C004906/1 (MP, PJK and TGB), an Underwood fund grant (MP, PJK and JRS), Wellcome Trust vacation studentship (SMJ), NIH EB00209 (HDW), NIH NIDCD 009335 (EF) and intramural funds from NHLBI (JRS).