The structure and function of a key component of the ‘glideosome’ have been established, providing researchers with a better understanding of how parasites move.
A recent interdisciplinary study between structural biologists and parasitologists, led by research groups from the European Molecular Biology Laboratory (Hamburg, Germany), has revealed the structure of a protein that is key to the mechanisms by which specific parasites move. This new information has shed light on how certain parasites ‘glide’ in between the cells of the host and could reveal new avenues for therapeutic development.
Gliding is a behavior exhibited by parasites in the phylum Apicomplexa and describes the process of a cell moving along a surface without altering its shape. Apicomplexa contains the parasites Plasmodium – species of which are responsible for 228 million malaria infections yearly – and Toxoplasma gondii, which infects one third of the entire human population. These parasites infect human tissues by first gliding between the skin of the cells and then into the blood vessels.
Gliding is dependent on the same molecular machinery that we use to contract muscles, via the proteins actin and myosin. However, in Apicomplexa the myosin binds to a variety of additional proteins, collectively referred to as the glideosome.
One group of proteins that makes up the glideosome and interact directly with myosin A are the essential light chains (ELCs). As the structures of ELCs are currently unknown, the research collaboration decided to focus on these proteins to better understand their structures and functions in the glideosome.
The team used X-ray crystallography and NMR techniques, including small-angle X-ray scattering, circular dichroism and triple-resonance NMR, to resolve the structure of ELCs in the parasite species T. gondii and Plasmodium falciparum.
Images displaying the structure of an ELC when bound to myosin A indicated that, on binding to the protein, ELCs stiffen, thereby strengthening the glideosome and allowing it act as a lever arm. This in turn enables the myosin to take longer ‘steps’ as it moves along the actin associated to the plasma membrane. The result is accelerated and more efficient movement and therefore a more successful infection into a host.
Calcium was shown to improve the stability of the ELC-myosin A complex without impacting the structure of the ELC. This result was a surprise as it had previously been believed that calcium interacted with the ELCs to alter their structure prior to myosin binding.
Commenting on the novelty of the study and its implications, Matthew Bowler (EMBL Grenoble, France), an external researcher not involved in the research, stated that, “this work has provided the first glimpse of how these organisms move around. It is fascinating to see new molecular details emerge on how these parasites work outside of the host cell. The beautiful structures show how the motor that drives this motion is put together and could provide a basis to develop new medicines to treat these diseases.”
To provide an insight into what this research could mean for the treatment of malaria, Maria Bernabeu (EMBL, Barcelona, Spain) who heads up cerebral malaria research in Barcelona added that, “Plasmodium passage through the skin is the first stage of human infection. The advantage of targeting Plasmodium at that stage is that only about a hundred parasites are present. Understanding the parasite’s gliding motility might help to develop drugs or vaccines that target Plasmodium before it multiplies.”