9.B.11 The Dense Granule Protein 6 (GRA6) Family
Gra6 of Toxoplasma gondii, also called protein p33, antigen P32 and TG24, has 230aas and two TMSs. It is post-translationally sorted to the parasite-containing vacuole, driven by its N-terminal domain as detailed by Gendrin et al. (2010).
How eukaryotic pathogens export and sort membrane-bound proteins destined for host-cell compartments is poorly understood. The dense granules of the intracellular protozoan Toxoplasma gondii constitute an unusual secretory pathway that allows soluble export of the GRA proteins which become membrane-associated within the parasite replicative vacuole. This process relies on both the segregation of the proteins routed to the dense granules from those destined to the parasite plasma membrane and on the sorting of the secreted GRA proteins to their proper final membranous system. Gendrin et al. (2010) provided evidence that the soluble trafficking of GRA6 to the dense granules relies on the N-terminal domain of the protein, which is sufficient to prevent GRA6 targeting to the parasite plasma membrane. They also showed that the GRA6 N-terminal domain, possibly by interacting with negatively charged lipids, is fundamental for proper GRA6 association with the vacuolar membranous network of nanotubes. These results support an emerging model: sorting of transmembrane GRA proteins to the host cell vacuole is mainly driven by the dual role of their N-terminal hydrophilic domain and is compartmentally regulated.