Actin in the malaria parasite
Actin is a critical protein for all eukaryotic cells. It has diverse functions from structural roles in the cytoskeleton, to dynamic roles in cell movement and muscle contraction. It exists in two forms: monomeric (G)-actin or filamentous (F)-actin. Uniquely it is able to spontaneously polymerise into filaments. The subunits are not, however, added evenly to both ends, but instead add preferentially to one end, the ‘barbed’ end, whilst being lost from the other, ‘pointed’, end. This biased growth ensures that filament elongation is polarised and gives actin its dynamic properties. However, spontaneous filament growth must be controlled, and cells invest heavily in factors (or regulators) that control actin’s state. The key role actin plays in malaria parasite invasion is demonstrated by drugs that disrupt its ability to polymerise: Drugs that prevent polymerisation, block further filament growth, or stabilise F-actin (preventing turnover) all prevent parasite invasion. This demonstrates that malaria parasites require dynamic actin for successful host cell invasion. The tight control of this process in the parasite highlights the importance of actin regulators and earmarks their potential as possible drug targets. Remarkably, malaria parasites have very few known regulators; for example, significantly lacking the arp2/3 complex. To understand actin regulation we are using a combination of molecular genetics, cell biology and biochemistry to characterise the known actin regulators that are present in the human malaria parasite Plasmodium falciparum, in particular to explore their spatiotemporal localisation and actin binding properties. The core actin regulators under study are the malaria parasite formins, actin-depolymerising factor/cofilins, cyclase-associated protein (CAP) and coronin. Part of this work is being done in close collaboration with the Lappalainen lab at the University of Helsinki, Finland.
