Research Spotlight: Inhibition of Toxoplasma Motility
Citation: Heaslip AT, Leung JM, Carey KL, Catti F, Warshaw DM, Westwood NJ, Ballif BA, Ward GE. 2010. A small-molecule inhibitor of T. gondii motility induces the posttranslational modification of myosin light chain-1 and inhibits myosin motor activity. PLoS Pathog. 6(1):e1000720.
Authors’ Association with MMG:
Aoife T. Heaslip – received her Ph.D. from the MMG program in 2008
Jacqueline M. Leung – is a 3rd year graduate student in the MMG program
Kimberly L. Carey – received her Ph.D. from the MMG program in 2004
Gary E. Ward – is a full Professor in the MMG department
We show in this publication that a recently identified pharmacological inhibitor of Toxoplasma gondii motility induces a posttranslational modification of TgMLC1, a protein that binds to the myosin motor protein, TgMyoA. We used quantitative proteomics to map the TgMLC1 modification to the peptide Val46-Arg59, and efforts are ongoing to determine the precise nature of the modification. Treatment with the compound is also associated with a decrease in TgMyoA mechanical activity as assayed in vitro. These data provide the first glimpse into how TgMyoA is regulated and how a change in the activity of the T. gondii myosin motor complex can affect the motility and infectivity of this important human pathogen. A greater understanding of how motility is regulated in T. gondii and other apicomplexan parasites has the potential to lead to new chemotherapeutic approaches to treating the devastating diseases these parasites cause.
Impact and Significance:
T. gondii and related parasites within the Phylum Apicomplexa are collectively responsible for a great deal of human disease and death worldwide. The ability of apicomplexan parasites to invade cells of their hosts, disseminate through tissues and cause disease depends critically on parasite motility. Motility is driven by a complex of proteins that is well conserved within the phylum; however, very little is known about how the unconventional myosin motor protein at the heart of this motility machinery is regulated. In the laboratory, we use T. gondii as a powerful model system for studying apicomplexan motile mechanisms since this parasite is more experimentally accessible than other members of the phylum, such as Plasmodium (causative agent of malaria) and Cryptosporidium (a life-threatening opportunistic pathogen of AIDS patients).