Abstract
Upon infection with Toxoplasma gondii, host cells produce immune-related GTPases (IRGs) to kill the parasite. T. gondii counters this response by releasing ROP18 kinase, which inactivates IRG GTPases and inhibits their recruitment to the T. gondii parasitophorous vacuole (PV). However, the molecular mechanisms of this process are entirely unknown. Here we report the atomic structures of Irgb6 with a phosphomimetic mutation by ROP18. The mutant has lower GTPase activity and is not recruited to the PV membrane (PVM). The crystal structure shows the mutant exhibit a distinct conformation from the physiological nucleotide-free form, thus preventing GTPase cycling. This change allosterically modifies the conformation of the membrane-binding interface, preventing physiological PVM-binding. Docking simulation of PI5P also supports the impaired binding of the mutant to PVM. We thus demonstrate the structural basis for T. gondii escape from host cell-autonomous defense, and provide a structural model for regulating enzymatic activity by phosphorylation.
Competing Interest Statement
The authors have declared no competing interest.
